Journal of Internal Medicine

Nociplastic pain features are common in systemic lupus erythematosus (SLE), yet its longitudinal trajectory remain poorly characterized. SLE patients in the FORWARD Databank were classified as Minimal, Type 1, Type 2, or Mixed using the Polysymptomatic Distress Scale (PSD[&ge;]8) and the Systemic Lupus Activity Questionnaire (SLAQ) inflammatory domain score ([&ge;]2). Cross-sectional analyses (N=372) compared clinical outcomes and medication use. Longitudinal analyses (n=301; median 3.7 years) characterized phenotype transitions using continuous-time Markov models and identified latent trajectories using joint group-based trajectory modeling (GBTM). At baseline, 29% were Minimal, 12% Type 1, 13% Type 2, and 47% Mixed. Functional impairment increased stepwise: from Minimal to Mixed, SF-36 physical component scores decreased from 49.7 to 30.0 and PROMIS Pain Interference scores increased from 46.2 to 63.6 (both p<0.001). Organ damage, depression, and opioid use were highest in Mixed. Longitudinally, Minimal and Mixed were persistent (mean duration 2.0 and 1.8 years; one-year retention 70%), while Type 1 and Type 2 were transient (~0.5 years; retention 18% and 28%). Exit trajectories were asymmetric: Type 1 moved preferentially to Minimal (49% of exits), whereas Type 2 moved to Mixed (65%; p<0.001). Population-average PSD was nearly flat (+0.014 SD/year, p=0.07); while opioid use declined to near zero in Minimal and Type 1 but remained high in Type 2 and Mixed. Joint GBTM identified four severity classes along a Minimal-to-Mixed diagonal. Nociplastic phenotypes in SLE are persistent, severity-stratified, with substantial functional, psychological, organ-damage, and opioid burdens. Transient Type 1 and Type 2 states have divergent longitudinal transitions.

BackgroundMany of those infected with COVID-19 experience long-term disability due to persistent symptoms known as Long-COVID, which include ongoing respiratory issues, loss of taste and smell, and impaired daily functioning. Research QuestionThis study aims to better understand the chronology of long-COVID symptoms. Study Design and MethodsWe prospectively enrolled 403 adults from the University of Iowa long-COVID clinic (June 2020 to February 2022). Participants provided symptom data during acute illness, symptom progression, and other clinical characteristics. Patients in this registry received a survey containing questions including current symptoms and status since long-COVID diagnosis (sliding status scale, PHQ2, GAD2, MMRC). Those >12 months since acute-COVID diagnosis had chart review done to track their symptomology. ResultsOf 403 participants contacted, 129 (32%) responded. The mean age (in years) was 50.17 +/-14.28, with 31.8% male and 68.2% female. Severity of acute covid treatment was stratified by treatment in the outpatient (70.5%), inpatient (16.3%), or ICU (13.2%) settings. 51.2% reported subjective improvement (sliding scale scores of 67-100) since long-COVID onset. Ages 18-29 reported significantly higher subjective status scores. Subjective status scores were unaffected by severity. 102 respondents were >12 months from their initial COVID-19 diagnosis and were tracked for longitudinal symptom persistence. All symptoms tracked had variance (mean fraction 0.58, range 0.34-0.75) in the reported symptoms at the time of long-COVID presentation when compared with patient survey report. 48 reported persistent dyspnea, 23 (48%) had resolved it at time of survey. For fatigue, 44 had persistence, 12 (27%) resolved. InterpretationOverall, 51.2% respondents improved since their long-COVID began. Pulmonary symptoms were more persistent than neuromuscular symptoms (anosmia, dysgeusia, myalgias). Gender, time since acute COVID infection, and its severity didnt affect subjective status or symptoms. This study highlights recall bias that may be prevalent in other long-COVID research reliant on participant memory.

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.

ObjectivePernicious anaemia (PA) is characterised by vitamin B12 deficiency due to autoimmune-mediated loss of gastric parietal cells and intrinsic factor. The Pernicious Anaemia Society (PAS) identified 10 research priorities for PA through a James-Lind Alliance Priority Setting Partnership (JLA-PSP). This study aimed to survey PAS members to identify and characterise a cohort of patients to form a PA research repository. MethodsAn online survey was designed using SurveyMonkey, comprising 21 questions on diagnosis, comorbidities, family history, and management. The survey was sent to 3,482 PAS members (April-September 2022) via the PAS website and email. ResultsA total of 1,191 PAS members completed the survey. Among individuals with a probable (n=471) or suspected PA (n=500) diagnosis, 84% were UK-based, and 81% were female, with an age range of 23-93 years. Diagnosis was predominantly based on low serum B12 (50%), positive intrinsic factor (38%), and/or parietal cell autoantibodies (15%). Diagnostic delays were common, with 37% waiting [&ge;]3 years for a diagnosis. Nearly half had one or more other autoimmune diseases. One-third reported having at least 2 and up to 7 family members with PA or other autoimmune diseases. Vitamin B12 treatment frequency varied widely, ranging from daily to 3-monthly injections. ConclusionThis study highlights gaps in current diagnostic and management approaches for PA, paving the way for future work in line with the JLA-PSP research priorities. By characterising a cohort of PA patients and compiling baseline data, we provide a foundation for research to develop more effective diagnostic and management strategies.

Quantitative sensory testing (QST) is a psychophysical test of sensory function which may assist in assessing neuropathic pain (NP). This study compares QST findings with a standardized NP questionnaire to assess their agreement among Jamaicans with sickle cell disease (SCD). A cross sectional study consecutively recruited SCD patients 14 years and older, not pregnant, and without history of clinical stroke or acute illness in Kingston, Jamaica. QST identified thresholds for cold detection, heat detection, heat pain and pressure pain at the dominant thenar eminence, opposite dorsolateral foot and the subjects most frequent pain site. The Douleur Neuropathique 4 (DN4) was interviewer-administered to diagnose NP. Subjects were divided into low and high sensitization groups if below the 5th and above the 95th percentiles, respectively on QST measures. Kappa agreement coefficients, and receiver operator characteristic (ROC) curves were performed to compare QST with the DN4. Two-hundred and fifty-seven SCD subjects were recruited (mean age 31.7 {+/-} 12.2 years, 55.7% female, 75% SS genotype). Kappa agreements were fair (0.2-0.4) to good (0.6-0.8) between DN4 individual items of itching, hypoesthesia to touch, hypoesthesia to pinprick and brush allodynia with various QST sensitization groups. However, kappa agreements between the NP overall diagnosis on the DN4 with sensitization groups were poor (<0.2). Only heat detection (0.75) and heat pain (0.75) at the leg as a pain site showed satisfactory area under the curve (>0.7). QST may assist in assessing individual components of NP but its use should be limited as a tool to augment clinical assessments.

BackgroundThis study examines potential, subtle and persistent adverse effects of COVID-19 vaccines on the cardiovascular system. Vaccine-associated myocardial injury was analysed by measuring high-sensitive troponin T (hsTnT); mid-regional pro-adrenomedullin (MR-proADM) levels were evaluated to assess endothelial dysfunction. MethodsThis was a prospective study with a vulnerable population of healthcare workers (HCWs) and elderly patients (> 70 years) who were vaccinated with either one dose of ChAdOx1 nCov-19 adenoviral vector vaccine (AZ) followed by one dose of the BNT162b2 messenger RNA vaccine (BNT), or with two doses of BNT (12th of January - 30th of November 2021). HsTnT and MR-proADM were measured in blood samples at three visits (V1: 1st immediately before vaccination; V2, 3: 3-4 weeks after 1st and 2nd vaccination). HsTnT of HCWs was compared to a healthy reference population. ResultsN=162 volunteers were included (V1=161; V2, V3=162 each). N=74 (45.7%) received AZ/BNT and n=88 (54.3%) received BNT/BNT (elderly: n=20 (12.3%), HCWs: n=68 (42.0%)). Median hsTnT levels were 4ng/L, 5ng/L and 4ng/L (V1-V3) for AZ/BNT and at 5ng/L, 6ng/L and 6ng/L (V1-V3) for BNT/BNT. Compared to the reference population (n=300), hsTnT was significantly higher at all visits for both vaccination groups (p<0.01), without differences between the AZ/BNT and BNT/BNT cohort. MR-proADM values were 0.43nmol/L, 0.45nmol/L, 0.44nmol/L (V1-V3) in the AZ/BNT cohort and 0.49nmol/L, 0.44nmol/L, 0.47nmol/L for BNT/BNT, respectively. Change of median hsTnT and MR-proADM between visits did not show significant increases. One HCW case had a permanent and three a transient hsTnT increase [&ge;]14ng/L. ConclusionWith one individual exception, no overall subtle, persistent cardiovascular involvement was observed after the 2nd COVID-19 vaccination. Structured graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/24307207v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@15eb8f2org.highwire.dtl.DTLVardef@1c03237org.highwire.dtl.DTLVardef@120c0f5org.highwire.dtl.DTLVardef@15c1ea2_HPS_FORMAT_FIGEXP M_FIG Summary of the vaccination scheme and visiting points in the study population (of HCWs and seniors > 70 years) between the 12th of January and the 30th of November 2021. The results showed no overall subtle, chronic myocardial or vascular involvement in our COVID-19 vaccinated cohorts. Abbreviations: AZ ChAdOx1 nCov-19 adenoviral vector vaccine from Astra Zeneca, BNT BNT162b2 messenger ribonucleic acid vaccine from BioNTech, EDTA Ethylenediaminetetraacetic acid, HCWs health care workers, hsTnT high-sensitive troponin T, mid-regional pro-adrenomedullin, V1-V3 visiting times 1-3, w week(s). C_FIG

IMPORTANCEPericarditis is the most common cardiac manifestation of Systemic Lupus Erythematosus (SLE) and known to recur among patients. Yet, the prevalence and risk factors of recurrent pericarditis in SLE patients are unknown. OBJECTIVEDetermine the frequency and risk factors for the recurrence of pericarditis in patients with SLE. DESIGNRetrospective analysis of a well-characterized, prospective cohort of SLE patients enrolled between 1988 and 2023. SETTINGA single-center cohort study of a diverse group of SLE patients treated at a tertiary medical center. PARTICIPANTSPatients diagnosed with pericarditis (n=590) among those enrolled in the Hopkins Lupus Cohort (n=2931). MAIN OUTCOMERe-occurrence of pericarditis. The SELENA revision of the SLE Disease Activity Index (SLEDAI) was used to define pericarditis. Clinical information was examined for all follow-up encounters after the first episode of pericarditis. Pericarditis that occurred at least six weeks after the first recorded episode was defined as "Recurrent". RESULTSOf 2931 patients within the cohort, 590 had a history of pericarditis. In 3.4% of patients, the diagnosis of pericarditis was confirmed via electrocardiogram (EKG) or dedicated imaging, with 100% concordance between clinical and data-based diagnoses. During a median follow-up of 7 years (IQR: 3 - 14), 20% (n=120) of patients experienced recurrent pericarditis (recurrence rate {approx} 0.05 per person-year of follow-up). Most patients (51%) experienced only one recurrence, whereas 49% had [&ge;]2 recurrences. In multivariate analysis, predictors of recurrence included younger age ([&ge;]60 years vs. <40, RR 0.11 (0.04, 0.32), P <.001), treatment with prednisone ([&ge;]20 mg vs. 0, RR 1.99 (1.17, 3.40), P = 0.012), active SLE disease (SLEDAI [&ge;]3 vs. 0, RR 1.55 (1.21, 2.00), P <.001), and time since initial episode (3-10 years vs. <1, RR 0.32 (0.20, 0.52), P <.001). CONCLUSION AND RELEVANCERecurrence is more likely to occur within one year of the onset of pericarditis, and younger patients and those with uncontrolled disease are at greater risk of recurrence. As in the general population, oral prednisone therapy is associated with a higher chance of recurrence in SLE patients, with a dose-dependent effect. These findings set the basis for future studies to define optimal treatment for recurrent pericarditis in SLE patients and suggest that oral corticosteroids should be avoided when treating pericarditis.

ObjectiveSomatic mutations in UBA1 cause the recently described systemic auto-inflammatory syndrome, VEXAS. Study of this disease has largely been limited to highly symptomatic patients. We sought to determine the prevalence of VEXAS-associated somatic mutations and their disease penetrance in a diverse, unselected population. MethodsWe analyzed clinical-grade whole genome sequencing data from 245,368 individuals in the All of Us Research Program. We compared persons with canonical VEXAS-associated mutations to ten age, sex, and ancestry matched controls across the domains of diagnoses, medications, and laboratory values. Results74 persons were identified with a VEXAS-defining somatic mutation at c.121A>C (p.Met41Leu) in UBA1. The variant allele fraction ranged from 4.5% to 33%. No other canonical VEXAS-associated mutations were identified. Of the 74 persons, 62 (84%) were women, 20 (27%) were African American, and 14 (19%) were American Admixed / Latino. There was no statistically significant association between case/control status and any diagnosis code, medication prescription, or laboratory value. ConclusionWe report the largest cohort to date of persons with the VEXAS-associated p.Met41Leu mutation. This cohort differed substantially from reported cohorts of patients with clinical VEXAS, having a higher proportion of persons who were young, female, and of diverse ancestry. Variant allele fractions of p.Met41Leu mutations were lower than reported in clinical VEXAS and none of the patients had bioinformatically apparent VEXAS syndrome. The p.Met41Leu UBA1 variant displayed incomplete penetrance for VEXAS. Further study is needed to determine the natural history of VEXAS-associated mutations in the pre-disease phase.

IntroductionSpontaneous coronary artery dissection (SCAD) is frequently accompanied by persistent symptoms of unknown pathogenesis after the index event. Autonomic dysfunction is a plausible mechanism for these but has not been systematically characterized. We quantified antecedent and contemporary autonomic symptoms in survivors of SCAD and examined their associations with cardiac and extra-cardiac symptoms and health-related quality of life. MethodsThis cross-sectional study recruited 227 volunteers from multiple countries with a self-reported history of SCAD. Participants completed validated patient-reported measures, including the Composite Autonomic Symptom Score-31 (COMPASS-31), Anxiety Sensitivity Index-3 (ASI-3), and EuroQol-5 Dimension-5L (EQ-5D-5L). They also completed an internally derived retrospective autonomic predisposition score assessing symptoms during adolescence and early adulthood. ResultsParticipants were predominantly female (97.8%), median age 53 (47-58) years, and were surveyed a median of 3 (1-5) years after their index SCAD event. 21.6% reported SCAD recurrence. Moderate autonomic symptom burden (COMPASS-31 [&ge;]20) was present in 56.4% and severe burden ([&ge;]40) in 16.3%. History of antecedent autonomic symptoms was the strongest independent predictor of contemporary autonomic symptom burden after adjustment for demographic and clinical covariates ({beta}=0.514; P <0.001). Greater autonomic symptom burden independently predicted lower EQ-5D health utility ({beta}=-0.150; P=0.029) and was associated with the ASI-3 physical concerns ({beta}=0.232; P <0.001), but not social concerns domain. Autonomic symptoms were not associated with SCAD recurrence. ConclusionSymptoms of autonomic dysregulation are common in survivors of SCAD and are associated with reduced quality of life. Their association with antecedent dysautonomic features during adolescence and early adulthood suggests a longstanding predisposition, the significance of which warrants further evaluation. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LISelf-reported antecedent and current autonomic symptoms are common in survivors of spontaneous coronary artery dissection and are associated with poorer health-related quality of life, greater fatigue, and greater psychological distress. C_LI What Are the Clinical Implications?O_LIAutonomic symptoms warrant clinical recognition in patients with prior spontaneous coronary artery dissection, not only as a post-event complaint but also as a potential marker of pre-existing autonomic vulnerability that may influence recovery experience. C_LIO_LIGreater awareness of autonomic symptom burden may support more personalized follow-up, patient counseling, and rehabilitation planning to help patients return more safely and confidently to daily activities, work, and family life. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/26351434v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@1589559org.highwire.dtl.DTLVardef@b5423forg.highwire.dtl.DTLVardef@103b97org.highwire.dtl.DTLVardef@1b8378f_HPS_FORMAT_FIGEXP M_FIG C_FIG

Very little is known about the molecular mechanisms underlying chronic neck pain, a highly prevalent and burdensome condition. We analyzed the C2 dorsal root ganglion (DRG) of patients with neck pain who underwent C1-2 arthrodesis surgery. Using spatial transcriptomics, we provide the first report of IGHG4 expression in a human DRG. IGHG4 encodes immunoglobulin G4 (IgG4). Infiltration of IgG4-producing lymphocytes characterizes IgG4-related disease, an immune-mediated inflammatory condition, and IgG4 autoantibodies sensitize DRG sensory neurons. The expression was found only in one of the 8 patients analyzed, was very high, and co-localized with B cells, which have a crucial role in IgG4 production. The findings uncover a molecular mechanism potentially involved in chronic neck pain in patients susceptible to infiltration of IgG4-producing B cells.

ABSTRACT Importance: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in patients with Systemic Lupus Erythematosus (SLE), due to both traditional CVD risk factors and SLE specific factors. Although statins are first-line therapy for primary prevention of CVD in the general population, it is unclear whether statins protect against first time cardiovascular events (CVEs) in patients with SLE. Objective: Determine whether statins are protective in primary prevention of CVEs among patients with SLE. Design, setting, and participants: This cohort study is a retrospective analysis of a well-characterized, prospective cohort of patients with SLE with patient follow-up beginning in 2013. Main outcome and measures: CVEs were defined as the occurrence of myocardial infarction, thrombotic stroke, onset of angina, or coronary bypass procedure. Statin use in the prior year was quantified based on standardized defined daily doses (DDD). Rates of occurrence were compared using pooled logistic regression. A multivariable model was performed to adjust for possible confounders. Results: The analysis was based on 8708 person-years of follow-up from 1396 cohort participants: 1283 (92%) were women, 567 (41%) Black, and 665 (48%) White. Patients were stratified by use of statin within the last year: none, < standard DDD, or [&ge;] standard DDD. The rate of events per 1000 person-years was respectively 5.3, 8.5, and 8.0 (p=0.31) within these 3 groups, suggesting potential lack of protective effect of statin treatment. The rates of CVEs among statin versus non-statin users remained the same after adjusting for and stratifying by total cholesterol level (p=0.18). Significantly higher rates of CVEs occurred among those with body mass index (BMI) 25-30 kg/m^2 (p=0.0066) and those prescribed [&ge;] 10 mg/day of prednisone (p=0.0003). Multivariable analysis also suggested a potential lack of protective effect of statins against CVEs (OR 1.48; 95% CI, 0.79-2.75; p=0.21883) and diabetes mellitus was found to be independently associated with an increased risk for development of CVEs (OR 4.48; 95% CI 1.99-10.08; p=0.00029). Conclusion and Relevance: Among patients with SLE, statin use may not be protective in primary prevention of CVEs, regardless of statin exposure. Prednisone use, history of diabetes mellitus, and elevated BMI were drivers of increased cardiovascular risk in univariate analysis. Diabetes mellitus persisted as an independent risk factor for CVEs in a multivariable model. Our work reinforces findings from clinical trials which have shown no reduction in subclinical measures of atherosclerosis with statin use among patients with SLE, as well as a mechanistic substudy which demonstrated that statins are ineffective in normalizing the pro-atherogenic changes induced by SLE.

Background and PurposeTripartite motif-containing protein 72 (TRIM72) mediates tissue-repair following injury in several organs, including muscle and lung. Autoantibodies directed against TRIM72 (anti-TRIM72) have been identified in patients with idiopathic inflammatory myopathies (IIM) and disrupt TRIM72 function in vitro. We hypothesized that IIM patients positive for anti-TRIM72 antibodies would have a more severe clinical phenotype. MethodsSera from IIM patient (antisynthetase syndrome [ASyS], immune mediated necrotizing myopathy [IMNM], and dermatomyositis [DM]) and healthy controls (HC) were included. Anti-TRIM72 autoantibodies were tested using enzyme linked immunosorbent assay. Anti-TRIM72 testing was positive if value was >2 standard deviations above the mean for HC. Clinicodemographic features were identified through chart review and compared between anti-TRIM72 positive (anti-TRIM72[+]) and negative (anti-TRIM72[-]) groups. ResultsAnti-TRIM72 levels were significantly increased in patients with ASyS and IMNM when compared to patients with DM and healthy controls. Anti-TRIM72 levels were also increased in patients expressing anti-Jo-1, anti-PL7, anti-HMGCR, anti-SRP, and anti-MDA5. In ASyS, when anti-TRIM72(+) and anti-TRIM72(-) patients were compared, there were significantly more anti-TRIM72(+) ASyS patients with normal DLCO (>75%) when compared to anti-TRIM72(-); however, there were no differences in demographic features, CK levels or FVC. In anti-HMGCR(+) IMNM, anti-TRIM72(+) was associated with a lower proportion of females, as well as older age at time of diagnosis and at time of anti-TRIM72 testing; however, there was no significant difference in other clinicodemographic features in anti-HMGCR(+) IMNM patients when anti-TRIM72(+) and anti-TRIM72(-) groups were compared. ConclusionsAnti-TRIM72 antibody titres are increased in patients with ASyS and IMNM. The presence of anti-TRIM72 antibodies was not associated with a more severe phenotype in ASyS or anti-HMGCR(+) IMNM, and there were more ASyS patients with normal DLCO in the anti-TRIM72(+) group.

Background: Crohn's disease is a chronic relapsing inflammatory bowel disease with an unpredictable clinical course that may lead to recurrent hospitalizations and surgery, making early identification of patients at risk a key challenge in longitudinal monitoring. Objective: To evaluate the prognostic value of blood biomarkers for anticipating hospitalizations in patients with Crohn's disease by moving beyond exclusive reliance on conventional reference intervals toward the analysis of personalized biological drift. The underlying premise is that fluctuations that remain within standard reference ranges (and are therefore invisible to conventional thresholds) may still carry a risk signal when interpreted relative to an individual's optimal baseline. Design: We conducted a retrospective study of 993 patients with Crohn's disease followed at the University Hospital of Liege between 2005 and 2023. Longitudinal laboratory measurements were linked to Crohn's disease-related hospitalizations. Biomarkers were transformed into z-scores relative to optimized and personalized reference populations and classified into drift categories. Time to first hospitalization was analyzed using the Kaplan-Meier method, and recurrent hospitalizations were modeled using Cox models. Results: Hospitalization-free survival differed significantly across drift categories, including for deviations within conventional reference ranges (e.g., albumin, global log-rank p<0.0001). Among 57 biomarkers screened, 32 were significant in the global log-rank analysis, including 5 that were significant for intra-reference drift classes: low lymphocytes (%), low monocytes (%), low albumin, high potassium, and low aspartate aminotransferase. Conclusion: Personalized biomarker drift detects clinically meaningful risk signals that are missed by conventional reference-interval thresholds and may enable earlier risk stratification in Crohn's disease.

ObjectiveGiant cell arteritis (GCA) is an age-related vasculitis. Prior studies have identified an association between GCA and hematologic malignancies (HM). How the presence of somatic mutations which drive development of HM, or clonal hematopoiesis (CH), may influence clinical outcomes in GCA is not well understood. MethodsTo examine an association between CH and GCA, we analyzed sequenced exomes of 470960 UK Biobank participants for the presence of CH and used multivariable Cox regression. To examine the clinical phenotype of GCA in patients with and without somatic mutations across the spectrum of CH to HM, we performed targeted sequencing of blood samples and electronic health record review on 114 patients with GCA seen at our institution. We then examined associations between specific clonal mutations and GCA disease manifestations. ResultsUKB participants with CH had a 1.48-fold increased risk of incident GCA compared to UKB participants without CH. GCA risk was highest among individuals with cytopenia (HR 2.98, p =0.00178) and with TET2 mutation (HR 2.02, p =0.00116). Mutations were detected in 27.2% of our institutional GCA cohort, 3 of whom had HM at GCA diagnosis. TET2 mutations were associated with vision loss in patients with GCA (OR 4.33, p = 0.047). ConclusionsCH increases risk for development of GCA in a genotype-specific fashion, with greatest risk being conferred by the presence of mutations in TET2. Somatic TET2 mutations likewise increase the risk of GCA-associated vision loss. Integration of somatic genetic testing in GCA diagnostics may be warranted in the future.

BackgroundPost-viral diseases, including post-COVID-19 syndrome (PCS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cause substantial long-term morbidity. Persistent cardiovascular (CV) risk after acute infection highlights the need for accessible tools to quantify microvascular health. MethodsAll Eyes on PCS is a prospective, observational study investigating the retinal microcirculation using retinal vessel analysis (RVA). We compared RVA parameters in 102 PCS patients with 204 age- and sex-matched healthy controls (HC, matched from n = 303). Secondary matched analyses included never infected controls (NI, n = 96), recovered individuals (n = 102), PCS patients, and ME/CFS patients (n = 62). Laboratory variables, circulating markers of endothelial dysfunction (ED) and inflammation were compared between cohorts and their associations with RVA parameters were examined. ResultsCompared with HC, PCS patients showed reduced venular flicker-induced dilation (3.7 {+/-} 2.2% vs. 4.5 {+/-} 2.7%, p = 0.005), narrow retinal arterioles (CRAE, 178.3 {+/-} 15.5 {micro}m vs. 183.3 {+/-} 15.9 {micro}m, p = 0.009), and lower arteriolar-to-venular ratio (0.83 {+/-} 0.06 vs. 0.86 {+/-} 0.07, p = 0.004). Findings persisted after adjustment for CV factors and remained evident in an extended secondary matched analysis across NI, recovered, and PCS patients. ME/CFS patients showed the most pronounced alterations. PCS severity correlated with lower AVR (r = -0.21, p = 0.037) and reduced arteriolar FID (r = -0.21, p = 0.039), particularly for neurocognitive symptoms. IL-6, ICAM-1 and VCAM-1 were elevated in PCS and ME/CFS and lower AVR correlated with inflammatory and iron-related markers (all adjusted p < 0.01). A combined model discriminated ME/CFS patients with good accuracy (AUC = 0.80). ConclusionsPCS is associated with persistent ED, most pronounced in ME/CFS patients and linked to symptom severity and ongoing inflammation. RVA may provide a noninvasive, readout of ED in post-viral syndromes. Trial RegistrationThe All Eyes on PCS Study has previously been registered at ClinicalTrials.gov (NCT05635552). Novelty and SignificanceO_ST_ABSWhat is known?C_ST_ABS- PCS and ME/CFS are associated with persistent endothelial dysfunction and increased long-term cardiovascular risk. - Neurocognitive symptoms in post-viral syndromes have been linked to impaired neurovascular coupling. - Retinal vessel analysis provides a validated, non-invasive readout of systemic and cerebral microvascular health. What new information does this article contribute?- PCS is characterized by persistent functional and structural retinal microvascular dysfunction - Retinal endothelial dysfunction scales continuously with post-viral disease severity and is most pronounced in patients fulfilling ME/CFS criteria. - Retinal microvascular alterations are linked to inflammatory-endothelial activation and iron dysregulation, identifying a biologically coherent vascular phenotype. This study provides the first comprehensive human in vivo assessment of retinal microvascular structure and function across the full post-COVID-19 spectrum, from never infected controls to recovered individuals, PCS patients, and those fulfilling ME/CFS criteria. Using retinal vessel analysis as a surrogate of neurovascular and endothelial function, we demonstrate that endothelial dysfunction persists in patients with ongoing post-viral symptomatology. Retinal venular flicker-induced dilation, arteriolar caliber, and autoregulatory capacity decline progressively with increasing clinical severity, indicating a dose-response relationship between microvascular injury and post-infectious disease burden. Importantly, these vascular alterations are linked to sustained inflammatory and endothelial activation and to disturbances in iron homeostasis, indicating an inflammatory-endothelial axis rather than isolated cardiovascular risk. By integrating microvascular phenotyping with symptom profiles and circulating biomarkers, this work identifies retinal endothelial dysfunction as a mechanistically informative and clinically accessible marker of post-viral disease severity. These findings advance understanding of post-infectious vascular pathology and provide a translational framework for biological stratification and risk assessment in PCS and ME/CFS.

BackgroundNew-onset chronic musculoskeletal (MSK) pain (> 3 months duration) is one of the commonest persistent symptoms of Post-COVID syndrome (PCS). There is emerging evidence that the chronic MSK pain and associated symptoms in PCS have similarities to Fibromyalgia Syndrome (FMS). This study aimed to characterise PCS related new-onset chronic MSK pain and its overlap with Fibromyalgia Syndrome (FMS). MethodsPatients with new-onset chronic MSK pain following COVID-19 infection were enrolled and the nature of pain and associated symptoms captured using the C19-YRS (Yorkshire Rehabilitation Scale). FMS assessment was conducted as part of standard clinical examination using the American College of Rheumatology (ACR) 2010 criteria. Diagnosis of FMS was made when they meet the standard criteria of (1) Widespread Pain Index (WPI) [&ge;] 7 and Symptoms Severity (SS) score [&ge;] 5, or WPI is 3-6 and SS score [&ge;] 9, (2) symptoms have been present at a similar level for at least 3 months, and (3) the patient does not have a disorder that would otherwise explain the symptoms. ResultsEighteen patients, twelve of whom were female, with an average age of 49.6 (SD 11.8) years and a Body Mass Index of 31.7 (SD 8.6) were enrolled. The average duration of symptoms from COVID-19 infection to assessment was 27.9 (SD 6.97) months. The new-onset chronic pain was widespread, primarily manifesting as muscle pain. Thirteen (72.2%) patients met the diagnostic criteria for FMS, with an average WPI score of 8.8 and an average SS score of 8.2, indicating a high level of pain and significant adverse impact on their quality of life. ConclusionThe study found that 72.2% of the patients with new-onset chronic MSK pain following COVID-19 infection met the criteria for FMS. These findings support the hypothesis that FMS may develop as a long-term sequela of a viral infection, underscoring the need for further research into post-viral long-term conditions.

Introduction Hospitalised community-acquired pneumonia (CAP) is heterogeneous in aetiology, severity, and outcome. Phenotyping and endotyping approaches offer potential to stratify patients biologically and guide targeted therapy, but require well-characterised cohorts with linked biosamples. We describe the PARIS (Pneumonia: Acute Respiratory Infection +/- Sepsis) study: a prospective observational cohort of hospitalised patients with pneumonia, designed to characterise functional outcomes and to provide a biobank for translational immunological research. Methods Adults admitted with CAP to a single NHS district general hospital were enrolled within 24 hours of admission between December 2020 and March 2022. Clinical, functional, and physiological data were collected at enrolment, hospital discharge, and 6-8 week follow-up. Serial blood samples were collected for flow cytometry, transcriptomics, pathogen DNA detection, and plasma biobanking. Results Forty-seven patients were enrolled (15 without and 32 with sepsis [SOFA >=2] at enrolment); 87% met sepsis criteria by 24 hours post enrolment. Most patients (30/47, 64%) were managed as COVID-19, microbiologically confirmed in 27. Mean age was 57 years (SD 16), 70% were male, and baseline comorbidity burden was low. Severity was moderate (median NEWS2 4 at enrolment, rising to 6 by 24 hours post enrolment; p<0.001). Mortality was 4/47 (8.5%), with 44/47 (94%) alive at hospital discharge. Median length of stay was 8 days (IQR 5.5-11). Translational samples were collected from the majority: fresh flow cytometry (44/47, 94%), transcriptomics from the sepsis subgroup (31/32, 97%), pathogen DNA sampling (35 samples received across study timepoints; see Table 5), and stored plasma (29/47, 62%). The primary outcome of functional decline (Barthel score decrease >=1.85) occurred in only 1/29 patients with paired assessments (3.4%). Persistent CRP elevation (>3 mg/L) at 6-8 week follow-up was present in 16/31 (52%) survivors with available data. Conclusions The PARIS cohort provides a well-characterised clinical platform and linked biobank to support translational studies of pneumonia and sepsis. The low rate of functional decline reflects the younger, lower-comorbidity, COVID-predominant population recruited. Primary protocol endpoints were not achieved owing to pandemic-related disruption. Data and samples underpin a programme of linked translational studies.

BackgroundPatients with AL amyloidosis present sustained paradoxical vasodilation in response to sympathetic stimulation by cold pressor test (CPT). The clinical relevance of this finding is unknown. We investigated the clinical role of CPT induced vascular and hemodynamic responses. MethodsWe prospectively recruited 113 treatment-naive AL amyloidosis patients. High resolution ultrasonography was used to measure the peak percent change of the brachial artery during CPT and 3 minutes after its withdrawal (postCPT), defined as sustained response. Peripheral and aortic (central) systolic (SBP) and diastolic blood pressure (DBP) were measured at the same timepoints before and 12 months after treatment initiation. All-cause and cardiovascular mortality were recorded (median follow-up 26 months). The same tests were performed in ten healthy volunteers. ResultsSustained vasodilation and reductions in central systolic (%CSBP_post) and peripheral diastolic BP were observed in AL as compared to controls (p<0.01 for all) and were associated with all-cause and cardiovascular death after adjustment for disease-related risk factors (p<0.05 for all). %CSBP_post provided incremental value over Mayo stage. Mechanistic analyses revealed associations of %CSBP_post with markers of neurological and cardiac dysfunction and of myocardial infiltration. Longitudinally, at 12 months, %CSBP_post further decreased in patients with earlier poor hematologic response to disease-specific treatment. ConclusionsUsing a noninvasive readily available method in treatment-naive AL amyloidosis patients, sustained reduction of central SBP after sympathetic stimulation was associated with cardiac dysfunction, poor survival and response to treatment.

BackgroundOlfactory dysfunction (OD) often accompanies acute coronavirus disease 2019 (COVID-19) and its sequelae. Herein, we investigated OD during COVID-19 recovery in the context of other symptoms, quality of life, physical and mental health. MethodsSymptom recovery patterns were analyzed in a bi-national, ambulatory COVID-19 survey (n = 906, [&ge;] 90 days follow-up) and a multi-center observational cross-sectional cohort of ambulatory and hospitalized individuals (n = 108, 360 days follow-up) with multi-dimensional scaling, association rule mining and partitioning around medoids clustering. ResultsBoth in the ambulatory collective (72%, n = 655/906) and the cross-sectional ambulatory and hospitalized cohort (41%, n = 44/108) self-reported OD was frequent during acute COVID-19, displayed a slow recovery pace (ambulatory: 28 days, cross-sectional: 90 days median recovery time) and commonly co-occurred with taste disorders. In the ambulatory collective, a predominantly young, female, comorbidity-free group of convalescents with persistent OD and taste disorder (>90 days) was identified. This post-acute smell and taste disorder phenotype was characterized by a low frequency of other leading post-acute symptoms including fatigue, respiratory and neurocognitive complaints. Despite a protracted smell and taste dysfunction, this subset had high ratings of physical performance, mental health, and quality of life. ConclusionOur results underline the clinical heterogeneity of post-acute COVID-19 sequelae calling for tailored management strategies. The persistent smell and taste disorder phenotype may represent a distinct COVID-19 recovery pathway characterized by a good recovery of other COVID-19 related symptoms. Study registrationClinicalTrials.gov: NCT04661462 (ambulatory collective), NCT04416100 (cross-sectional cohort).

Patients with immune-mediated inflammatory diseases (IMIDs) and acquired and genetic immunodeficiencies receiving therapeutic infusions are considered high risk for SARS-CoV-2 infection. However, the seroprevalance in this group and the safety of routine administrations at outpatient infusion centers are unknown. To determine the infection rate and clinical-social factors related to SARS-CoV-2 in asymptomatic patients with IMIDs and immunodeficiencies receiving routine non-cancer therapeutic infusions, we conducted a seroprevalence study at our outpatient infusion center. We report the first prospective SARS-CoV-2 sero-surveillance of 444 IBD/IMID, immunodeficiency, and immune competent patients at an outpatient infusion center in the U.S. showing lower seroprevalence in patients compared with the general population and provide clinical and social characteristics associated with seroprevalence in this group. These data suggest that patients can safely continue infusions at outpatient centers.