Early Disease Activity Research Articles

Unmet needs in axial spondyloarthritis. Proceedings of the French spondyloarthritis taskforce workshop

The progress observed over the last 30 years in the field of axial spondyloarthritis (axSpA) has not made it possible to answer all the current questions. This manuscript represents the proceedings of the meeting of the French spondyloArthitiS Task force (FAST) in Besançon on September 28 and 29, 2023. Different points of discussion were thus individualized as unmet needs: biomarkers for early diagnosis and disease activity, a common electronic file dedicated to SpA nationwide, a better comprehension of dysbiosis in the disease, a check-list for addressing to the rheumatologist, adapt patient reported outcomes thresholds for female gender, implementation of comorbidities screening programs, new imaging tools, in research cellular and multi omics approaches, grouping, at a nationwide level, different cohorts and registries, therapeutic strategy studies, consensual definition of difficult to treat disease and management, preclinical stage of the disease, mastering AI as a tool in the various aspects of research. These elements may represent a framework for the research agenda in axSpA for the years to come.

Multiple Sclerosis: From the Application of Oligoclonal Bands to Novel Potential Biomarkers

Multiple sclerosis is a chronic immune-mediated disorder of the central nervous system with a high heterogeneity among patients. In the clinical setting, one of the main challenges is a proper and early diagnosis for the prediction of disease activity. Current diagnosis is based on the integration of clinical, imaging, and laboratory results, with the latter based on the presence of intrathecal IgG oligoclonal bands in the cerebrospinal fluid whose detection via isoelectric focusing followed by immunoblotting represents the gold standard. Intrathecal synthesis can also be evidenced by the measurement of kappa free light chains in the cerebrospinal fluid, which has reached similar diagnostic accuracy compared to that of oligoclonal bands in the identification of patients with multiple sclerosis; moreover, recent studies have also highlighted its value for early disease activity prediction. This strategy has significant advantages as compared to using oligoclonal band detection, even though some issues remain open. Here, we discuss the current methods applied for cerebrospinal fluid analysis to achieve the most accurate diagnosis and for follow-up and prognosis evaluation. In addition, we describe new promising biomarkers, currently under investigation, that could contribute both to a better diagnosis of multiple sclerosis and to its monitoring of the therapeutic treatment response.

Targeted metabolomics combined with machine learning to identify and validate new biomarkers for early SLE diagnosis and disease activity

BackgroundThe early diagnosis of systemic lupus erythematosus (SLE) and the assessment of disease activity progression remain a great challenge. Targeted metabolomics has great potential to identify new biomarkers of SLE. MethodsSerum from 44 healthy participants and 89 SLE patients were analyzed using HM400 high-throughput targeted metabolomics. Machine learning (ML) with seven learning models and trained the model several times iteratively selected the two best prediction model in a competitive way, which were independent validated by enzyme-linked immunosorbent (ELISA) with 90 SLE patients. ResultsIn this study, 146 differential metabolites, most of them organic acids, amino acids, and bile acids, were detected between patients with initial SLE and healthy participants, and 8 potential biomarkers were found by intersection of ML and statistics (area under the curve [AUC] > 0.95) showing a significant positive correlation with clinical indicators. In addition, we identified and validated 2 potential biomarkers for SLE classification (P < 0.05, AUC > 0.775; N-Methyl-L-glutamic acid, L-2-aminobutyric acid) showing a significant correlation with the SLE Disease Activity Index. These differential metabolites were mainly involved in metabolic pathways, amino acid biosynthesis, 2-oxocarboxylic acid metabolism and other pathways. ConclusionThis study indicated that the tricarboxylic acid cycle might be associated with SLE drug therapy. We identified 8 diagnostic models biomarkers and 2 biomarkers that could be used to identify initial SLE and distinguish different activity degree, which will promote the development of new tools for the diagnosis and evaluation of SLE.

2023 Management Recommendations of Bangladesh Rheumatology Society on Pharmacological Treatment of Rheumatoid Arthritis With Synthetic and Biologic Disease-Modifying Drugs.

Rheumatoid arthritis (RA) is the most common inflammatory polyarthritis in Bangladesh. Bangladesh Rheumatology Society (BRS) proposes these management recommendations to treat the considerable burden of RA in the resource-constrained situation based on the best current evidence combined with societal challenges and opportunities.BRS formed a task force (TF) comprising four rheumatologists. The TF searched for all available literature, including updated American College of Rheumatology (ACR), European Alliance of Associations for Rheumatology (EULAR), and Asia-Pacific League of Associations for Rheumatology (APLAR) and several other guidelines, and systematic literature reviews until October 2023, and then a steering committee was formed, which included rheumatologists and internists. We followed the EULAR standard operating procedures to categorize levels of evidence and grading of recommendations. This recommendation has two parts -- general (diagnosis of RA, nomenclature of disease-modifying anti-rheumatic drugs [DMARDs], disease activity indices) and management portion. The TF agreed on four overarching principles and 12 recommendations. Overarching principles deal with early diagnosis and disease activity monitoring. Recommendations 1-5 discuss using glucocorticoids, NSAIDs, and conventional synthetic DMARDs (csDMARD). Recommendations 6-9 stretch the use of targeted synthetic DMARDs (tsDMARDs) and biological DMARDs (bDMARDs). The suggested DMARD therapy includes initiation with methotrexate (MTX) or another csDMARD (in case of contraindication to MTX) in the first phase and the addition of a tsDMARD in the second phase, switching to an alternative tsDMARDs or bDMARDs in the subsequent phases. The TF included the Padua prediction score for the thromboembolism risk estimation. Recommendations 10-12 cover infection screening, vaccination, and DMARD tapering. Bangladesh has a higher prevalence of RA. This recommendation will serve as a tool to treat this high burden of patients with RA scientifically and more effectively.

CSF levels of Chitinase3like1 correlate with early response to cladribine in multiple sclerosis.

Cladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed. To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine. Forty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The 'no evidence of disease activity' (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs. Three patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91). CSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug's effect on chronic macrophage and microglia activation deserves further evaluation.

P264 The utility of ANCA in Ulcerative Colitis and Crohn’s Disease: A Retrospective Cohort Study in Taiwan

Abstract Background Inflammatory bowel disease (IBD) includes two chronic idiopathic inflammatory diseases: ulcerative colitis (UC) and Crohn disease (CD). The diagnosis of IBD depends on clinical, endoscopic, histological, radiological and biochemical criteria, which may be invasive, time consuming and usually not accepted by patients with IBD. Antineutrophil cytoplasmic antibodies (ANCAs) is believed to be related to IBD. The aim of this study was to investigate these serological markers and the evidence for their use in the diagnosis and management of IBD in Taiwan. Methods We conducted a retrospective cohort study in adult IBD patients who had received the serum examinations using the medical records of China Medical University Hospital between 1 January 1980 and 31 October. 2023. Results A total of 301 IBD patients (194 with UC, 107 with CD) were included in this current study. A high proportion were male (IBD 70.41%; UC 65.63%, and CD 76.71%). The mean diagnostic age of these enrolled patients was 42.9 years. In our patients, the prevalence of positive anti-HCV Ab is 0.0% in UC patients and 0.96% in CD patients. However, the prevalence of positive HBsAg was 14.5% in UC patients and 9.4% in CD patients. The prevalence of pANCA was 21.2% in UC patients and 1.4% in CD patients, respectively. The prevalence of cANCA was 3.1% in UC patients and 0.0% in CD patients. This pattern of low sensitivity and high specificity for pANCA is also seen in UC patients in various cohort studies. The serum positivity of p-ANCA was significantly higher in UC patients (Figure 1). UC patients with positive p-ANCA were older than CD patients with positive p-ANCA (44.9 vs. 37.3 years). Furthermore, we found that the incidence of positive p-ANCA in UC patients with E1, E2, and E3 at diagnosis was 3.5%, 39.2%, and 57.1%, respectively (Table 1). The serum levels of ANCA-IgG were indeed higher in patients in the severe group than those in the moderate and mild groups. Conclusion Serological biomarkers have been demonstrated to be a series of rapid, non-invasive approaches for assessments of early diagnosis, disease activity and prognosis for IBD. ANCA may be helpful in the early diagnosis of UC and in differentiating it from CD. UC patients with positive ANCA have a higher rate of intestinal mucosal vasculitis than UC patients with negative ANCA. Furthermore, ANCA may also contributes to the pathogenesis of HBV-related systemic vasculitis. Therefore, the management of HBV-related vasculitis includes control the immune complex formation and reaction as well as antiviral agents to reduce the antigenic load resulting in reduction of inflammation. Moreover, effective biomarkers with high sensitivity and specificity need to be investigated in the future.

Disease activity trajectories in juvenile dermatomyositis from childhood to adulthood.

To assess whether there are identifiable subgroups of disease activity trajectory in a population of JDM patients-followed throughout childhood and into adulthood-and determine factors that predict those trajectory groupings. This is a retrospective, longitudinal inception cohort of patients with idiopathic inflammatory myopathies, largely JDM. We sought to identify baseline factors that predict membership into different groups (latent classes) of disease activity trajectory. A total of 172 patients (64% females), with median age at diagnosis of 7.7 years, were analysed. We studied 4725 visits (1471 patient-years). We identified three latent classes of longitudinal disease activity, as measured by the modified DAS (DASm), with distinct class trajectories predicted by DASm at baseline, and by the changes of DASm from either baseline to 3 months or baseline to 6 months (early response to therapy). In the analysis in which DASm at baseline and the changes of DASm from baseline to 6 months are included as predictors, Class 1 (10%) has persistently high disease activity, Class 2 (34%) is characterized by moderate disease activity and Class 3 (56%) is characterized by individuals with a high early disease activity but an apparently good response to treatment and long-term low disease activity. High early disease activity, and treatment resistance in the first few months, predict a more chronic longitudinal course of JDM.

Assessment of Musculoskeletal Ultrasound of Rheumatoid Arthritis.

Musculoskeletal ultrasound (MSUS) is a valuable tool that is used in outpatient clinics or at the bedside to assess multiple joint sites, including small joints. It provides detailed images of structures commonly observed in rheumatoid arthritis (RA), such as synovitis, tenosynovitis, bone erosions, cartilage damage, and synovial fluid accumulation. MSUS is frequently used in the management of RA and provides more objective information for an early diagnosis and disease activity assessment through imaging findings.

Assessment of pulmonary fibrosis induced by paraquat using Al18F-NODA-FAPI-04 PET/CT.

The lack of a highly sensitive method to evaluate paraquat (PQ)-induced pulmonary fibrosis and predict disease progression remains an unresolved clinic issue. Fibroblast activation protein (FAP) may play an important role in the pathogenesis of PQ-induced pulmonary fibrosis. We aimed to evaluate the role of FAP in the PQ-induced pulmonary fibrosis and the utility of fibroblast activation protein inhibitor (FAPI) for positron emission tomography (PET) imaging in PQ-induced pulmonary fibrosis. In our study, two cases of PQ poisoning were presented and FAPI PET/CT was performed as a novel imaging technique. The uptake of FAPI increased in both cases of PQ poisoning. Animal experiments were then performed to validate the findings in the patients. Physiological FAPI lung uptake was higher in mice of the PQ group than in the control group. The results of histological analysis and Western blot were consistent with the findings of PET/CT imaging. The pulmonary fibrosis animal model was developed by intragastric gavage of PQ. PET/CT imaging was performed after injection of FAPI. Lung tissues of mice were collected for fibrosis assessment after imaging. Immunohistochemistry for FAP, histology and Western blot for collagen were performed to further validate the imaging findings. In conclusion, FAPI was involved in the pathogenesis of fibrosis induced by PQ, and PET/CT with FAPI could detect lung fibrogenesis, making it a promising tool to assess early disease activity and predict disease progression.

Brain MRI Activity During the Year Before Pregnancy Can Predict Long-Term Clinical Worsening in Patients with Multiple Sclerosis (P11-3.018)

<h3>Objective:</h3> The aim of the study was to evaluate the correlation between Magnetic Resonance Imaging (MRI) activity in the year before pregnancy and the long-term clinical meaningful worsening in Expanded Disability Status Scale (EDSS). <h3>Background:</h3> While fewer Multiple Sclerosis (MS) relapses occur during pregnancy, relapse risk increases in the early post-partum period. We showed in a previous study a correlation between an active-MRI pre-conception and the early post-partum disease activity as evidenced by MRI activity and relapses. Increased post-partum disease activity may predict a poor long-term prognosis. <h3>Design/Methods:</h3> An observational retrospective case–control study included 141 pregnancies in 99 females with MS. Statistical analyses were used to evaluate the correlation between MRI-activity in the year pre-pregnancy and post-partum clinical worsening during 5-years follow-up. Clustered logistic regression was used to investigate the predictors of 5-years clinical meaningful worsening in EDSS (lt-EDSS). <h3>Results:</h3> We found a significant correlation for an active-MRI pre-pregnancy and lt-EDSS (p=0.0006). EDSS pre-pregnancy and lt-EDSS also significantly correlated (p=0.043). Using a multivariate model, we predicted which females won’t experience long-term clinical deterioration by a stable-MRI pre-pregnancy (89.6% specificity; p=0.012). <h3>Conclusions:</h3> An active-MRI pre-conception is a strong predictor of lt-EDSS and higher annual relapse-rate (ARR) during the follow-up period, regardless of whether the female had clinical evidence of disease activity prior to conception and delivery. Optimizing disease control and achieving both clinical and imaging stability pre-conception and post-delivery may reduce the risk of long-term clinical deterioration. <b>Disclosure:</b> Mr. Zveik has nothing to disclose. Miss Kahila has nothing to disclose. Dr. Levin has nothing to disclose. Mr. Rechtman has nothing to disclose. Ms. Haham has nothing to disclose. Adi Vaknin-Dembinsky has nothing to disclose.

Kappa free light chain and neurofilament light independently predict early multiple sclerosis disease activity—a cohort study

Inter-individual courses of multiple sclerosis (MS) are extremely variable. The objective of this study was to investigate whether κ-free light chain (κ-FLC) index and serum neurofilament light (sNfL) have an additive predictive value for MS disease activity. Patients with early MS who had cerebrospinal fluid (CSF) and serum sampling at disease onset were followed for four years. At baseline, age, sex, disease duration, number of T2-hyperintense (T2L), and contrast-enhancing T1 lesions (CEL) on MRI were determined. During follow-up, the occurrence of a second clinical attack and start of disease-modifying treatment (DMT) were registered. κ-FLC was measured by nephelometry, and κ-FLC index calculated as [CSF κ-FLC/serum κ-FLC]/albumin quotient. sNfL was determined by single-molecule array, and age- and body-mass-index adjusted Z scores were calculated. A total of 86 patients at a mean age of 33±10 years and with a female predominance of 67% were included; 36 (42%) patients experienced a second clinical attack during follow-up. Cox regression analysis adjusted for age, sex, T2L, CEL, disease and follow-up duration, and DMT use during follow-up revealed that both κ-FLC index as well as sNfL Z score independently predict time to second clinical attack. The chance for freedom of relapse within 12 months was 2% in patients with high levels of κ-FLC index (>100) and high sNfL Z score (>3), 30% in patients with high κ-FLC index (>100) and lower sNfL Z score (≤3), 70% in patients with lower κ-FLC index (≤100) but high sNfL Z score (>3), and 90% in patients with lower levels of κ-FLC index (≤100) and sNfL Z score (≤3). κ-FLC index and sNfL Z score have an additive predictive value for early MS disease activity that is independent of known predictors. This study was funded by a grant of the charitable foundation of the Austrian Multiple Sclerosis Society.

P104 Exploring the transcriptomic miRNA signatures of Egyptian Inflammatory Bowel Disease patients

Abstract Background Inflammatory Bowel Disease (IBD) is a chronic autoimmune gastrointestinal disease, sub-classified into Crohn’s disease (CD) and ulcerative colitis (UC). The two subclasses are characterized by a relapsing-remitting course with an increasingly high incidence and prevalence worldwide. Molecular mechanisms guarding the pathogenesis of these diseases remain, to the present day, ambiguous to researchers. MicroRNAs are 22 nucleotides long small noncoding RNAs that have been recently described as essential participants in immune cell development and the immune response to pathogens. During the past decade, genetic and epigenetic studies in IBD have been labeled as essential; since endoscopic assessment and biopsies provide limited data concerning early disease activity, factors for relapse, and response to treatment. To the best of our knowledge, IBD research has never addressed miRNA profiles in Egyptian CD and UC patients as compared to unaffected controls. Methods Therefore, this study aims to profile miRNAs in Egyptian patients suffering from UC and CD, using RNA-seq of total RNA extracted from colonoscopically obtained tissue pinch biopsies. Results The sequencing results showed that 30 miRNAs were uniquely expressed in tissue biopsies obtained from the CD patients, as compared to only 14 uniquely expressed in UC patients. Further web-based functional enrichment analysis showed that the miRNAs- in both disease groups- are mainly involved in six interlinked molecular pathways; including the JAK/STAT, WNT, PI3K/AKT, FOXO, MAPK, and NF-κB signaling pathways. One of the most interesting findings of the current study is the fact that the downregulation of the miR-204-5p in UC patients (log2 FC= 5.05)-as compared to CD patients- may be caused by the sponging effect of the MALAT1 long non-coding RNA (lncRNA); affecting related signaling pathways such as the Wnt/β-catenin signaling. This suggests an essential interplay between miRNAs and lncRNAs in shaping the molecular pathogenesis of UC vs. CD. Conclusion The results of the current study revealed explicit-previously undetermined- differences in the miRNA profiles of patients suffering from UC and CD. Such results are expected to impact the understanding of the difference in the molecular pathogenesis of IBD subtypes affecting patients’ response to treatment.

Changes of C-reactive protein and Procalcitonin after four weeks of treatment in patients with pulmonary TB

ObjectiveTuberculosis (TB) remains a public health concern worldwide, affecting millions of people every year. Detailed characterization of disease pathophysiology is key to proper diagnosis, disease progression, or treatment follow-up and evaluation. The present study investigated C-reactive protein and Procalcitonin (PCT) as candidate markers of early treatment response and disease activity. MethodsFrom September to December 2019, 21 HIV-negative consecutive TB patients were recruited, within the setting of the Gabonese TB specialized hospital and the National Laboratory of Public Health, in a prospective study. CRP and PCT levels were measured by chemiluminescence at diagnosis and 4 weeks following the initiation of anti-TB treatment. ResultsThe mean concentration of CRP in TB patients was 114.7 mg/L (95 % CI: [83.8–145.6]) at diagnosis and 20.2 mg/L (95 % CI: [14.1–26.4]) 4 weeks following anti-TB treatment. The drop in CRP concentrations between diagnosis, and week 4 following anti-TB treatment showed was significant (p < 0.0001). The average concentration of PCT at the time of diagnosis was 0.3 ng/mL (95 % CI: [0.19–0.41]). PCT Concentration dropped below 0.05 ng/mL 4 weeks following the start of anti-TB treatment (p < 0.01). ConclusionCRP and PCT are potential TB biomarkers, each, carrying important keys. If the drop in both proteins may indicate a significant reduction of the Mtb burden, the maintenance of CRP above the inflammation threshold could indicate the presence of residual bacilli. However, the clinical translation of the present finding will require more investigation.

Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

Irregular anatomical features can alter hemodynamics in Takayasu arteritis

ObjectiveTakayasu arteritis (TA) is a difficult disease to deal with because there are neither reliable clinical signs, laboratory biomarkers, nor a single noninvasive imaging technique that can be used for early diagnosis and disease activity monitoring. Knowledge of aortic hemodynamics in TA is lacking. This study aimed to fill this gap by assessing hemodynamics in patients with TA using image-based computational fluid dynamics (CFD) simulations. MethodsEleven patients with TA were included in the present study. Patient-specific geometries were reconstructed from either clinical aortic computed tomography angiography or magnetic resonance angiography studies and coupled with physiological boundary conditions for CFD simulations. Key anatomical and hemodynamic parameters were compared with a control group consisting of 18 age- and sex-matched adults without TA who had healthy aortas. ResultsCompared with controls, patients with TA had significantly higher aortic velocities (0.9 m/s [0.7, 1.1 m/s] vs 0.6 m/s [0.5, 0.7 m/s]; P = .002), maximum time-averaged wall shear stress (14.2 Pa [9.8, 20.9 Pa] vs 8.0 Pa [6.2, 10.3 Pa]; P = .004), and maximum pressure drops between the ascending and descending aorta (36.9 mm Hg [29.0, 49.3 mm Hg] vs 28.5 mm Hg [25.8, 31.5 mm Hg]; P = .004). These significant hemodynamic alterations in patients with TA might result from abnormal anatomical features including smaller arch diameter (20.0 mm [13.8, 23.3 mm] vs 25.2 mm [23.3, 26.8 mm]; P = .003), supra-aortic branch diameters (21.9 mm [18.5, 24.6 mm] vs 25.7 mm [24.3, 28.3 mm]; P = .003) and descending aorta diameter (14.7 mm [12.2, 16.8 mm] vs 22.5 mm [19.8, 24.0 mm]; P < .001). ConclusionsCFD analysis reveals hemodynamic changes in the aorta of patients with TA. The applicability of CFD technique coupled with standard imaging assessments in predicting disease progression of such patients will be explored in future studies. Future large cohort study with outcome correlation is also warranted. Clinical RelevanceBased on patient-specific computational fluid dynamics simulations, the present retrospective study revealed significant difference in aortic hemodynamics between the patients with and without Takayasu arteritis (TA). To the best of our knowledge, this study is the first to evaluate hemodynamic conditions within TA, demonstrating the potential of computational flow modeling in capturing abnormal hemodynamic forces, such as high wall shear stress, resulted from irregular morphological changes. In the future, assessing the hemodynamic parameters within patients with TA during the prestenotic period, together with longitudinal computational fluid dynamics studies may allow better monitoring and management of TA.

Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping

Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson’s disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal “n-of-few” clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA.

Comparison of Hand Features in Systemic Sclerosis and Rheumatoid Arthritis Patients by Diagnostic Ultrasound and its Correlation to Disease Activity, Clinical and Radiological Findings

Introduction and Aim: Imaging evaluation of the rheumatoid arthritis and systemic sclerosis represents a significant part in disease evaluation and follow up. However, it had many limitations and new tools are introduced continuously. The current work aimed to compare ultrasound characteristics of the hand involvement in systemic sclerosis (SSc) and rheumatoid arthritis (RA).&#x0D; Patients and methods: The study included 30 SSc and 40 RA patients. All were evaluated by the full history taking, detailed clinical examination, disease activity scores and the health assessment questionnaires were completed. All necessary laboratory investigations were performed. Finally, radiological examination (plain X-rays and ultrasound for joints of hands and wrist) was performed.&#x0D; Results: Patient age ranged from 22 to 58 years, and RA patients were significantly older, with female sex predominance. SSc was of diffuse (30%) and (70%) were of limited type. The disease activity of RA ranged from 2 to 9, while disease activity of SSc ranged between 1.3 to 3.5. In the SSc group, 56.7% had active disease compared to 40% in RA groups. Patients in the SSc group had a degree of disability, while 82.5% of patients in the RA group had mild- to- moderate disability. Ultrasound examination revealed that, synovitis was significantly increased in RA when compared to the SSc group (55.0% vs 23.3%). The sclerosing pattern of tenosynovitis was significantly increased in SSc than the RA group (92.3% vs 0.0% respectively). Results of ultrasound completely coincides with results of MRI. Finally, there was statistically significant, moderate, proportional correlation between ultrasound and each of erythrocyte sedimentation rate (ESR), and disease activity scores.&#x0D; Conclusion: Ultrasound hand examination in scleroderma and RA is more accurate than separate clinical or X-ray examinations. However, it could not completely substitute clinical examination. But it is a suitable add on especially in detection of early disease activity.

68Ga]Ga-FAPI-46 PET for non-invasive detection of pulmonary fibrosis disease activity.

The lack of effective molecular biomarkers to monitor idiopathic pulmonary fibrosis (IPF) activity or treatment response remains an unmet clinical need. Herein, we determined the utility of fibroblast activation protein inhibitor for positron emission tomography (FAPI PET) imaging in a mouse model of pulmonary fibrosis. Pulmonary fibrosis was induced by intratracheal administration of bleomycin (1 U/kg) while intratracheal saline was administered to control mice. Subgroups from each cohort (n = 3-5) underwent dynamic 1h PET/CT after intravenously injecting FAPI-46 radiolabeled with gallium-68 ([68Ga]Ga-FAPI-46) at 7days and 14days following disease induction. Animals were sacrificed following imaging for ex vivo gamma counting and histologic correlation. [68Ga]Ga-FAPI-46 uptake was quantified and reported as percent injected activity per cc (%IA/cc) or percent injected activity (%IA). Lung CT density in Hounsfield units (HU) was also correlated with histologic examinations of lung fibrosis. CT only detected differences in the fibrotic response at 14days post-bleomycin administration. [68Ga]Ga-FAPI-46 lung uptake was significantly higher in the bleomycin group than in control subjects at 7days and 14days. Significantly (P = 0.0012) increased [68Ga]Ga-FAPI-46 lung uptake in the bleomycin groups at 14days (1.01 ± 0.12%IA/cc) vs. 7days (0.33 ± 0.09%IA/cc) at 60min post-injection of the tracer was observed. These findings were consistent with an increase in both fibrinogenesis and FAP expression as seen in histology. CT was unable to assess disease activity in a murine model of IPF. Conversely, FAPI PET detected both the presence and activity of lung fibrogenesis, making it a promising tool for assessing early disease activity and evaluating the efficacy of therapeutic interventions in lung fibrosis patients.

Diagnosis and Psychotherapeutic Needs by Early Maladaptive Schemas in Patients With Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is chronic and incurable. Imperious diarrhea, rectal bleeding, fatigue, and weight loss, the main manifestations, cause a decrease in the quality of the patient’s personal and professional life. The objectives of this study were to identify a possible relationship between early maladaptive schemas and disease activity status using logistic regression, to identify the prevalence of early maladaptive schemes in patients and to propose a psychotherapeutic intervention plan. The following were found in a sample of 46 patients aged 16–76 years. An increase in the domain overvigilance and inhibition score had a significant effect (Wald = 6.583, p = 0.010), with an increase of 1.137 CI95% [1.031, 1.254] of the risk of the disease being diagnosed as active. High and very high scores were observed for the emotional deprivation scheme (nearly three-quarters) and dependence/incompetence, vulnerability to harm and illness and subjugation schemas (over 80%). The results show that the proposed model could predict and reconfirm the diagnosis; patients have specific psychotherapeutic needs. The therapeutic goal would be to offer care, empathy and protection, to strengthen self-confidence, to make patients realize that they have the ability to cope, to provide permission, encourage the patient to experiment, and guide the patient to express their anger healthily. The therapy scheme’s intervention could lead to increased long-term disease management capacity and, consequently, reduce costs directly and indirectly caused by this condition.

Early treatment responses to peginterferon beta-1a are associated with longer-term clinical outcomes in patients with relapsing-remitting multiple sclerosis: Subgroup analyses of ADVANCE and ATTAIN

BackgroundEarly intervention with well-tolerated disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) is recommended in order to delay disease progression, reduce neurologic damage, preserve brain volume, and optimize long-term patient outcomes. Lack of conversion of new/newly enlarging T2 (NET2) or gadolinium-enhancing (Gd+) lesions to chronic hypointensities (black hole conversion) and achievement of no evidence of disease activity (NEDA) early in the course of treatment are considered potential indicators of treatment effect and predictors of longer-term clinical outcomes. MethodsPatients with RRMS who were treated with peginterferon beta-1a in the 2-year ADVANCE phase 3 clinical trial (NCT0090639) and its 2-year open-label extension study, ATTAIN (NCT01332019), were grouped as newly diagnosed (diagnosed ≤1 year prior to enrollment and DMT naive) or non–newly diagnosed. For analyses of the impact of early treatment and disease activity control, the newly diagnosed and non–newly diagnosed subgroups were further divided based on whether they initiated peginterferon beta-1a every 2 weeks (Q2W) starting in study year 1 (continuously treated) or peginterferon beta-1a Q2W or every 4 weeks in study year 2 (delayed treatment). Patient subgroups were evaluated for conversion of NET2 or Gd+ lesions to persistent black holes (PBHs), brain atrophy (percentage change in whole brain volume [WBV]), achievement of NEDA composite outcomes, and the association of these disease activity measures with longer-term clinical outcomes (annualized relapse rate [ARR] and confirmed disability worsening [CDW]). ResultsAt 2 years, significantly fewer PBHs developed from NET2 lesions or Gd+ lesions in newly diagnosed and non–newly diagnosed patients continuously treated with peginterferon beta-1a than in the corresponding delayed-treatment groups (all p<0.0001). Percentage decrease in WBV from 6 months (rebaselined) to 2 years was significantly lower for newly diagnosed and non–newly diagnosed patients who received continuous peginterferon beta-1a treatment than for patients who received delayed treatment (both p ≤ 0.0442). In study year 1, a higher proportion of newly diagnosed and non–newly diagnosed patients treated with peginterferon beta-1a than those treated with placebo achieved NEDA (newly diagnosed: 28.3% vs 13.5% [p = 0.0010]; non–newly diagnosed: 40.8% vs 15.8% [p<0.0001]). NEDA rates remained stable over study years 2–4 for the newly diagnosed (range: 50.0%–53.9%) and non–newly diagnosed (range: 54.4%–57.0%) subgroups. Patients without PBH conversion had significantly lower ARR at 2 years (newly diagnosed: p = 0.0109; non–newly diagnosed: p = 0.0044) and a lower proportion of patients with 12-week CDW at 2 years (newly diagnosed: p = 0.2787; non–newly diagnosed: p = 0.0045) than the corresponding patient subgroups with PBH conversion. Patients who achieved NEDA in ADVANCE (study years 1–2) had a significantly lower ARR in ATTAIN (study years 3–4) than patients who did not achieve NEDA (newly diagnosed, p = 0.0003; non–newly diagnosed, p = 0.0001). Over 4 years, safety outcomes did not differ for the newly diagnosed and non–newly diagnosed patient subgroups. ConclusionsThese results indicate that newly diagnosed and non–newly diagnosed patients treated continuously with peginterferon beta-1a Q2W experienced better disease control over time than those who received delayed treatment. Patients with NEDA or evidence of less radiological disease activity in the first 2 years of treatment had better longer-term clinical outcomes than those with evidence of greater disease activity.