Relapse Phase Research Articles

Alterations in peripheral blood monocyte and dendritic cell subset homeostasis in relapsing-remitting multiple sclerosis patients

Antigen-presenting cells participate and are implicated in the pathogenesis of multiple sclerosis. In our study we assessed the frequency of plasmacytoid (pDC) and myeloid (mDC) dendritic cells and the classical, intermediate and non-classical monocytes subsets, as well as their phenotypic and functional profile. We evaluated peripheral blood from relapsing-remitting patients treated with IFN-β in remission and relapse phases and from healthy subjects. In remission, we observed a decrease of mDC/pDC ratio and a return to normal values in relapse. In both phases the frequency of non-classical monocytes decreases. Concerning the phenotypic characterization, an increased HLA-DR expression was observed in remission and a decrease in relapse, revealing alterations in monocytes and dendritic cells homeostasis.

The Bone Marrow Microenvironment of Multiple Myeloma Long-Term Survivors at Single Cell Resolution

The Bone Marrow Microenvironment of Multiple Myeloma Long-Term Survivors at Single Cell Resolution

Increased Level of Caspase-1 in the Serum of Relapsing-remitting Multiple Sclerosis (RRMS) Patients.

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system, in which proinflammatory cytokines play a critical role in the pathogenic formation of lesions. Caspase-1 is a cysteine protease that proteolytically cleaves precursors of interleukin (IL)-18 and IL-1β and turns them into their active forms. These inflammatory cytokines play an important role in the development of MS. The aim of the present study was the investigation of caspase-1 and its downstream products, IL-18 and IL-1β, in relapsing-remitting MS (RRMS) patients. In this study, we used an ELISA assay to measure serum and cellular caspase-1 and serum levels of IL-18 and IL-1β in RRMS patients in the relapse phase (n=23) and healthy age-and gender-matched controls (n=19). We observed that the caspase-1 level was significantly increased in the serum of MS patients compared to the healthy controls (p=0.03). Although caspase-1 concentration in the lysate of peripheral blood mononuclear cells (PBMCs) was higher than serum among patients and controls (p<0.001), no significant difference was found in cellular levels of caspase-1 between the two groups. There was no significant difference in serum levels of IL-18 and IL-1β between patients and controls. In this study, we found an elevation of extracellular caspase-1, as a reflection of its intracellular level, in the serum of RRMS patients during the relapse phase. Therefore, it suggests being a suitable peripheral biomarker of disease activity in multiple sclerosis.

Evaluation of FOXP1 gene expression in pediatric B-cell precursor acute lymphoblastic leukemia patients at remission induction therapy

Background: Transcription factors (TFs) play a key role in the development, therapy, and relapse of B-cell malignancies, such as B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Given the essential function of Forkhead box protein P1 (FOXP1) transcription factor in the early development of B-cells, this study was designed to evaluate FOXP1 gene expression levels in pediatric BCP-ALL patients and NALM6 cell-line. Materials and Methods: This case-control study was done on the NALM6 cell-line and bone marrow specimens of 23 pediatric BCP-ALL patients (median age: 7.5 years; range: 2.0 – 15.0 years) at different clinical stages including new diagnosis, 15th day after the treatment, and relapse. Also, 10 healthy children were included as the control group. FOXP1 gene expression was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The correlation analysis was performed between the FOXP1 gene expression and patients’ demographic and laboratory characteristics. Results: The results showed that FOXP1 gene expression was significantly downregulated in the NALM-6 cell-line (median=0.05, P&lt;0.001) and patients at new diagnosis (median=0.06, p&lt;0.0001), and relapse (median=0.001, p&lt;0.0001) phases, compared to the control group (median=0.08). FOXP1 gene expression on the 15th day of the treatment was significantly higher than its level at the new diagnosis stage (p&lt;0.001). Moreover, FOXP1 gene was significantly downregulated in the relapse phase compared to the new diagnosis. Patients whose number of bone marrow blasts on the 15th day of the treatment was below 5% had higher FOXP1 gene expression at the diagnosis phase (Spearman’s correlation, P&lt;0.05, r=-0.485) and higher ratio of diagnosis/day 15 (p&lt;0.001, Mann-Whitney U test). Conclusions: FOXP1 levels could be a potential biomarker of therapy response in remission induction therapy for pediatric BCP-ALL patients.

RNA-Seq profiling of leukocytes reveals a sex-dependent global circular RNA upregulation in multiple sclerosis and 6 candidate biomarkers.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, with higher prevalence in women, that leads to neurological disability. The disease course and clinical phenotype are highly variable, and therefore, biomarkers for the diagnosis, classification, monitoring of the disease and treatment assessment are needed. Studies have shown a dysregulation in the coding and non-coding RNAs and proposed some as biomarkers. However, still none of them have reached the clinical practice. Recently, circular RNAs (circRNAs) have emerged as new players in the transcriptome that hold a great potential as biomarkers in several diseases. Leukocytes from 30 MS patients and 20 healthy controls (HCs) were RNA-sequenced to study the linear and circular transcriptome. Differential expression analysis was performed by DESeq, and circRNA candidates were studied in a second cohort (70 MS and 46 HC) by RT-qPCR and in paired samples drawn during the relapse and remission phases (20 patients). Among the differentially expressed circRNAs, 96.1% are upregulated in patients compared with controls, but similar circRNA profiles are found between MS types. The same upregulation trend was observed in females but not in males or in the linear transcriptome. The upregulation of 6 circRNAs was validated, and a change in their expression was found between relapse and remission. The 6 circRNAs showed a good performance to discriminate patients from HC with a combined area under the curve of 0.852. There is global, specific and sex-dependent increase of circRNA expression in MS, and 6 circRNAs are proposed as potential biomarkers.

CASE REPORT-NEUROMYELITIS OPTICA/ DEVIC'S DISEASE: A RARE DISEASE

Neuromyelitis Optica spectrum disorder or Devic’s disease are autoimmune diseases that manifest clinically with 6 core symptoms, which include acute optic neuritis, transverse longitudinal segment myelitis, and acute brainstem syndrome.{1}Neuromyelitis optica is characterized by attacks of optic neuritis and longitudinally extensive transverse myelitis. It is often confused with multiple sclerosis. Early discrimination between NMO and MS is important because the two diseases have different natural histories and treatment regimens. Despite the absence of a definitive therapeutic strategy for NMO syndrome, methylprednisolone pulse therapy is recommended in acute phase. Treatment strategies in relapse phases are aimed at preventing relapses, and increasing evidences show a better clinical response of immunosuppressive therapy than immunomodulating therapy. We report a case of NMSOD in a patient of age 55 , with transverse myelopathy as the initial manifestation. The patient presented with acute gait disturbance and hypoesthesia in right lower limb since 10 days . After thorough physical examination and various lab investigations and imaging, the patient received high dose methylprednisolone. The patient’s serum was positive for anti-AQP4 antibodies .During the course of treatment , patient again presented with complaint of blurred vision in the ER after 1 year. Diagnosis of NMSOD was established. After combining methylprednisolone and immunosuppressant therapy , the patient’s medical condition was stable and relapses were prevented.

Abstract 2682: Extrafollicular high CD163/CD8 ratio is associated with progression of disease within 24 months in follicular lymphoma patients

Abstract Follicular lymphoma (FL) still remains an incurable disease, with most of the patients undergoing subsequent phases of remission and relapse. In the era of immunotherapy, understanding the immunobiology of FL patients who experience progression of disease within 24 months (POD24) and show chemotherapy resistance remains a priority and an unmet clinical need. Tumor-associated macrophages (TAM) are multifaceted cellular components of the tumor microenvironment (TME). In concert with lymphoid-lineage B and T cells at various developmental stages, TAM can mediate enhanced tumor progression, often leading to poor clinical prognosis and impact the clinical response to chemotherapy. Recently, Joshua and colleagues demonstrated that a subset of FL patients with low immune infiltration was enriched in POD24 events. In our work, we characterized the immune repertoire of lymph node biopsies collected retrospectively from 30 patients with histological diagnosis of FL according WHO criteria. Median follow up was 8 years. The expression levels of TAM (CD68, CD163, MS4a4a) and tumor-infiltrating T-lymphocytes (CD8, PD-1 positive subsets) were assessed by immunohistochemistry and summarized using descriptive statistics. Our data highlighted that the subset of patients with a high extrafollicular CD163/CD8 ratio was enriched in POD24 events (p = 0.01). In addition, patients who showed an higher number of intrafollicular CD68+ macrophages, showed a longer disease free survival (p= 0.04). Another difference was related to the number of CD68, CD163, MS4A4A-positive polarized macrophages that resulted higher in bcl-2 negative than bcl-2 positive cases (p&amp;lt; 0.05 for all markers). In the evaluation of T lymphocytes, most relevant associations were found between the content and distribution of PD1+ cells and the treatment response: the higher the number of intrafollicular PD1+ lymphocytes the lower chemotherapy response rates (p= 0.04). No association was found between the number of positive elements in extrafollicular areas, where instead the PD1/CD8 ratio seems to be related with therapy response: the higher the ratio the lower response rate (p= 0.01). This finding could be explained assuming that there may be different types of cellular interactions inside and outside the neoplastic follicles. No other statistically significant difference in terms of expression of these markers was observed in relation to clinical pathological features such as staging, grade and FLIPI score. In conclusion, extrafollicular high CD163/CD8 ratio is associated with POD24 in FL patients, this finding underlines the pathological significance of CD163-expresing macrophages in TME, suggesting this biomarker as a potential therapeutic target in this disease. Citation Format: Clara Bertuzzi, Maria Maddalena Tumedei, Sara Ravaioli, Claudio Agostinelli, Maurizio Puccetti, Sara Bravaccini, Simona Righi, Beatrice Casadei, Andrea Pession, Giovanni Martinelli, Giorgia Simonetti, Elena Sabattini, Serena De Matteis. Extrafollicular high CD163/CD8 ratio is associated with progression of disease within 24 months in follicular lymphoma patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2682.

Induction of a Timed Metabolic Collapse to Overcome Cancer Chemoresistance

Cancer relapse begins when malignant cells pass through the extreme metabolic bottleneck of stress from chemotherapy and the byproducts of the massive cell death in the surrounding region. In acute myeloid leukemia, complete remissions are common, but few are cured. We tracked leukemia cells invivo, defined the moment of maximal response following chemotherapy, captured persisting cells, and conducted unbiased metabolomics, revealing a metabolite profile distinct from the pre-chemo growth or post-chemo relapse phase. Persisting cells used glutamine in a distinctive manner, preferentially fueling pyrimidine and glutathione generation, but not the mitochondrial tricarboxylic acid cycle. Notably, malignant cell pyrimidine synthesis also required aspartate provided by specific bone marrow stromal cells. Blunting glutamine metabolism or pyrimidine synthesis selected against residual leukemia-initiating cells and improved survival in leukemia mouse models and patient-derived xenografts. We propose that timed cell-intrinsic or niche-focused metabolic disruption can exploit a transient vulnerability and induce metabolic collapse in cancer cells to overcome chemoresistance.

Audiovestibular symptoms in patients with multiple sclerosis: A correlation between self-reported symptomatology and MRI findings to monitor disease progression

BackgroundsThe interest about audiovestibular symptoms in patients with multiple sclerosis (MS) is recently growing. However, these symptoms can be often underestimated by patients. We aim to evaluate the presence of audiovestibular symptoms in patients with MS as reported by themselves and correlate these symptoms with the different phases of MS. Audiovestibular symptoms, if correlated with relapsing phase could be an indicator of disease progression. MethodsIn this prospective study 80 patients with MS were screened for the presence of audiovestibular symptoms, during their first neurological consultation, using a self-administered questionnaire developed by our research team. Magnetic Resonance Imaging (MRI) scans were performed within a week from the consultation and were compared with scan performed 12-month before, looking for the presence of new active lesions or enlargement of the ones already present. Data on the year of diagnosis, symptom onset, treatment history and expanded disability status scale (EDSS) were collected. Statistical analysis was performed to identify a correlation between audiovestibular symptoms and active lesions in MRI scan. Odds ratio were calculated. Results75% of patients reported audiovestibular symptoms and 37.5% of them had an active or enlarged (compared with previous MRI) lesion/s in their brain MRI scan when they referred to the symptoms’ presence. Active lesion/s in MRI were positively correlated with the presence of audiovestibular symptoms (p = 0.0009). Based on our analysis, patients with active lesions had an increased risk of developing audiovestibular symptoms compared to patients with enlarged but non-active lesions (odds ratio: 4.7). Lesions in the cortex rather than in the medulla (odds ratio: 0.6) or optic nerve (odds ratio:1.6), were more common in patients that developed audiovestibular symptoms. Patients with supratentorial active lesions were more at risk to present audiological symptoms than subjects with the infratentorial lesions (odds ratio: 1.3). ConclusionsAudio-vestibular symptoms can arise in the relapsing phases of MS and their presence may be correlated with an active lesion in the brain. The self-administered questionnaire can be useful both for patients and physicians, to early identify the presence of audiovestibular symptoms that might be related to the progression of the disease.

Identification of markers of relapse in EAE using high-resolution quantitative mass spectrometry

Abstract Approximately 85 percent of individuals newly diagnosed with multiple sclerosis have the relapsing-remitting form of the disease characterized by attacks of neurologic symptoms that are unpredictable in occurrence and duration. Currently there are no clinically available biomarkers predictive of relapse. To address this need, we investigated CNS proteome changes over the disease course of relapsing-remitting experimental autoimmune encephalomyelitis (EAE) in SJL mice as a preclinical model of the disease. Using a high-throughput quantitative preparation technique and high-resolution Bruker timsTOF mass spectrometry, we were able to identify thousands of unique proteins at each disease timepoint. Principal component analysis of protein expression confirmed that the remission and relapse phases of disease cluster independently, indicating distinguishable variation in protein expression profiles between the two disease states. Importantly, statistical testing identified proteins with differential expression in the CNS at different stages of disease, several of which are CNS specific. We are seeking to detect corollary changes in these CNS-specific proteins in the serum, pointing to a minimally invasive means of monitoring disease progress and measuring drug efficacy. Our study will validate homologous human biomarkers to guide treatment in individual patients and allow for proactive therapeutic intervention. Furthermore, our results may provide insights into mechanisms that contribute to disease pathology and offer novel therapeutic targets.

Raloxifene administration enhances retention in an orthodontic relapse model.

Orthodontic relapse is a physiologic process that involves remodelling of the alveolar bone and principle periodontal ligament fibres. Raloxifene is an Food and Drug Administration (FDA)-approved selective oestrogen receptor modulator that inhibits systemic bone loss. In our study, we examined the effects of Raloxifene on alveolar bone modelling and orthodontic relapse in a rodent model. The efficacy of raloxifene was evaluated in 15-week-old male Wistar rats, 8 in each group (Control, Raloxifene, Raloxifene + 7-day relapse, Raloxifene + 14-day relapse) for a total of 42 days. All animals had 14 days of orthodontic tooth movement with a closed nickel-titanium coil spring tied from incisors to right first molar applying 5-8 gm of force. On the day of appliance removal, impression was taken with silicon material and the distance between first molar and second molar was filled with light-cured adhesive resin cement for retention phase. Raloxifene Retention, Raloxifene Retention + 7D, Raloxifene Retention + 14D groups received 14 daily doses of raloxifene (2.0 mg/kg/day) subcutaneously after orthodontic tooth movement during retention. After 14 days of retention, the retainer was removed and right first molar was allowed to relapse for a period of 14 days. Raloxifene injection continued for the Raloxifene + 14-day relapse group during relapse phase too. Control group received saline injections during retention. Animals were euthanized by CO2 inhalation. The outcome measure included percentage of relapse, bone volume fraction, tissue density, and histology analysis using tartrate-resistant acid phosphatase staining and determining receptor activator of nuclear factor-кB-ligand (RANKL) and osteoprotegerin expression. Raloxifene Retention + 14D group had significantly less (P < 0.05) orthodontic relapse when compared with other groups. There was a significant increase (P < 0.05) in bone volume fraction and tissue density in the Raloxifene Retention + 14D group when compared with other groups. Similarly, there was significant decrease in number of osteoclasts and RANKL expression in Raloxifene Retention + 14D group when compared with Raloxifene Retention + 7D group (P < 0.05). Raloxifene could decrease post-orthodontic treatment relapse by decreasing bone resorption and indirectly enhancing bone formation.

Glucocorticoid-Induced Leucine Zipper as a Druggable Target in Inflammatory Bowel Diseases.

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex pathogenesis, affecting people of all ages. They are characterized by alternating phases of clinical relapse and remission, depending on the fine balance between immune cells and the gut microbiota. The cross talk between cells of the immune system and the gut microbiota can result in either tolerance or inflammation, according to multifactorial triggers, ranging from environmental factors to genetic susceptibility. Glucocorticoid (GC) administration remains the first-line treatment for IBDs, although long-term use is limited by development of serious adverse effects. Recently, new alternative pharmacological therapies have been developed, although these are not always effective in IBD patients. There is a constant demand for effective new drug targets to guarantee total remission and improve the quality of life for IBD patients. The glucocorticoid-induced leucine zipper (GILZ) has been implicated as a promising candidate for this purpose, in view of its powerful anti-inflammatory effects that mimic those of GCs while avoiding their unwanted adverse reactions. Here we present and discuss the latest findings about the involvement of GILZ in IBDs.

Clinical implications of oxidative stress in schizophrenia: Acute relapse and chronic stable phase

Several studies have suggested a higher oxidative stress in schizophrenia. However, the implications of oxidative stress on clinical symptoms remain unclear. This study aimed to investigate the platelet oxidative stress in different stages of schizophrenia (i.e., chronic stable and acute relapse) in order to clarify the clinical implications of oxidative stress and the treatment effects. We recruited 43 chronic stable patients with schizophrenia and 48 non-psychiatric controls. Platelets were collected for measuring the levels of nitric oxide (NO), lipid peroxidation (LPO), and glutathione (GSH) and the activity of GSH peroxidase (GPx) and superoxide dismutase (SOD). The levels and activity were compared between patients and controls and were examined for their relationship with clinical severity. Further, we evaluated the changes of levels and activity before and after treatment in an independent sample with acute relapse (N = 19). Patients with chronic stable schizophrenia had lower SOD activity compared to non-psychiatric controls. In chronic stable patients, NO level was positively correlated with positive and disorganized symptoms, while the GPx activity were negatively correlated with excitement. In patients with acute relapse, the levels and activity were not different before and after four weeks of antipsychotic treatment, but LPO level was negatively correlated with pretreatment disorganized symptoms. The change of LPO can also predict the change of disorganized symptoms and negative symptoms. Our findings suggest that platelet SOD was lower in chronic stable schizophrenia. Platelet LPO may be associated with less disorganized symptoms in acute relapse patients and better treatment response.

Induction of a Timed Metabolic Collapse to Overcome Cancer Chemoresistance

Cancer relapse begins at the moment malignant cells pass through the extreme metabolic bottleneck of stress from chemotherapy and the by-products of massive surrounding cell death. In acute myeloid leukemia (AML), complete remissions are common, but few are cured. We tracked AML cells in vivo, defined the moment of maximal response following chemotherapy, captured persisting cells and conducted unbiased metabolic analysis, revealing a metabolite profile distinct from the pre-chemo growth or post-chemo relapse phase. Persisting cells used glutamine in a distinctive manner, preferentially fueling pyrimidine synthesis and glutathione generation, but not oxidative phosphorylation. Notably, malignant cell pyrimidine synthesis also required aspartate provided by specific bone marrow stromal cells. Blunting glutamine metabolism or pyrimidine synthesis selected against residual cells and improved survival in AML mouse models. We propose that timed cell-intrinsic or niche-focused metabolic disruption can exploit a transient vulnerability and induce a metabolic collapse in cancer cells to overcome chemoresistance.

Initial and relapse prodromes in adult patients with episodes of bipolar disorder: A systematic review.

Distinguishing prodromes of bipolar disorder (BD) specific to children/adolescents, adults, and elderly patients is essential. The primary objective of this systematic review was to determine initial and relapse prodromes identifying adult patients with BD. PubMed, PsycINFO, and Web of Science databases were searched using a predetermined strategy. A controlled process of study selection and data extraction was performed. The 22 articles selected included 1,809 adult patients with BD. Initial prodromes cited most frequently in these studies showed low specificity. Among relapse prodromes cited most frequently, more talkative than usual, increased energy/more goal-directed behavior, thoughts start to race, increased self-esteem, strong interest in sex, increase in activity, and spending too much were identified exclusively before a manic/hypomanic episode, while loss of interest and hypersomnia were detected only before a depressive episode. Initial prodromal phases lasted longer than prodromal relapse phases. In the selected studies, the most used prodrome identification procedure was the clinical interview. For adult patients with BD, initial and relapse prodromes of manic, hypomanic, and depressive episodes were identified. It is proposed that the most frequent prodromes found in this review be incorporated into a smartphone app that monitors the functioning of people at risk of BD and patients who have already been diagnosed. Data from this app would constitute a relevant source of big data.

Influencia de los factores psicosociales en la enfermedad de Crohn

Objetivo: Conocer la influencia de los factores psicosociales en la enfermedad de Crohn. Metodología: Se utilizó la Escala de Estrés Percibido, la Escala de Apoyo Social Percibido y la Escala Multidimensional de Locus de Control. Se recopilaron los datos de pacientes con enfermedad de Crohn – en fase de brote y quiescencia - y sanos. Los niveles de estos factores se compararon para conocer su impacto en la enfermedad de Crohn. Resultados: Diferencias estadísticamente significativas se encontraron en las tres variables en los grupos. Los pacientes con enfermedad de Crohn en fase de brote percibieron los niveles de estrés más altos. Los pacientes con enfermedad de Crohn que estaban en fase de recidiva presentaron los mayores niveles de apoyo social, identificándose el efecto modulador que tiene esta variable sobre el estrés. Y, por último, los pacientes con enfermedad de Crohn con brote presentaron mayor nivel de locus de control externo. Conclusión: Son necesarias intervenciones enfermeras en la enfermedad de Crohn relacionadas con mayor manejo del estrés, aumento del apoyo social y disminución del locus de control externo.

Arpp19 Promotes Myc and Cip2a Expression and Associates with Patient Relapse in Acute Myeloid Leukemia.

Disease relapse from standard chemotherapy in acute myeloid leukemia (AML) is poorly understood. The importance of protein phosphatase 2A (PP2A) as an AML tumor suppressor is emerging. Therefore, here, we examined the potential role of endogenous PP2A inhibitor proteins as biomarkers predicting AML relapse in a standard patient population by using three independent patient materials: cohort1 (n = 80), cohort2 (n = 48) and The Cancer Genome Atlas Acute Myeloid Leukemia (TCGA LAML) dataset (n = 160). Out of the examined PP2A inhibitors (CIP2A, SET, PME1, ARPP19 and TIPRL), expression of ARPP19 mRNA was found to be independent of the current AML risk classification. Functionally, ARPP19 promoted AML cell viability and expression of oncoproteins MYC, CDK1, and CIP2A. Clinically, ARPP19 mRNA expression was significantly lower at diagnosis (p = 0.035) in patients whose disease did not relapse after standard chemotherapy. ARPP19 was an independent predictor for relapse both in univariable (p = 0.007) and in multivariable analyses (p = 0.0001) and gave additive information to EVI1 expression and risk group status (additive effect, p = 0.005). Low ARPP19 expression was also associated with better patient outcome in the TCGA LAML cohort (p = 0.019). In addition, in matched patient samples from diagnosis, remission and relapse phases, ARPP19 expression was associated with disease activity (p = 0.034), indicating its potential usefulness as a minimal residual disease (MRD) marker. Together, these data demonstrate the oncogenic function of ARPP19 in AML and its risk group independent role in predicting AML patient relapse tendency.

PMH23 A RETROSPECTIVE CHART REVIEW STUDY TO QUANTIFY THE MONTHLY MEDICAL RESOURCE USE AND COSTS OF TREATING PATIENTS WITH TREATMENT RESISTANT DEPRESSION IN THE UNITED KINGDOM

Treatment-Resistant Depression (TRD), defined as Major Depressive Disorder (MDD) patients who didn’t respond to two successive oral antidepressants of adequate dose/duration. Despite the high level of TRD disease burden, the health care resource utilization (HCRU) and cost of TRD to healthcare systems is unknown. Understanding where intervention is required can inform healthcare systems how to manage patients/resource accordingly, particularly when considering the patient health state. We aimed to quantify monthly HCRU costs of TRD patients, per TRD health states, from the UK healthcare system perspective. A retrospective medical chart review of 295 adult TRD patients in the UK classified as TRD between 1st Jan 2016 – 31st May 2016 with data abstracted up to 31st May 2018 on patient demographics, clinical characteristics, HCRU (primary/secondary care, non-drug and drug interventions for depression, hospitalizations). Costs were split by health states using pooled averages where a state occurred multiple times; Major Depressive Episode (MDE), remission, recovery. MDE costs are the pooled costs collected during the relapse phase and the initial MDE phase. Analyses were descriptive and unit costs derived from the “Unit Costs of Health and Social Care 2017” and British National Formulary. Means [95% CI] are presented for two cost parameters, 1) overall HCRU cost 2) overall HCRU cost minus drug treatment cost. On average, patients were 43.34 years old, 60% female, 26% in full/part-time employment, 75% had ≥1 comorbidity. Monthly HCRU costs for MDE were (£991.82 [£775.14, 1208.50]) which reduced at remission (£254.30 [£187.13, 321.46]) and recovery (£98.85 [£65.51, 132.19]). Monthly HCRU costs, minus drug treatment costs, for MDE were (£980.08 [£761.48, 1198.67]) which reduced at remission (£164.46 [£102.81, 226.11]) and recovery (£83.75 [£47.97, 119.53]). These data demonstrate a high monthly cost associated with TRD, especially during MDE health state, highlighting the need for more cost-effective interventions which prevent wider HCRU.

Analysis of intestinal immunity and flora in a collagen-induced mouse arthritis model: differences during arthritis progression.

Intestinal immunity and flora are reported to be associated with the onset of rheumatoid arthritis. However, differences in the intestinal immunity and flora dynamics between the initial peak and relapse of arthritis have not been investigated. Here we analyzed the lymphocyte populations in different lymphoid tissues, the IgA in feces, and the intestinal flora at the initial peak and the relapse phase of arthritis in a collagen-induced arthritis (CIA) mouse model. In this model compared with the control group, the percentage of RORγt+CD4+ T cells in the mesenteric lymph nodes (mLN) was increased at the initial peak but decreased at the relapse stage of arthritis, and the opposite changes were observed in the spleen. The percentage of Foxp3+CD4+ T cells was unchanged at the initial peak in both tissues but increased only in the mLN at the relapse stage. The IgA in feces increased with the progression of arthritis, and bacterial analysis revealed that some specific bacterial families were changed at the peak and relapse stages of arthritis. Finally, the immune dynamics under different arthritic conditions were examined by integrating these factors using principal component analysis (PCA). PCA showed that the immunological and intestinal flora profiles were different between the initial peak and the relapse of the arthritis. Our findings suggest that the intestinal immunity and the environment change drastically with the progress of arthritis.

The imbalance between regulatory and memory B cells accompanied by an increased number of circulating T-follicular helper cells in MOG–antibody-associated demyelination

ObjectiveTo explore the alteration of T and B lymphocyte subsets proportions in myelin oligodendrocyte glycoprotein (MOG)-antibody-associated demyelination. Methods19 MOG-antibody-positive, 25 AQP4-antibody-positive and 25 double-negative NMOSD patients in the acute phase of the diseases were included in the study, as well as 29 healthy controls. The frequencies of different lymphocyte subsets, including CD19+CD27+ memory B cells, CD19+CD24hiCD38hi, and CD19+CD5+CD1dhi regulatory B cells, IFN-γexpressing B cells, IL-10 expressing B cells and CD4+CXCR5+ICOS+T-follicular helper cells (TFH) were measured via flow cytometry and compared among the four groups. ResultsThe frequencies of CD19+CD24hiCD38hi, CD19+CD5+CD1dhi regulatory B cells as well as the IL-10 expressing B cells were significantly lower in the MOG-antibody-associated demyelination compared to the healthy controls, whereas the frequencies of CD19+CD27+ memory B cells were significantly higher in the MOG-antibody-positive group. The frequencies of TFH were significantly higher in the MOG-antibody-positive group as compared to the healthy controls. No significant difference was detected in the above mentioned lymphocytic profile between the MOG-antibody-positive and the AQP4-antibody-positive groups. ConclusionsThe immuno-regulatory functions of B cells were significantly impaired whereas TFH cells were markedly increased in the acute phase of MOG-antibody-associated demyelination. Despite having distinct clinical features, MOG-antibody-associated demyelination shared a similar lymphocytic profile with AQP4-antibody-positive NMOSD in the acute relapse phase.