Explore the vast range of titles available.

Graft versus host disease (GvHD) is the clinical condition in which bone marrow-derived mesenchymal stromal cells (MSCs) have been most frequently studied. In this review, we summarize the experience from clinical trials that have paved the way to translation. While MSC-based therapy has shown an exceptional safety profile, identifying potency assays and disease biomarkers that reliably predict the capacity of a specific MSC batch to alleviate GvHD has been difficult. As GvHD diagnosis and staging are based solely on clinical criteria, individual patients recruited in the same clinical trial may have vastly different underlying biology, obscuring trial outcomes and making it difficult to determine the benefit of MSCs in subgroups of patients. An accumulating body of evidence indicates the importance of considering not only the cell product but also patient-specific biomarkers and/or immune characteristics in determining MSC responsiveness. A mode of action where intravascular MSC destruction is followed by monocyte-efferocytosis-mediated skewing of the immune repertoire in a permissive inflammatory environment would both explain why cell engraftment is irrelevant for MSC efficacy and stress the importance of biologic differences between responding and nonresponding patients. We recommend a combined analysis of clinical outcomes and both biomarkers of disease activity and MSC potency assays to identify patients with GvHD who are likely to benefit from MSC therapy.

Using a philosophical approach or deductive reasoning, we challenge the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central nervous system (CNS). We provide a range of evidence to argue that the ‘real MS’ is in fact driven primarily by a smouldering pathological disease process. In natural history studies and clinical trials, relapses and focal activity revealed by magnetic resonance imaging (MRI) in MS patients on placebo or on disease-modifying therapies (DMTs) were found to be poor predictors of long-term disease evolution and were dissociated from disability outcomes. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. Many putative pathological drivers of smouldering MS can be potentially modified by specific therapeutic strategies, an approach that may have major implications for the management of MS patients. We hypothesise that therapeutically targeting a state of ‘no evident inflammatory disease activity’ (NEIDA) cannot sufficiently prevent disability accumulation in MS, meaning that treatment should also focus on other brain and spinal cord pathological processes contributing to the slow loss of neurological function. This should also be complemented with a holistic approach to the management of other systemic disease processes that have been shown to worsen MS outcomes.

Background: Levels of CXCL13, a potent B-cell chemoattractant, are elevated in the cerebrospinal fluid (CSF) during multiple sclerosis (MS) and are associated with markers of MS activity. Levels decrease upon effective treatments. Objective: Here we validate the potential role of CSF CXCL13 as a biomarker for aspects of MS in a large amount of clinical material, the majority collected at early diagnostic work-up. Methods: CXCL13 was measured by ELISA in 837 subjects: relapsing–remitting MS (RRMS; n = 323), secondary progressive MS (SPMS; n = 40), primary progressive MS (PPMS; n = 24), clinically isolated syndrome (CIS; n = 79), other neurological diseases (ONDs; n = 181), ONDs with signs of inflammation or viral/bacterial infections (iONDs; n = 176) and healthy controls (n = 14). Results: Subjects with viral/bacterial infections had extremely high CXCL13 levels compared to all included groups (p < 0.0001). CXCL13 was otherwise significantly higher in MS compared to the remaining controls (p < 0.0001), and CIS (p < 0.01). A significant and positive correlation between CXCL13 and relapse rate, the results obtained for the Expanded Disability Status Scale (EDSS) and the number of lesions detected by MRI was demonstrated. CXCL13 was increased in CIS conversion to clinically definite MS (p < 0.001). Oligoclonal immunoglobulin band (OCB)-positive CIS or MS had significantly increased CXCL13 levels compared to OCB-negative CIS or MS (p < 0.001 and p < 0.0001, respectively). Conclusion: CXCL13 was associated with disease exacerbations and unfavourable prognosis in RRMS. Increased CXCL13 was not specific for MS since subjects with viral/bacterial infections exhibited even higher levels. High levels predicted CIS conversion to MS. We suggest that measurement of CSF CXCL13 can be part of the armamentarium in the diagnostic and prognostic work-up in MS and be of help in future treatment decisions.

Neurological manifestations in patients with COVID-19 have been reported previously as outcomes of the infection. The purpose of current study was to investigate the occurrence of neurological signs and symptoms in COVID-19 patients, in the county of Östergötland in southeastern Sweden. This is a retrospective, observational cohort study. Data were collected between March 2020 and June 2020. Information was extracted from medical records by a trained research assistant and physician and all data were validated by a senior neurologist. Seventy-four percent of patients developed at least one neurological symptom during the acute phase of the infection. Headache (43%) was the most common neurological symptom, followed by anosmia and/or ageusia (33%), confusion (28%), hallucinations (17%), dizziness (16%), sleep disorders in terms of insomnia and OSAS (Obstructive Sleep Apnea) (9%), myopathy and neuropathy (8%) and numbness and tingling (5%). Patients treated in the ICU had a higher male presentation (73%). Several risk factors in terms of co-morbidities, were identified. Hypertension (54.5%), depression and anxiety (51%), sleep disorders in terms of insomnia and OSAS (30%), cardiovascular morbidity (28%), autoimmune diseases (25%), chronic lung diseases (24%) and diabetes mellitus type 2 (23%) founded as possible risk factors. Neurological symptoms were found in the vast majority (74%) of the patients. Accordingly, attention to neurological, mental and sleep disturbances is warranted with involvement of neurological expertise, in order to avoid further complications and long-term neurological effect of COVID-19. Furthermore, risk factors for more severe COVID-19, in terms of possible co-morbidities that identified in this study should get appropriate attention to optimizing treatment strategies in COVID-19 patients.

Mesenchymal stromal cell (MSC) therapy is a promising tool in the treatment of chronic inflammatory diseases. This has been ascribed to the capacity of MSC to release a large variety of immune-modulatory factors. However, all aspects of the mode of therapeutic MSC action in different diseases remain unresolved, mainly because most of the infused MSC are undetectable in the circulation within hours after infusion. The aim of this study was to elucidate the fate of MSC after contact with plasma. We found that upon contact with blood, complement proteins including C3b/iC3b are deposited on MSC. Importantly, we also found that complement bound to MSC enhanced their phagocytosis by classical and intermediate monocytes via a mechanism that involves C3 but not C5. Thus, we describe for the first time a mechanism which might explain, at least partly, why MSC are not found in the blood circulation after infusion. Our results indicate that MSC immune-modulatory effects could be mediated by monocytes that have phagocytosed them.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system involving dysregulated encephalitogenic T cells. Myeloid‐derived suppressor cells (MDSCs) have been recognized for their important function in regulating T‐cell responses. Recent studies have indicated a role for MDSCs in autoimmune diseases, but their significance in MS is not clear. Here, we assessed the frequencies of CD14+HLA‐DRlow monocytic MDSCs (Mo‐MDSCs) and CD33+CD15+CD11b+HLA‐DRlow granulocytic MDSCs (Gr‐MDSCs) and investigated phenotypic and functional differences of Mo‐MDSCs at different clinical stages of MS and in healthy subjects (HC). Increased frequencies of Mo‐MDSCs (P < 0.05) and Gr‐MDSCs (P < 0.05) were observed in relapsing‐remitting MS patients during relapse (RRMS‐relapse) compared to stable RRMS (RRMS‐rem). Secondary progressive MS (SPMS) patients displayed a decreased frequency of Mo‐MDSCs and Gr‐MDSCs compared to HC (P < 0.05). Mo‐MDSCs within RRMS patients expressed significantly higher cell surface protein levels of CD86 and CD163 compared to SPMS patients. Mo‐MDSCs within SPMS exhibited decreased mRNA expression of interleukin‐10 and heme oxygenase 1 compared to RRMS and HC. Analysis of T‐cell regulatory function of Mo‐MDSCs demonstrated T‐cell suppressive capacity in RRMS and HCs, while Mo‐MDSCs of SPMS promoted autologous T‐cell proliferation, which aligned with a differential cytokine profile compared to RRMS and HCs. This study is the first to show phenotypic and functional shifts of MDSCs between clinical stages of MS, suggesting a role for MDSCs as a therapeutic target to prevent MS disease progression. This study demonstrated alterations in numbers of myeloid‐derived suppressor cells (MDSCs) during progression of the disease course of multiple sclerosis (MS). We also showed phenotypic and functional shifts of MDSCs between clinical stages of MS, suggesting a role for MDSCs as a therapeutic target to prevent MS disease progression.

Acute hemorrhagic encephalomyelitis (AHEM) is a rare hyperacute form of acute disseminated encephalomyelitis (ADEM). The disease is characterized by fulminant inflammation and demyelination in the brain and spinal cord and is often preceded by an infection or vaccination. This case report presents a 53-year-old male with rheumatoid arthritis and ongoing treatment with methotrexate and etanercept who developed fatal AHEM following the second dose of the COVID-19 vaccine. The disease course was complicated by multiorgan thromboembolic disease and the presence of high/moderate levels of cardiolipin IgG antibodies and anti-beta-2 glycoprotein 1 IgG antibodies suggesting a possible antiphospholipid syndrome. Treatment with immunosuppressive therapies failed to improve the course. The report comprises comprehensive clinical, neuroimaging, and neuropathological findings. The case highlights diagnostic challenges in a patient with several preceding risk factors, including autoimmune disease, immunotherapy, and vaccination, with possible pathophysiological implications. The temporal association with the COVID-19 vaccination may suggest possible causality although evidence cannot be ascertained. Reporting possible adverse events following COVID-19 vaccination is important to identify at-risk populations and to accomplish control of the current pandemic.

ObjectiveThe management of neuropsychiatric (NP) systemic lupus erythematosus (SLE) is poorly optimised and specific treatment is lacking. The aim of this study was to perform an in-depth investigation of the transcriptome of SLE patients with active central nervous system (CNS) involvement to gain insights into underlying molecular mechanisms and identify new potential drug targets for CNS lupus.MethodsWe analysed differentially expressed genes in peripheral blood from patients with active CNS lupus (n=26) and active non-NP SLE (n=43) versus healthy controls (n=497) from the European PRECISESADS project (NTC02890121), as well as dysregulated gene modules. Gene modules were subjected to correlation analyses with serological markers, and regulatory network and druggability analysis.ResultsUnsupervised co-expression network analysis revealed 23 dysregulated gene modules (figure 1A). Four showed differential dysregulation between two distinct subgroups of CNS lupus patients. The interferon module was upregulated in both subgroups. The ‘B cell’, ‘T cell’, ‘cytotoxic/NK cell’, and ‘mitochondrial cluster’ gene modules were all found to be more downregulated in one subgroup, while the other subgroup showed varied dysregulation patterns. Drugs annotated to the cytotoxic/NK cell network included pegaptanib, a selective vascular endothelial growth factor (VEGF) antagonist, while many anticonvulsants such as zonisamide, lamotrigine, and oxcarbazepine showed potential for counteracting the transcriptomic signature associated with the B cell module. Druggability analysis for the mitochondrial cluster module revealed potential for the centrally acting angiotensin-converting enzyme inhibitor captopril, the mammalian target of rapamycin (mTOR) inhibitor everolimus, the proteasome inhibitor bortezomib, the toll-like receptor 5 (TLR5) agonist entolimod, and the spleen tyrosine kinase (SYK) inhibitor fostamatinib. In silico prediction algorithms demonstrated a greater anticipated response to anifrolumab and calcineurin inhibitors for the active CNS subgroup with B cell, T cell, cytotoxic/NK cell, and mitochondrial gene downregulation compared with the patient subgroup of mixed dysregulation patterns (figure 1B).ConclusionIn this cohort of SLE patients of European origin, B cell, T cell, cytotoxic/NK cell, and mitochondrial gene dysregulation patterns separated active CNS lupus patients into two distinct subgroups with differential anticipated response to type I interferon and calcineurin inhibition. Our study provides a conceptual framework for precision medicine in CNS lupus.Conflicts of interestIP has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia, Bristol Myers Squibb, Elli Lilly, Gilead, GlaxoSmithKline, Janssen, Novartis, Otsuka, and Roche. The other authors declare that they have no conflicts of interest related to this work.The funders had no role in the design of the study, the analyses or interpretation of data, or the writing of the manuscript.Abstract O15 Figure 1B cell, T cell, cytotoxic/NK cell, and mitochondrial gene dysregulation patterns separate patients with active CNS lupus into two distinct subgroups with differential anticipated response to targeted therapies. (A) Heatmap displaying the 23 dysregulated gene modules, grouping the patients into two main subgroups Subgroup 1 was characterised by a more prominent downregulation of the B cell, T cell, cytotoxic/NK cell, and mitochondrial gene modules. Subgroup 2 showed mixed dysregulation patterns. Red colour denote upregulated gene modules and blue colour downregulated gene modules compared to healthy controls. (B) Bars depicting proportions of patients with an anticipated benefit from inhibition of selected drug targets between the two active CNS lupus patient subgroups.

Most patients with relapsing-remitting multiple sclerosis (RRMS) eventually enter a secondary progressive (SPMS) phase, characterized by increasing neurological disability. The mechanisms underlying transition to SPMS are unknown and effective treatments and biomarkers are lacking. Vascular endothelial growth factor-A (VEGF-A) is an angiogenic factor with neuroprotective effects that has been associated with neurodegenerative diseases. SPMS has a prominent neurodegenerative facet and we investigated a possible role for VEGF-A during transition from RRMS to SPMS. VEGF-A mRNA expression in peripheral blood mononuclear (PBMC) and cerebrospinal fluid (CSF) cells from RRMS (n = 128), SPMS (n = 55) and controls (n = 116) were analyzed using real time PCR. We demonstrate reduced expression of VEGF-A mRNA in MS CSF cells compared to controls (p<0.001) irrespective of disease course and expression levels are restored by natalizumab treatment(p<0.001). VEGF-A was primarily expressed in monocytes and our CSF findings in part may be explained by effects on relative monocyte proportions. However, VEGF-A mRNA expression was also down regulated in the peripheral compartment of SPMS (p<0.001), despite unchanged monocyte counts, demonstrating a particular phenotype differentiating SPMS from RRMS and controls. A possible association of allelic variability in the VEGF-A gene to risk of MS was also studied by genotyping for six single nucleotide polymorphisms (SNPs) in MS (n = 1114) and controls (n = 1234), which, however, did not demonstrate any significant association between VEGF-A alleles and risk of MS. Expression of VEGF-A in CSF cells is reduced in MS patients compared to controls irrespective of disease course. In addition, SPMS patients display reduced VEGF-A mRNA expression in PBMC, which distinguish them from RRMS and controls. This indicates a possible role for VEGF-A in the mechanisms regulating transition to SPMS. Decreased levels of PBMC VEGF-A mRNA expression should be further evaluated as a biomarker for SPMS.

BackgroundA growing evidence base supports the use of autologous haematopoietic stem cell transplantation (aHSCT) for treatment of relapsing-remitting multiple sclerosis (RRMS), but it has not yet been integrated into most national clinical guidelines. The objective of this study was to assess efficacy and safety when aHSCT is implemented in routine healthcare.MethodsWe assessed 231 patients and the final analysis included 174 RRMS patients who were treated with aHSCT in Sweden before 1 January 2020. Efficacy was evaluated by performing a retrospective analysis of prospectively collected data from the Swedish MS registry. Procedure-related safety was assessed by analysing data from electronic patient records covering a period of 100 days following aHSCT.ResultsWith a median follow-up time of 5.5 (IQR: 3.4–7.5) years, the Kaplan-Meier estimate for no evidence of disease activity was 73% (95% CI 66% to 81%) at 5 years and 65% (95% CI 57% to 75%) at 10 years. Out of the 149 patients with baseline disability, 80 (54%) improved, 55 (37%) were stable and 14 (9%) deteriorated. The mean number of adverse events per patient was 1.7 (±SD: 1.5) for grade 3 events and 0.06 (±SD: 0.3) for grade 4 events. Febrile neutropenia was the most common adverse event, affecting 68% of patients. There was no treatment-related mortality.ConclusionsTreatment with aHSCT for RRMS is associated with freedom from disease activity in a majority of patients, with acceptable adverse events. This procedure should be considered a standard of care for patients with highly active RRMS.