Publications by authors named "Joachim Burman"

54 Publications

Hematopoietic stem cell transplantation for autoimmune diseases in the time of COVID-19: EBMT guidelines and recommendations.

Bone Marrow Transplant 2021 May 24. Epub 2021 May 24.

Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

Coronavirus disease-19 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), represents one of the biggest challenges of 21st century, threatening public health around the globe. Increasing age and presence of co-morbidities are reported risk factors for severe disease and mortality, along with autoimmune diseases (ADs) and immunosuppressive treatments such as haematopoietic stem cell transplantation (HSCT), which are also associated with adverse outcomes. We review the impact of the pandemic on specific groups of patients with neurological, rheumatological, and gastroenterological indications, along with the challenges delivering HSCT in adult and pediatric populations. Moving forward, we developed consensus-based guidelines and recommendations for best practice and quality of patient care in order to support clinicians, scientists, and their multidisciplinary teams, as well as patients and their carers. These guidelines aim to support national and international organizations related to autoimmune diseases and local clinical teams delivering HSCT. Areas of unmet need and future research questions are also highlighted. The waves of the COVID-19 pandemic are predicted to be followed by an "endemic" phase and therefore an ongoing risk within a "new normality". These recommendations reflect currently available evidence, coupled with expert opinion, and will be revised according to necessary modifications in practice.
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http://dx.doi.org/10.1038/s41409-021-01326-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143059PMC
May 2021

Retention of antiseizure medications for epilepsy in multiple sclerosis: A retrospective observational study.

Epilepsy Behav 2021 May 15;121(Pt A):108034. Epub 2021 May 15.

Department of Clinical Neuroscience, Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, Sahlgrenska Academy, Gothenburg, Sweden. Electronic address:

Purpose: Epilepsy in multiple sclerosis (MS) is rare, and longitudinal clinical studies evaluating treatment with antiseizure medications (ASMs) are difficult to conduct. We instead designed a nationwide register study to estimate retention rates of ASMs prescribed as initial monotherapy for epilepsy in MS and investigated factors influencing their retention.

Methods: multiple sclerosis patients with a first prescription of ASM for epilepsy were identified by cross-referencing the Swedish MS register with comprehensive national registers. One and five-year retention rates of ASMs were estimated using Kaplan-Meier analysis. Cox proportional regression was employed to estimate hazard ratios (HR) of discontinuation for different ASMs as well as for baseline predictors.

Results: One hundred and twenty-nine MS patients were included. The most commonly prescribed ASMs were: carbamazepine (n = 38, 29.5%), lamotrigine (n = 33, 25.6%) and levetiracetam (n = 19, 14.7%). One-year retention rates (95% CI) were: lamotrigine 87.5% [76, 98.9], carbamazepine 60.5% [45, 76], levetiracetam 60.2% [37.2, 83.2], valproate 51.3% [23, 79.6] and phenytoin 44.4% [11.8, 77]. Fiveyear retention rates (95% CI) were: lamotrigine 74.4% [57.3, 91.5], carbamazepine 52.2% [34.9, 69.4], valproate 51.3% [23.1, 79.5] and phenytoin 14.8% [0, 40.9]. With carbamazepine as reference, lamotrigine was the only ASM that displayed a lower hazard of discontinuation, HR 0.41 [0.17, 0.99]. We could not identify any baseline factors that influenced the risk of discontinuation.

Conclusion: Lamotrigine displayed the lowest risk of discontinuation when prescribed as initial monotherapy for epilepsy in MS. Newer ASMs generally compared well to older ones, at least suggesting non-inferiority.
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http://dx.doi.org/10.1016/j.yebeh.2021.108034DOI Listing
May 2021

New autoimmune diseases after autologous hematopoietic stem cell transplantation for multiple sclerosis.

Bone Marrow Transplant 2021 Apr 28. Epub 2021 Apr 28.

Department of Neurology, Uppsala University, Uppsala, Sweden.

Secondary autoimmune diseases (2ndADs), most frequently autoimmune cytopenias (AICs), were first described after allogeneic hematopoietic stem cell transplantation (HSCT) undertaken for malignant and hematological indications, occurred at a prevalence of ~5-6.5%, and were attributed to allogeneic immune imbalances in the context of graft versus host disease, viral infections, and chronic immunosuppression. Subsequently, 2ndADs were reported to complicate roughly 2-14% of autologous HSCTs performed for an autoimmune disease. Alemtuzumab in the conditioning regimen has been identified as a risk for development of 2ndADs after either allogeneic or autologous HSCT and is consistent with the high rates of 2ndADs when using alemtuzumab as monotherapy. Due to the significant consequences but variable incidence, depending on conditioning regimen, of 2ndADs and similarity in known immune reconstitution kinetics after autologous HSCT for autoimmune diseases and after alemtuzumab monotherapy, we propose that an imbalance between B and T lineage regeneration early after HSCT may underlie the pathogenesis of 2ndADs.
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http://dx.doi.org/10.1038/s41409-021-01277-yDOI Listing
April 2021

Metabolomics of Cerebrospinal Fluid from Healthy Subjects Reveal Metabolites Associated with Ageing.

Metabolites 2021 Feb 23;11(2). Epub 2021 Feb 23.

Department of Medical Sciences, Clinical Chemistry, Uppsala University, 751 85 Uppsala, Sweden.

To increase our understanding of age-related diseases affecting the central nervous system (CNS) it is important to understand the molecular processes of biological ageing. Metabolomics of cerebrospinal fluid (CSF) is a promising methodology to increase our understanding of naturally occurring processes of ageing of the brain and CNS that could be reflected in CSF. In the present study the CSF metabolomes of healthy subjects aged 30-74 years ( = 23) were studied using liquid chromatography high-resolution mass spectrometry (LC-HRMS), and investigated in relation to age. Ten metabolites were identified with high confidence as significantly associated with ageing, eight with increasing levels with ageing: isoleucine, acetylcarnitine, pipecolate, methionine, glutarylcarnitine, 5-hydroxytryptophan, ketoleucine, and hippurate; and two decreasing with ageing: methylthioadenosine and 3-methyladenine. To our knowledge, this is the first time the CSF metabolomes of healthy subjects are assessed in relation to ageing. The present study contributes to the field of ageing metabolomics by presenting a number of metabolites present in CSF with potential relevance for ageing and the results motivate further studies.
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http://dx.doi.org/10.3390/metabo11020126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927110PMC
February 2021

Urokinase, CX3CL1, CCL2, TRAIL and IL-18 induced by interferon-β treatment.

Acta Neurol Scand 2021 Jun 24;143(6):602-607. Epub 2021 Feb 24.

Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden.

Objective: To identify serum proteins associated with MS and affected by interferon beta treatment.

Methods: Plasma samples from 29 untreated relapsing-remitting MS patients and 15 healthy controls were investigated with a multiplexed panel containing 92 proteins related to inflammation. Follow-up samples were available from 13 patients at 1 and 3 months after initiation of treatment with interferon beta-1a.

Results: Ten proteins were differentially expressed in MS patients. Five of these were altered by treatment with IFN-β 1a: uPA, CX3CL1, CCL2, TRAIL and IL18.

Conclusion: CCL2 and TRAIL were confirmed to be modulated with interferon beta treatment in MS. As novel findings, we now report that uPA and CX3CL1 were differentially expressed in MS and increased after IFN-beta-1a treatment. Conflicting results have been reported on how interferon beta affects IL-18.
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http://dx.doi.org/10.1111/ane.13400DOI Listing
June 2021

Neuronal and glial CSF biomarkers in multiple sclerosis: a systematic review and meta-analysis.

Rev Neurosci 2021 Feb 16. Epub 2021 Feb 16.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Multiple sclerosis (MS) is a neurodegenerative disease associated with inflammatory demyelination and astroglial activation, with neuronal and axonal damage as the leading factors of disability. We aimed to perform a meta-analysis to determine changes in CSF levels of neuronal and glial biomarkers, including neurofilament light chain (NFL), total tau (t-tau), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein (GFAP), and S100B in various groups of MS (MS versus controls, clinically isolated syndrome (CIS) versus controls, CIS versus MS, relapsing-remitting MS (RRMS) versus progressive MS (PMS), and MS in relapse versus remission. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, we included 64 articles in the meta-analysis, including 4071 subjects. For investigation of sources of heterogeneity, subgroup analysis, meta-regression, and sensitivity analysis were conducted. Meta-analyses were performed for comparisons including at least three individual datasets. NFL, GFAP, t-tau, CHI3L1, and S100B were higher in MS and NFL, t-tau, and CHI3L1 were also elevated in CIS patients than controls. CHI3L1 was the only marker with higher levels in MS than CIS. GFAP levels were higher in PMS versus RRMS, and NFL, t-tau, and CHI3L1 did not differ between different subtypes. Only levels of NFL were higher in patients in relapse than remission. Meta-regression showed influence of sex and disease severity on NFL and t-tau levels, respectively and disease duration on both. Added to the role of these biomarkers in determining prognosis and treatment response, to conclude, they may serve in diagnosis of MS and distinguishing different subtypes.
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http://dx.doi.org/10.1515/revneuro-2020-0145DOI Listing
February 2021

Cerebral blood flow measurements with O-water PET using a non-invasive machine-learning-derived arterial input function.

J Cereb Blood Flow Metab 2021 Feb 8:271678X21991393. Epub 2021 Feb 8.

Department of Radiation Sciences, Umeå University, Umeå, Sweden.

Cerebral blood flow (CBF) can be measured with dynamic positron emission tomography (PET) of O-labeled water by using tracer kinetic modelling. However, for quantification of regional CBF, an arterial input function (AIF), obtained from arterial blood sampling, is required. In this work we evaluated a novel, non-invasive approach for input function prediction based on machine learning (MLIF), against AIF for CBF PET measurements in human subjects.Twenty-five subjects underwent two 10 min dynamic O-water brain PET scans with continuous arterial blood sampling, before (baseline) and following acetazolamide medication. Three different image-derived time-activity curves were automatically segmented from the carotid arteries and used as input into a Gaussian process-based AIF prediction model, considering both baseline and acetazolamide scans as training data. The MLIF approach was evaluated by comparing AIF and MLIF curves, as well as whole-brain grey matter CBF values estimated by kinetic modelling derived with either AIF or MLIF.The results showed that AIF and MLIF curves were similar and that corresponding CBF values were highly correlated and successfully differentiated before and after acetazolamide medication. In conclusion, our non-invasive MLIF method shows potential to replace the AIF obtained from blood sampling for CBF measurements using O-water PET and kinetic modelling.
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http://dx.doi.org/10.1177/0271678X21991393DOI Listing
February 2021

Safety of Alemtuzumab and Autologous Hematopoietic Stem Cell Transplantation Compared to Noninduction Therapies for Multiple Sclerosis.

Neurology 2021 03 29;96(11):e1574-e1584. Epub 2021 Jan 29.

From the Department of Clinical Neuroscience (P.A., F.P.) and Clinical Epidemiology Division (P.A., T.F.), Department of Medicine Solna, Karolinska Institutet, Stockholm; Department of Neuroscience (J.B.), Uppsala University; Department of Clinical Neuroscience (J.L.), Institute of Neuroscience and Physiology, University of Gothenburg; and Academic Specialist Centre (F.P.), Stockholm Health Services, Sweden.

Objective: To assess safety outcomes for the induction therapies alemtuzumab and autologous hematopoietic stem cell transplantation (AHSCT) compared to noninduction disease-modifying therapies.

Methods: We performed a population-based cohort study linking the Swedish Multiple Sclerosis Register to national health care registers. Alemtuzumab, AHSCT, and a matched reference group of noninduction therapies (natalizumab, dimethyl fumarate, rituximab, fingolimod) were included if started between 2008 and 2017. Main outcomes were death, thyroid disease, nonthyroid autoimmune disease, and infection.

Results: We identified 132 alemtuzumab-treated and 139 AHSCT-treated (68% high-dose cyclophosphamide and anti-thymocyte globulin [ATG], 32% BCNU, etoposide, cytosine-arabinoside, and melphalan/ATG) patients, together with 2,486 matched patients treated with noninduction therapies. Four patients in the alemtuzumab group died (incidence rate [IR] per 1,000 person-years 8.6, 95% confidence interval [CI] 2.3-22.0) compared to 1 patient in the AHSCT group (IR 1.7, 95% CI 0.0-9.6), and the mortality rate in the reference group was 0.7 (95% CI 0.3-1.3). Thyroid disease was most frequent in the alemtuzumab group (IR 109, 95% CI 75-154) but also occurred more often for AHSCT (IR 34, 95% CI 18-56) compared to the reference (IR 5.3 95% CI 3.9-7.1). The incidence of nonthyroid autoimmune disease was similar in all groups. IR for infection diagnosed ≥6 months from therapy initiation was 53 (95% CI 30-87) for alemtuzumab, 108 (95% CI 75-150) for AHSCT, and 51 (95% CI 46-57) for the reference.

Conclusion: We confirmed a high incidence of thyroid disease in alemtuzumab- and, to a smaller extent, AHSCT-treated patients and found a higher incidence of infection for AHSCT compared to both alemtuzumab and noninduction therapies. The incidence of nonthyroid autoimmune disease was low for both therapies.

Classification Of Evidence: This study provides Class III evidence of an increased risk of thyroid disease with alemtuzumab and an increased risk of infection with AHSCT treatment.
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http://dx.doi.org/10.1212/WNL.0000000000011545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032381PMC
March 2021

Rehabilitation Before and After Autologous Haematopoietic Stem Cell Transplantation (AHSCT) for Patients With Multiple Sclerosis (MS): Consensus Guidelines and Recommendations for Best Clinical Practice on Behalf of the Autoimmune Diseases Working Party, Nurses Group, and Patient Advocacy Committee of the European Society for Blood and Marrow Transplantation (EBMT).

Front Neurol 2020 11;11:556141. Epub 2020 Dec 11.

Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.

Autologous haematopoietic stem cell transplantation (AHSCT) is increasingly used to treat people with multiple sclerosis (MS). Supported by an evolving evidence base, AHSCT can suppress active inflammation in the central nervous system and induce long-term changes in immune cell populations, thereby stabilizing, and, in some cases, reversing disability in carefully selected MS patients. However, AHSCT is an intensive chemotherapy-based procedure associated with intrinsic risks, including profound cytopenia, infection, and organ toxicity, accompanied by an on-going degree of immuno-compromise and general deconditioning, which can be associated with a transient increase in functional impairment in the early stages after transplantation. Although international guidelines and recommendations have been published for clinical and technical aspects of AHSCT in MS, there has been no detailed appraisal of the rehabilitation needed following treatment nor any specific guidelines as to how this is best delivered by hospital and community-based therapists and wider multidisciplinary teams in order to maximize functional recovery and quality of life. These expert consensus guidelines aim to address this unmet need by summarizing the evidence-base for AHSCT in MS and providing recommendations for current rehabilitation practice along with identifying areas for future research and development.
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http://dx.doi.org/10.3389/fneur.2020.556141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759663PMC
December 2020

Proenkephalin Decreases in Cerebrospinal Fluid with Symptom Progression of Huntington's Disease.

Mov Disord 2021 02 28;36(2):481-491. Epub 2020 Nov 28.

Department of Neuroscience; Neurosurgery, Uppsala University, Uppsala, Sweden.

Objective: Identifying molecular changes that contribute to the onset and progression of Huntington's disease (HD) is of importance for the development and evaluation of potential therapies.

Methods: We conducted an unbiased mass-spectrometry proteomic analysis on the cerebrospinal fluid of 12 manifest HD patients (ManHD), 13 pre-manifest (preHD), and 38 controls. A biologically plausible and significant possible biomarker was validated in samples from a separate cohort of patients and controls consisting of 23 ManHD patients and 23 controls.

Results: In ManHD compared to preHD, 10 proteins were downregulated and 43 upregulated. Decreased levels of proenkephalin (PENK) and transthyretin were closely linked to HD symptom severity, whereas levels of 15 upregulated proteins were associated with symptom severity. The decreased PENK levels were replicated in the separate cohort where absolute quantitation was performed.

Conclusions: We hypothesize that declining PENK levels reflect the degeneration of medium spiny neurons (MSNs) that produce PENK and that assays for PENK may serve as a surrogate marker for the state of MSNs in HD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984171PMC
February 2021

Multipel skleros och covid-19 – kunskapen ännu begränsad.

Lakartidningen 2020 10 30;117. Epub 2020 Oct 30.

professor, överläkare, institutionen för neurovetenskap, Uppsala universitet; Neurologi, Akademiska sjukhuset, Uppsala.

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October 2020

Autologous haematopoietic stem cell transplantation compared with alemtuzumab for relapsing-remitting multiple sclerosis: an observational study.

J Neurol Neurosurg Psychiatry 2021 02 26;92(2):189-194. Epub 2020 Oct 26.

Department of Neuroscience, Uppsala University, Uppsala, Sweden

Objective: To compare outcomes after treatment with autologous haematopoietic stem cell transplantation (AHSCT) and alemtuzumab (ALZ) in patients with relapsing-remitting multiple sclerosis.

Methods: Patients treated with AHSCT (n=69) received a conditioning regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulinerG (6.0 mg/kg). Patients treated with ALZ (n=75) received a dose of 60 mg over 5 days, a repeated dose of 36 mg over 3 days after 1 year and then as needed. Follow-up visits with assessment of the expanded disability status scale score, adverse events and MR investigations were made at least yearly.

Results: The Kaplan-Meier estimates of the primary outcome measure 'no evidence of disease activity' was 88% for AHSCT and 37% for ALZ at 3 years, p<0.0001. The secondary endpoint of annualised relapse rate was 0.04 for AHSCT and 0.1 for ALZ, p=0.03. At last follow-up, the proportions of patients who improved, were stable or worsened were 57%/41%/1% (AHSCT) and 45%/43%/12% (ALZ), p=0.06 Adverse events grade three or higher were present in 48/69 patients treated with AHSCT and 0/75 treated with ALZ in the first 100 days after treatment initiation. The most common long-term adverse event was thyroid disease with Kaplan-Meier estimates at 3 years of 21% for AHSCT and 46% for ALZ, p=0.005.

Conclusions: In this observational cohort study, treatment with AHSCT was associated with a higher likelihood of maintaining 'no evidence of disease activity'. Adverse events were more frequent with AHSCT in the first 100 days, but thereafter more common in patients treated with ALZ.
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http://dx.doi.org/10.1136/jnnp-2020-323992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841472PMC
February 2021

Intrathecal treatment trial of rituximab in progressive MS: results after a 2-year extension.

J Neurol 2021 Feb 8;268(2):651-657. Epub 2020 Sep 8.

Department of Clinical Science, Umeå University, Umeå, Sweden.

Objectives: To evaluate the effect of intrathecally (IT) delivered rituximab as a therapeutic intervention for progressive multiple sclerosis (PMS) during a 3-year follow-up period.

Methods: Participants of a 1-year open-label phase 1b study of IT delivered rituximab to patients with PMS were offered extended treatment with follow-up for an additional 2 years. During the extension phase, treatment with 25 mg rituximab was administered every 6 months via a subcutaneous Ommaya reservoir connected to the right frontal horn with a ventricular catheter.

Results: Mild to moderate vertigo and nausea occurred in 4 out of 14 participants as temporary adverse events associated with IT rituximab infusion. During the entire 3-year period, two cases of low-virulent bacterial meningitis occurred, which were successfully treated. Walking speed deteriorated significantly during the study.

Conclusions: IT administration of rituximab via a ventricular catheter was well tolerated. Considering the meningitis cases, the risk of infection was not negligible. The continued loss of walking speed indicates that IT rituximab was not able to stop disease progression.

Classification Of Evidence: This study provides class IV evidence that intraventricularly administered rituximab in progressive MS is associated with a risk for bacterial meningitis and does not halt disease progression.

Eu Clinical Trial Register: EudraCT; 2008-002626-11 and 2012-000721-53.
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http://dx.doi.org/10.1007/s00415-020-10210-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880973PMC
February 2021

Location matters: highly divergent protein levels in samples from different CNS compartments in a clinical trial of rituximab for progressive MS.

Fluids Barriers CNS 2020 Jul 29;17(1):49. Epub 2020 Jul 29.

Department of Neurosciences, Uppsala University, Uppsala, Sweden.

Background: The relationship between proteins in different CNS extracellular compartments is unknown. In this study the levels of selected proteins in three compartments in people with progressive multiple sclerosis (PMS) were compared.

Methods: During an open label, phase 1b study on intraventricular administration of rituximab for PMS, samples were collected from the interstitial space (ISS) of the brain through microdialysis. Samples were also obtained from ventricular and lumbar cerebrospinal fluid (CSF). These samples were analyzed with a multiplexed proximity extension assay, measuring the levels of 180 proteins split equally between two panels, detecting proteins associated with immunology and neurology, respectively.

Results: Considerable differences in concentrations were observed between the three analyzed compartments. Compared to ventricular CSF, ISS fluid contained statistically significant higher levels of 25 proteins (84% immunology panel and 16% neurology panel). Ventricular CSF contained significantly higher levels of 54 proteins (31% immunology panel and 69% neurology panel) compared to ISS fluid, and 17 proteins (76% immunology panel and 24% neurology panel) compared to lumbar CSF. Lumbar CSF showed significantly higher levels of 115 proteins (32% immunology panel and 68% neurology panel) compared to ventricular CSF. The three compartments displayed poor correlation with a median Spearman's rho of -0.1 (IQR 0.4) between ISS and ventricular CSF and 0.3 (IQR 0.4) between ventricular and lumbar CSF.

Conclusion: A substantial heterogeneity in the protein levels of samples obtained from different CNS compartments was seen. Therefore, data obtained from analysis of lumbar CSF should be interpreted with caution when making conclusions about pathophysiological processes in brain tissue.
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http://dx.doi.org/10.1186/s12987-020-00205-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390226PMC
July 2020

Cancer Risk for Fingolimod, Natalizumab, and Rituximab in Multiple Sclerosis Patients.

Ann Neurol 2020 05 9;87(5):688-699. Epub 2020 Mar 9.

Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.

Objective: Novel, highly effective disease-modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking.

Methods: In this nationwide register-based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first-ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non-MS general population subjects. Primary outcome was time to first invasive cancer.

Results: We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate [IR] per 10,000 person-years = 34.4, 95% confidence interval [CI] = 23.7-48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2-63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1-41.6). The general population IR was 31.0 (95% CI = 27.8-34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio [HR] = 1.53, 95% CI = 0.98-2.38) and rituximab (HR = 1.68, 95% CI = 1.00-2.84).

Interpretation: In this first large comparative study of 3 highly effective MS disease-modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline-significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings. ANN NEUROL 2020;87:688-699.
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http://dx.doi.org/10.1002/ana.25701DOI Listing
May 2020

Targeted metabolomics of CSF in healthy individuals and patients with secondary progressive multiple sclerosis using high-resolution mass spectrometry.

Metabolomics 2020 02 12;16(2):26. Epub 2020 Feb 12.

Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala University Hospital, Entrance 61, 3rd Floor, Dag Hammarskjölds Väg 18, 751 85, Uppsala, Sweden.

Introduction: Standardized commercial kits enable targeted metabolomics analysis and may thus provide an attractive complement to the more explorative approaches. The kits are typically developed for triple quadrupole mass spectrometers using serum and plasma.

Objectives: Here we measure the concentrations of preselected metabolites in cerebrospinal fluid (CSF) using a kit developed for high-resolution mass spectrometry (HRMS). Secondarily, the study aimed to investigate metabolite alterations in patients with secondary progressive multiple sclerosis (SPMS) compared to controls.

Methods: We performed targeted metabolomics in human CSF on twelve SPMS patients and twelve age and sex-matched healthy controls using the Absolute IDQ-p400 kit (Biocrates Life Sciences AG) developed for HRMS. The extracts were analysed using two methods; liquid chromatography-mass spectrometry (LC-HRMS) and flow injection analysis-MS (FIA-HRMS).

Results: Out of 408 targeted metabolites, 196 (48%) were detected above limit of detection and 35 were absolutely quantified. Metabolites analyzed using LC-HRMS had a median coefficient of variation (CV) of 3% and 2.5% between reinjections the same day and after prolonged storage, respectively. The corresponding results for the FIA-HRMS were a median CV of 27% and 21%, respectively. We found significantly (p < 0.05) elevated levels of glycine, asymmetric dimethylarginine (ADMA), glycerophospholipid PC-O (34:0) and sum of hexoses in SPMS patients compared to controls.

Conclusion: The Absolute IDQ-p400 kit could successfully be used for quantifying targeted metabolites in the CSF. Metabolites quantified using LC-HRMS showed superior reproducibility compared to FIA-HRMS.
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http://dx.doi.org/10.1007/s11306-020-1648-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015966PMC
February 2020

Prognostic impact of epilepsy in multiple sclerosis.

Mult Scler Relat Disord 2020 Feb 5;38:101497. Epub 2019 Nov 5.

Department of Clinical Neuroscience, Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address:

Background: The incidence of epilepsy, a disease generally associated with increased morbidity and mortality, is increased in multiple sclerosis (MS) but its impact on MS prognosis is largely unknown.

Objectives: To investigate the association between acquired epilepsy and mortality in MS and to examine the occurrence of epilepsy as a stated cause of death in MS. To examine the association between acquired epilepsy and subsequent conversion to secondary progressive MS (SPMS).

Methods: Using the Swedish MS register, we conducted a nationwide register-based cohort study including 10,383 patients with MS onset between 31/12/1991 and 31/12/2014, and with no history of epilepsy before MS onset. Data on epilepsy diagnosis and cause of death (COD) were extracted from comprehensive national registers. Cox regression was used to estimate hazard ratios (HR) of death stratified by MS course, and SPMS conversion after epilepsy diagnosis. The HRs were adjusted for age at MS onset and sex.

Results: The adjusted HR of death after epilepsy diagnosis for unselected MS patients was 3.85 (95% CI: 2.53-5.85). Stratifying by disease course, the adjusted HR of death after epilepsy diagnosis in primary progressive MS was 2.28 (95% CI: 0.99-5.26) and in relapsing-onset MS (ROMS), 5.48 (95% CI: 3.33-9.04). Further subdivision of ROMS revealed the adjusted risk of death after epilepsy diagnosis in relapsing remitting MS to be 3.84 (95% CI: 1.57-9.42) and 6.66 (95% CI: 3.18-13.92) in SPMS. Epilepsy was the underlying COD in 4.55% of MS patients with epilepsy. The majority (50%) of MS patients with epilepsy had MS as their stated underlying COD. Adjusted HR of conversion to SPMS after epilepsy diagnosis was 0.83 (95% CI: 0.45-1.56).

Conclusion: Epilepsy in MS is associated with increased mortality although death from epilepsy is rare. Most MS patients with epilepsy died of MS, and epilepsy was most lethal when developed in SPMS. We thus suggest that development of epilepsy is a marker of severe MS. Despite this, we found no association between epilepsy and conversion to SPMS.
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http://dx.doi.org/10.1016/j.msard.2019.101497DOI Listing
February 2020

Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies.

JAMA Neurol 2020 02;77(2):184-191

Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

Importance: Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden.

Objective: To examine the risk of serious infections associated with disease-modifying treatments for MS.

Design, Setting, And Participants: This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included.

Exposures: Treatment with rituximab, natalizumab, fingolimod, and interferon beta and GA.

Main Outcomes And Measures: Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions.

Results: A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 [95% CI, 6.4-12.1] vs 5.2 [95% CI, 4.8-5.5] per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 [95% CI, 10.8-18.5] per 1000 person-years), natalizumab (incidence rate, 11.4 [95% CI, 8.3-15.3] per 1000 person-years), and rituximab (incidence rate, 19.7 [95% CI, 16.4-23.5] per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 [95% CI, 1.11-2.61]) but not fingolimod (HR, 1.30 [95% CI, 0.84-2.03]) or natalizumab (HR, 1.12 [95% CI, 0.71-1.77]) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 [1.34-2.46]) and fingolimod (HR, 1.71 [95% CI, 1.27-2.32]).

Conclusions And Relevance: Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.
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http://dx.doi.org/10.1001/jamaneurol.2019.3365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784753PMC
February 2020

Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE).

Bone Marrow Transplant 2020 02 26;55(2):283-306. Epub 2019 Sep 26.

Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials.
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http://dx.doi.org/10.1038/s41409-019-0684-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995781PMC
February 2020

Profound but Transient Changes in the Inflammatory Milieu of the Blood During Autologous Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2020 01 13;26(1):50-57. Epub 2019 Sep 13.

Department of Neuroscience, Uppsala University, Uppsala, Sweden.

Little is known about the inflammatory milieu in the blood during autologous hematopoietic stem cell transplantation (AHSCT) and how it is affected by the stem cell mobilization, collection, and reinfusion and conditioning regimen. In this study, we analyzed 92 proteins connected to inflammation at 10 time points during and after AHSCT in 16 patients with multiple sclerosis (MS). Serum from 29 patients with newly diagnosed MS and 15 healthy controls were included for comparative analysis. There were no significant differences in inflammatory serum protein levels between patients with newly diagnosed MS and healthy controls, but 29 out of 73 detectable proteins were significantly altered between at least 2 adjacent sampling time points during AHSCT. The predominant changes occurred after the conditioning regimen had been administered, whereas stem cell mobilization, collection, and reinfusion appeared to have less impact. Two distinct response patterns could be discerned, likely representing loss of basal cytokine production and homeostasis. The analyzed serum proteins gradually returned to baseline levels after treatment, with no remaining differences at 3 months after AHSCT. We conclude that treatment with AHSCT has a major but transient impact on the inflammatory milieu of peripheral blood.
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http://dx.doi.org/10.1016/j.bbmt.2019.09.010DOI Listing
January 2020

Comparative effectiveness of dimethyl fumarate as the initial and secondary treatment for MS.

Mult Scler 2020 10 8;26(12):1532-1539. Epub 2019 Aug 8.

Department of Clinical Neuroscience, Center for Molecular Medicine (CMM), Karolinska Institutet, Stockholm, Sweden.

Background: Population-based real-world evidence studies of the effectiveness and tolerability of dimethyl fumarate in relation to common treatment alternatives are still limited.

Objective: To evaluate the clinical effectiveness and tolerability of dimethyl fumarate (DMF) as the initial and secondary treatment for relapsing-remitting multiple sclerosis (RRMS) patients compared with common treatment alternatives in Sweden.

Methods: We conducted a nationwide retrospective observational cohort study of all RRMS patients identified through the Swedish MS registry initiating DMF ( = 641) or interferons/glatiramer acetate (IFN/GA;  = 555) as the initial therapy, or DMF ( = 703) or fingolimod (FGL;  = 194) after switch from IFN/GA between 1 January 2014 and 31 December 2016.

Results: The discontinuation rate was lower with DMF as the initial treatment than IFN/GA (adjusted hazard rate (HR): 0.46, 95% confidence interval (CI): 0.37-0.58,  < 0.001), but higher than FGL as the secondary treatment (HR: 1.51, CI: 1.08-2.09,  < 0.05). Annualized relapse rate (ARR) was lower with DMF compared to IFN/GA (0.04, CI: 0.03-0.06 vs 0.10, CI: 0.07-0.13;  < 0.05), but not FGL (0.03, CI: 0.02-0.05 vs 0.02, CI: 0.01-0.04;  = 0.41). Finally, time to first relapse (TTFR) was longer with DMF as the initial, but not secondary, therapy ( < 0.05 and  = 0.20, respectively).

Conclusion: Our findings indicate that DMF performs better than IFN/GA as the initial treatment for RRMS. Compared to FGL, DMF displayed a lower tolerability, but largely similar effectiveness outcomes.
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http://dx.doi.org/10.1177/1352458519866600DOI Listing
October 2020

Intrathecal immunoglobulins and neurofilament light after autologous haematopoietic stem cell transplantation for multiple sclerosis.

Mult Scler 2020 10 26;26(11):1351-1359. Epub 2019 Jul 26.

Department of Neuroscience, Uppsala University, Uppsala, Sweden.

Background: Oligoclonal bands (OCB) are widely believed to be stable over time and rarely affected by disease-modifying treatment in MS. It is presently unknown how intrathecal immunoglobulin production and other cerebrospinal fluid (CSF) biomarkers are impacted by a highly efficacious procedure such as autologous haematopoietic stem cell transplantation (aHSCT).

Objective: To describe the evolution of intrathecal immunoglobulin and neurofilament light (NFL) over time in MS patients treated with aHSCT.

Methods: In this retrospective study, available data from previously made CSF investigations in 46 patients treated with aHSCT were analysed.

Results: After a median follow-up time of 745 days, immunoglobulin G (IgG) OCB remained detectable in 74% of patients, the proportion of patients with a pathological IgG index went down from 70% to 46%, and the proportion of patients with a pathological NFL went down from 72% to 24%. In patients with follow-up time >1500 days, IgG OCB were detectable in 50% of patients, 14% had a pathological IgG index and none a pathological NFL.

Conclusions: Intrathecal immunoglobulin production and NFL were lower after treatment with aHSCT, decreased over time and were normalised in a significant portion of patients. This challenges the notion that OCB are unaffected by therapeutic intervention in MS.
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http://dx.doi.org/10.1177/1352458519863983DOI Listing
October 2020

Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation.

Acta Neurol Scand 2019 Nov 5;140(5):320-327. Epub 2019 Aug 5.

Department of Neuroscience, Uppsala University, Uppsala, Sweden.

Objectives: To determine whether treatment with autologous hematopoietic stem cell transplantation (HSCT) can induce sustained complete remission in patients with multiple sclerosis (MS).

Material And Methods: Case series of patients with relapsing-remitting MS (n = 10) treated at a single center between 2004 and 2007 and followed up for 10 years. The patients were treated with a BEAM/ATG conditioning regimen (n = 9) or a cyclophosphamide/ATG conditioning regimen (n = 1) followed by infusion of unmanipulated autologous hematopoietic stem cells. The primary endpoint was sustained complete remission. Sustained complete remission was defined as "no evidence of disease activity-4," sustained for a period of at least 5 years without any ongoing disease-modifying treatment. Furthermore, MS was considered as "resolved" if intrathecal IgG production and cerebrospinal fluid neurofilament light levels were normalized as well.

Results: Five out of 10 patients were in sustained complete remission at the end of the study. In three of them, MS was resolved.

Conclusions: Our data demonstrate that sustained complete remission after autologous HSCT for MS is possible.
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http://dx.doi.org/10.1111/ane.13147DOI Listing
November 2019

Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis.

JAMA Neurol 2019 Sep;76(9):1035-1048

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg.

Importance: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.

Objectives: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.

Data Sources: PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.

Study Selection: Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.

Data Extraction And Synthesis: Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.

Main Outcome And Measure: The cNfL levels adjusted for age and sex across diagnoses.

Results: Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.

Conclusions And Relevance: These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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http://dx.doi.org/10.1001/jamaneurol.2019.1534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580449PMC
September 2019

Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease.

J Neuroimmunol 2019 07 25;332:31-36. Epub 2019 Mar 25.

Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden. Electronic address:

Background: Laboratory tests to assist in the diagnosis and monitoring of neuroinflammatory diseases are scarce. The soluble form of the CD27 molecule (sCD27) is shed in high concentrations by activated T cells and can be detected in the cerebrospinal fluid. The aim of this study was to investigate whether CSF quantitation of sCD27 could discriminate between inflammatory and non-inflammatory neurological diseases.

Methods: The concentration of sCD27 was measured using a commercially available ELISA in 803 well-defined subjects from a study cohort comprised of 338 patients with neuroinflammatory disease, 338 with non-inflammatory neurological disease and 127 controls without neurological disease.

Results: The median value of cerebrospinal fluid sCD27 was 64 pg/mL (IQR 0-200) in controls, 58 pg/mL (IQR 0-130) in patients with non-inflammatory disease and 740 pg/mL (IQR 230-1800) in patients with inflammatory disease. The likelihood ratio of having an inflammatory disease was 10 (sensitivity 74% and specificity 93%) if the sCD27 concentration was >250 pg/mL. In patients with a known inflammatory condition, the likelihood ratio of having an infection was 10 (sensitivity 40% and specificity 96%) if the sCD27 concentration was >2500 pg/mL.

Conclusions: The likelihood of having an inflammatory neurological condition is increased with elevated concentrations of sCD27 in cerebrospinal fluid. Rapid tests of sCD27 should be developed to assist clinicians in diagnosis of neuroinflammatory disease.
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http://dx.doi.org/10.1016/j.jneuroim.2019.03.015DOI Listing
July 2019

Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington's disease subjects.

Sci Rep 2019 03 11;9(1):4129. Epub 2019 Mar 11.

Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.

Huntington's disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects. Inter-group differences revealed that the tyrosine metabolism, including tyrosine, thyroxine, L-DOPA and dopamine, was significantly altered in manifest compared with premanifest HD. These metabolites demonstrated moderate to strong associations to measures of disease severity and symptoms. Thyroxine and dopamine also correlated with the five year risk of onset in premanifest HD subjects. The phenylalanine and the purine metabolisms were also significantly altered, but associated less to disease severity. Decreased levels of lumichrome were commonly found in mutated HTT carriers and the levels correlated with the five year risk of disease onset in premanifest carriers. These biochemical findings demonstrates that the CSF metabolome can be used to characterize molecular pathogenesis occurring in HD, which may be essential for future development of novel HD therapies.
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http://dx.doi.org/10.1038/s41598-019-40186-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411723PMC
March 2019

Interoperable and scalable data analysis with microservices: applications in metabolomics.

Bioinformatics 2019 10;35(19):3752-3760

CEA, LIST, Laboratory for Data Analysis and Systems' Intelligence, MetaboHUB, Gif-sur-Yvette, France.

Motivation: Developing a robust and performant data analysis workflow that integrates all necessary components whilst still being able to scale over multiple compute nodes is a challenging task. We introduce a generic method based on the microservice architecture, where software tools are encapsulated as Docker containers that can be connected into scientific workflows and executed using the Kubernetes container orchestrator.

Results: We developed a Virtual Research Environment (VRE) which facilitates rapid integration of new tools and developing scalable and interoperable workflows for performing metabolomics data analysis. The environment can be launched on-demand on cloud resources and desktop computers. IT-expertise requirements on the user side are kept to a minimum, and workflows can be re-used effortlessly by any novice user. We validate our method in the field of metabolomics on two mass spectrometry, one nuclear magnetic resonance spectroscopy and one fluxomics study. We showed that the method scales dynamically with increasing availability of computational resources. We demonstrated that the method facilitates interoperability using integration of the major software suites resulting in a turn-key workflow encompassing all steps for mass-spectrometry-based metabolomics including preprocessing, statistics and identification. Microservices is a generic methodology that can serve any scientific discipline and opens up for new types of large-scale integrative science.

Availability And Implementation: The PhenoMeNal consortium maintains a web portal (https://portal.phenomenal-h2020.eu) providing a GUI for launching the Virtual Research Environment. The GitHub repository https://github.com/phnmnl/ hosts the source code of all projects.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761976PMC
October 2019

Biochemical Differences in Cerebrospinal Fluid between Secondary Progressive and Relapsing⁻Remitting Multiple Sclerosis.

Cells 2019 01 24;8(2). Epub 2019 Jan 24.

Department of Medical Sciences, Clinical Chemistry, Uppsala University, 751 85 Uppsala, Sweden.

To better understand the pathophysiological differences between secondary progressive multiple sclerosis (SPMS) and relapsing-remitting multiple sclerosis (RRMS), and to identify potential biomarkers of disease progression, we applied high-resolution mass spectrometry (HRMS) to investigate the metabolome of cerebrospinal fluid (CSF). The biochemical differences were determined using partial least squares discriminant analysis (PLS-DA) and connected to biochemical pathways as well as associated to clinical and radiological measures. Tryptophan metabolism was significantly altered, with perturbed levels of kynurenate, 5-hydroxytryptophan, 5-hydroxyindoleacetate, and -acetylserotonin in SPMS patients compared with RRMS and controls. SPMS patients had altered kynurenine compared with RRMS patients, and altered indole-3-acetate compared with controls. Regarding the pyrimidine metabolism, SPMS patients had altered levels of uridine and deoxyuridine compared with RRMS and controls, and altered thymine and glutamine compared with RRMS patients. Metabolites from the pyrimidine metabolism were significantly associated with disability, disease activity and brain atrophy, making them of particular interest for understanding the disease mechanisms and as markers of disease progression. Overall, these findings are of importance for the characterization of the molecular pathogenesis of SPMS and support the hypothesis that the CSF metabolome may be used to explore changes that occur in the transition between the RRMS and SPMS pathologies.
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http://dx.doi.org/10.3390/cells8020084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406712PMC
January 2019

Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial.

JAMA 2019 01;321(2):165-174

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Importance: Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS).

Objective: To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression.

Design, Setting, And Participants: Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018.

Interventions: Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55).

Main Outcomes And Measures: The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios.

Results: Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, -1.7; 95% CI, -2.03 to -1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events).

Conclusions And Relevance: In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety.

Trial Registration: ClinicalTrials.gov Identifier: NCT00273364.
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http://dx.doi.org/10.1001/jama.2018.18743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439765PMC
January 2019

Intrathecal treatment trial of rituximab in progressive MS: An open-label phase 1b study.

Neurology 2018 11 10;91(20):e1893-e1901. Epub 2018 Oct 10.

From the Department of Pharmacology and Clinical Neuroscience (J. Bergman, J.D.G., T.B., A.S.), Umeå University; Department of Neurosciences (J. Burman, E.J.), Uppsala University; Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (H.Z.), London; and Department of Clinical Sciences (A.S.), Karolinska Institute Danderyd Hospital, Stockholm, Sweden.

Objectives: To perform a phase 1b assessment of the safety and feasibility of intrathecally delivered rituximab as a treatment for progressive multiple sclerosis (PMS) and to evaluate the effect of treatment on disability and CSF biomarkers during a 1-year follow-up period.

Methods: Three doses of rituximab (25 mg with a 1-week interval) were administered in 23 patients with PMS via a ventricular catheter inserted into the right frontal horn and connected to a subcutaneous Ommaya reservoir. Follow-ups were performed at 1, 3, 6, 9, and 12 months.

Results: Mild to moderate vertigo and nausea were common but temporary adverse events associated with intrathecal rituximab infusion, which was otherwise well tolerated. The only severe adverse event was a case of low-virulent bacterial meningitis that was treated effectively. Of 7 clinical assessments, only 1 showed statistically significant improvement 1 year after treatment. No treatment effect was observed during the follow-up period among 6 CSF biomarkers.

Conclusions: Intrathecal administration of rituximab was well tolerated. However, it may involve a risk for injection-related infections. The lack of a control group precludes conclusions being drawn regarding treatment efficacy.

Clinicaltrialsgov Identifier: NCT01719159.

Classification Of Evidence: This study provides Class IV evidence that intrathecal rituximab treatment is well tolerated and feasible in PMS but involves a risk of severe infections.
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http://dx.doi.org/10.1212/WNL.0000000000006500DOI Listing
November 2018