Publications by authors named "Jan Fagius"

16 Publications

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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

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

Tack för erbjudandet, men nej tack...

Authors:
Jan Fagius

Lakartidningen 2018 04 24;115. Epub 2018 Apr 24.

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April 2018

Discontinuation of disease modifying treatments in middle aged multiple sclerosis patients. First line drugs vs natalizumab.

Mult Scler Relat Disord 2017 Feb 24;12:82-87. Epub 2017 Jan 24.

Department of Neuroscience, Uppsala University, Uppsala, Sweden.

Background: Several disease-modifying drugs (DMD) are available for the treatment of MS, and most patients with relapsing-remitting disease are currently treated. Data on when and how DMD treatment can be safely discontinued are scarce.

Methods: Fifteen MS patients, treated with natalizumab for >5 years without clinical and radiological signs of inflammatory disease activity, suspended treatment and were monitored with MRI examinations and clinical follow-up to determine recurrence of disease activity. This group was compared with a retrospectively analysed cohort comprising 55 MS patients treated with first-line DMDs discontinuing therapy in the time period of 1998-2015 after an analogous stable course.

Results: Natalizumab discontinuers were followed for on average 19 months, and follow-up data for 56 months were available for first-line DMD quitters. Two-thirds of natalizumab treated patients experienced recurrent inflammatory disease activity, and one third had recurrence of rebound character. In contrast, 35% of first-line DMD quitters had mild recurrent disease activity, and no one exhibited rebound.

Conclusions: Withdrawal of a first-line DMD after prolonged treatment in middle-aged MS patients with stable disease appears to be relatively safe, while natalizumab withdrawal in a similar group of patients cannot be safely done without starting alternative therapy.
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http://dx.doi.org/10.1016/j.msard.2017.01.009DOI Listing
February 2017

The cerebrospinal fluid cytokine signature of multiple sclerosis: a homogenous response that does not conform to the Th1/Th2/Th17 convention.

J Neuroimmunol 2014 Dec 18;277(1-2):153-9. Epub 2014 Oct 18.

Department of Immunology, Genetics and Pathology, Science for Life Laboratories, Uppsala University, Uppsala, Sweden.

In this cross-sectional study, we wanted to identify key cytokines characteristic of different stages of multiple sclerosis (MS). To this end, cerebrospinal fluid from patients with MS was investigated with a multiplexed fluorescent bead-based immunoassay. In total 43 cytokines were assessed and related to clinical and imaging data. Increased levels of CCL22, CXCL10 and sCD40L characterized relapsing-remitting MS patients with the presence of gadolinium-enhancing lesions; decreased CCL2 and increased CXCL1 and CCL5 were typical of relapsing-remitting MS patients irrespectively of the presence of gadolinium-enhancing lesions. These homogenous patterns of cytokine activation do not conform to conventional Th1/Th2/Th17 responses.
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http://dx.doi.org/10.1016/j.jneuroim.2014.10.005DOI Listing
December 2014

Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience.

J Neurol Neurosurg Psychiatry 2014 Oct 19;85(10):1116-21. Epub 2014 Feb 19.

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

Background: Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS.

Methods: Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months.

Results: At 5 years, relapse-free survival was 87%; MRI event-free survival 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%).

Conclusions: HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres.
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http://dx.doi.org/10.1136/jnnp-2013-307207DOI Listing
October 2014

T-cell responses after haematopoietic stem cell transplantation for aggressive relapsing-remitting multiple sclerosis.

Immunology 2013 Oct;140(2):211-9

Department of Neurosciences, Uppsala University, Uppsala, Sweden; Department of Neurology, Uppsala University Hospital, Uppsala, Sweden; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Autologous haematopoietic stem cell transplantation (HSCT) for relapsing-remitting multiple sclerosis is a potentially curative treatment, which can give rise to long-term disease remission. However, the mode of action is not yet fully understood. The aim of the study was to evaluate similarities and differences of the CD4(+) T-cell populations between HSCT-treated patients (n = 12) and healthy controls (n = 9). Phenotyping of memory T cells, regulatory T (Treg) cells and T helper type 1 (Th1) and type 17 (Th17) cells was performed. Further, T-cell reactivity to a tentative antigen, myelin oligodendrocyte glycoprotein, was investigated in these patient populations. Patients treated with natalizumab (n = 15) were included as a comparative group. White blood cells were analysed with flow cytometry and T-cell culture supernatants were analysed with magnetic bead panel immunoassays. HSCT-treated patients had similar levels of Treg cells and of Th1 and Th17 cells as healthy subjects, whereas natalizumab-treated patients had lower frequencies of Treg cells, and higher frequencies of Th1 and Th17 cells. Cells from HSCT-treated patients cultured with overlapping peptides from myelin oligodendrocyte glycoprotein produced more transforming growth factor-β1 than natalizumab-treated patients, which suggests a suppressive response. Conversely, T cells from natalizumab-treated patients cultured with those peptides produced more interleukin-17 (IL-17), IL-1 and IL-10, indicating a Th17 response. In conclusion, we demonstrate circumstantial evidence for the removal of autoreactive T-cell clones as well as development of tolerance after HSCT. These results parallel the long-term disease remission seen after HSCT.
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http://dx.doi.org/10.1111/imm.12129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784167PMC
October 2013

High resting level and weak response of baroreflex-governed sympathetic outflow in amyotrophic lateral sclerosis.

Muscle Nerve 2011 Mar 8;43(3):432-40. Epub 2011 Feb 8.

Department of Neurology, University Hospital, Uppsala SE-751 85, Sweden.

Both altered sympathetic function and insulin resistance have been observed in amyotrophic lateral sclerosis (ALS). Insulin is a sympathetic stimulator. We recorded muscle sympathetic nerve activity (MSNA) by microneurography in 9 patients with ALS and 9 healthy controls during rest. We also initiated a number of sympathoexcitatory maneuvers, including intake of 100 g of glucose. Patients showed reduced glucose tolerance and a higher heart rate and higher level of MSNA at rest than controls (61.0 ± 15.2 vs. 41.2 ± 5.8 bursts/min, P = 0.006); baroreflex inhibitory influence was present. In contrast, MSNA in ALS patients responded more weakly to maneuvers. This inverse relationship is interpreted as a "ceiling effect," as ALS patients use nearly maximal MSNA capacity already at rest and do not have sympathetic failure. The increased level of MSNA may be a primary feature of ALS, but insulin stimulation may also contribute. Our findings are assessed in relation to previous, sometimes seemingly contradictory observations.
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http://dx.doi.org/10.1002/mus.21894DOI Listing
March 2011

Strong potential for baroreflex-governed sympathetic outflow revealed during nausea.

Clin Auton Res 2010 Dec 1;20(6):371-4. Epub 2010 Aug 1.

Department of Neurology, Akademiska sjukhuset/University Hospital, 751 85 Uppsala, Sweden.

Muscle sympathetic nerve activity (MSNA) was recorded in two patients with amyotrophic lateral sclerosis. As expected, they exhibited a high level of MSNA at rest, with an inverse weak response to different maneuvers normally eliciting strong increase in MSNA. About 30 min after the intake of a glucose solution, they developed nausea with an extreme rise in MSNA and blood pressure. In one patient, a quantified analysis of this reaction could be done: the outflow was close to 200% above the already high resting level and >100% stronger than the response to any of the performed maneuvers. We regard this observation of importance, because it seems to unveil resources utilized only rarely, and strongly overcoming the "ceiling effect" that seemingly is a hindrance for sympathetic activation in subjects with high lever of MSNA at rest. An inhibitory "safety limit" might exist, the trespassing of which would damage the organism and thus occurs only during extraordinary circumstances.
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http://dx.doi.org/10.1007/s10286-010-0076-4DOI Listing
December 2010

T regulatory cells lacking CD25 are increased in MS during relapse.

Autoimmunity 2010 Dec 7;43(8):590-7. Epub 2010 Apr 7.

Clinical Immunology division, Uppsala University, Uppsala, 751 85, Sweden.

Dysregulation of inflammatory responses is considered to be a key element in autoreactive immune responses. T regulatory cells (Tregs) are important to maintain self-tolerance and the role of CD4(+)CD25(+)FoxP3(+) Tregs in autoimmunity has been extensively investigated. Recently, it was shown that Tregs in systemic lupus erythematosus lacked CD25 but were biologically functional. These data warrants for further investigation of CD25(- ) Tregs in human autoimmunity. We analyzed relapsing-remitting multiple sclerosis (MS) patients by multicolor flow cytometry for the expression of CD3, CD4, IL2R (CD25), FoxP3, and the IL7R (CD127). Further, the level of Tregs was compared in remitting and relapsing patients and correlated with disease duration. Patients in relapse exhibited higher levels of FoxP3-positive Tregs lacking CD25 compared to healthy controls (p < 0.05), indicating that Tregs attempt to restrain immune activity during relapse. The proportion of Tregs tended to be decreased with disease duration, while CD25(+)CD4(+) and CD25(+)CD8(+) effector T-cell proportions were elevated and positively correlated with overall disease duration (p < 0.05). In conclusion, while MS patients in remission have normal levels of Tregs of different phenotype, relapsing patients show an increased proportion of systemic CD25(-)FoxP3(+) Tregs. With time, the proportion of Tregs decrease while effector T cells expand.
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http://dx.doi.org/10.3109/08916930903541190DOI Listing
December 2010

The T-cell pool is anergized in patients with multiple sclerosis in remission.

Immunology 2009 Jan 24;126(1):92-101. Epub 2008 Jun 24.

Clinical Immunology Division, Uppsala University, Uppsala, Sweden.

Relapsing-remitting multiple sclerosis (RRMS) is a complex autoimmune disease of the central nervous system with oscillating phases of relapse and remission. RRMS has been considered to be driven by T helper type 1 (Th1) lymphocytes but new data indicate the involvement of Th17 responses. In the present study, blood samples from patients (n=48) and healthy individuals (n=44) were evaluated for their immunological status. T cells from patients with RRMS expressed high levels of the activation marker CD28 (P<0.05) and secreted both interferon-gamma (CD8: P<0.05) and interleukin-17 upon polyclonal mitogen or myelin oligodendrocyte glycoprotein antigen stimulation. However, T cells from patients with RRMS in remission, in contrast to relapse, had poor proliferative capacity (P<0.05) suggesting that they are controlled and kept in anergy. This anergy could be broken with CD28 stimulation that restored the T-cell replication. Furthermore, the patients with RRMS had normal levels of CD4(+) Foxp3(+) T regulatory cells but the frequency of Foxp3(+) cells lacking CD127 (interleukin-7 receptor) was lower in patients with MS (mean 12%) compared to healthy controls (mean 29%). Still, regulatory cells (CD25(+) sorted cells) from patients with RRMS displayed no difference in suppressive capacity. In conclusion, patients in relapse/remission demonstrate in vitro T-cell responses that are both Th1 and Th17 that, while in remission, appear to be controlled by tolerogenic mechanisms yet to be investigated.
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http://dx.doi.org/10.1111/j.1365-2567.2008.02881.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2632699PMC
January 2009

[Hematopoietic stem cell transplantation in MS. Justified, and if so, when?].

Lakartidningen 2006 Mar 1-7;103(9):640-2

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April 2006

[TGA: Clinical assessment is sufficient in the investigation!].

Authors:
Jan Fagius

Lakartidningen 2005 Jul 11-24;102(28-29):2093; author reply 2093

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August 2005

[Disease-modifying treatment of MS--progress with complications].

Authors:
Jan Fagius

Lakartidningen 2003 Mar;100(13):1164, 1167-8

Neurologiska kliniken, Neurocentrum, Akademiska sjukhuset, Uppsala.

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March 2003

Sympathetic nerve activity to amputated lower leg in humans. Evidence of altered skin vasoconstrictor discharge.

Pain 2002 Jul;98(1-2):37-45

Department of Neurology, University Hospital, S-751 85 Uppsala, Sweden.

Transection of a peripheral nerve in the cat is known to cause a regional change in sympathetic impulse pattern. Our aim was to determine whether microneurography can be used to study sympathetic activity in the transected nerve of human amputees, and whether any such activity shows an abnormal pattern similar to that observed in the cat. Seven successful sympathetic recording sessions were performed in the peroneal nerve of four subjects with posttraumatic transtibial leg amputation; one of them was studied on four occasions. Muscle nerve sympathetic activity (MSA) was detected in all four subjects. Skin nerve sympathetic activity (SSA) was found in one patient only, but on three occasions. It was more difficult to obtain high quality sympathetic recordings than for intact nerves, particularly in patients amputated many years before our studies. MSA showed a qualitatively normal pattern at rest and during various manoeuvres. In three recordings from skin nerve fascicles without innervation zone, SSA displayed normal characteristics at room temperature and qualitatively normal responses to arousal stimuli and various manoeuvres. During body cooling there was an abnormal shift in SSA pattern with a reduction in burst duration instead of the increase occurring normally. Cardiac rhythmicity of SSA was more pronounced during body cooling than during body heating. This is also a reversal of the normal pattern. The abnormal SSA pattern during body cooling suggests increased baroreflex regulation of cutaneous vasoconstrictor neurones, similar to the change after nerve transection in the cat. This is the first time that human nerve recordings support the hypothesis of a regional alteration in sympathetic impulse pattern following a nerve lesion. The implications of this phenomenon for pain conditions remains to be explored; our patients did not suffer from phantom or stump pain.
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http://dx.doi.org/10.1016/s0304-3959(01)00466-3DOI Listing
July 2002

Antibody-mediated suppression of Vbeta5.2/5.3(+) T cells in multiple sclerosis: results from an MRI-monitored phase II clinical trial.

Ann Neurol 2002 Apr;51(4):467-74

Department of Neurology, VU Medical Center, Amsterdam, The Netherlands.

The objective of this study was to evaluate the safety and efficacy of the humanized antibody ATM-027 in a baseline versus treatment magnetic resonance imaging-monitored study. Expansion of Vbeta5.2/5.3(+) T cells has been demonstrated in the peripheral blood, cerebrospinal fluid, and brain lesions of MS patients. In a phase I study, ATM-027 depleted these cells in peripheral blood and, in parallel, T-cell MBP reactivity and IFN-gamma expression were reduced. We studied 59 patients with relapsing-remitting MS (47 on ATM-027 and 12 on placebo) stratified for HLA-DR2 status. Monthly intravenous injections were given for 6 months. Individual dose titration was employed to obtain depletion of the target T-cell level and downregulation of antigen receptor density as monitored by flow cytometry. Five monthly magnetic resonance imaging scans were performed before treatment to establish baseline activity, six during treatment, and three during follow-up. Additional immunological assessments were performed to elucidate the mechanism of action of ATM-027. The treatment was safe and well tolerated, inducing consistent suppression of the target cell population. During run-in, active lesions were found in 78.7% (37/47) of patients treated with ATM-027. During treatment, the median number of lesions was reduced by 33% (p = 0.13) independent of DR2 status. The corresponding volume of enhancement was 221 mm(3) at baseline, with a reduction of 10% during treatment. Decreased numbers of cells expressing interferon-gamma messenger RNA, and decreased T-cell reactivity to several myelin antigens were found in ATM-027 treated patients. In conclusion, consistent suppression of Vbeta 5.2/5.3(+) T cells was achieved. However, the effect size on magnetic resonance imaging was considerably less than the targeted 60%.
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http://dx.doi.org/10.1002/ana.10146DOI Listing
April 2002