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Fagius, Jan
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Publications (10 of 28) Show all publications
Burt, R. K., Balabanov, R., Burman, J., Sharrack, B., Snowden, J. A., Oliveira, M. C., . . . Helenowski, I. B. (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. Journal of the American Medical Association (JAMA), 321(2), 165-174
Open this publication in new window or tab >>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
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2019 (English)In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 321, no 2, p. 165-174Article in journal (Refereed) Published
Abstract [en]

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 (200mg/kg) and antithymocyte globulin (6mg/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.

Place, publisher, year, edition, pages
AMER MEDICAL ASSOC, 2019
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-375869 (URN)10.1001/jama.2018.18743 (DOI)000455606300015 ()30644983 (PubMedID)
Available from: 2019-02-04 Created: 2019-02-04 Last updated: 2019-02-04Bibliographically approved
Skoog, B., Link, J., Tedeholm, H., Longfils, M., Nerman, O., Fagius, J. & Andersen, O. (2019). Short-term prediction of secondary progression in a slinding window: A test of a prdicting alogrithm in a validation cohort.. Multiple Sclerosis Journal, Experimental, Translational and Clinical, 1-10
Open this publication in new window or tab >>Short-term prediction of secondary progression in a slinding window: A test of a prdicting alogrithm in a validation cohort.
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2019 (English)In: Multiple Sclerosis Journal, Experimental, Translational and Clinical, E-ISSN 2055-2173, p. 1-10Article in journal (Refereed) Published
Keywords
Epidemiology, multiple sclerosis, outcome measurement, progressive, relapsing/remitting
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-402262 (URN)10.1177/2055217319875466 (DOI)
Available from: 2020-01-13 Created: 2020-01-13 Last updated: 2020-01-20Bibliographically approved
Tolf, A., Fagius, J., Carlson, K., Åkerfeldt, T., Granberg, T., Larsson, E.-M. & Burman, J. (2019). Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation. Acta Neurologica Scandinavica, 140(5), 320-327
Open this publication in new window or tab >>Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation
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2019 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 140, no 5, p. 320-327Article in journal (Refereed) Published
Abstract [en]

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.

 

Keywords
cerebrospinal fluid, hematopoietic stem cell transplantation, magnetic resonance imaging, multiple sclerosis
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-390961 (URN)10.1111/ane.13147 (DOI)000479109700001 ()31297793 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)
Available from: 2019-08-16 Created: 2019-08-16 Last updated: 2019-10-30Bibliographically approved
Tolf, A., Granberg, T., Larsson, E.-M., Landtblom, A.-M., Fagius, J. & Burman, J. (2017). Corpus callosum atrophy in MS is halted by autologous haematopoietic stem cell transplantation. Paper presented at 7th Joint European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS)-Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS), OCT 25-28, 2017, Paris, FRANCE. Multiple Sclerosis, 23, 1006-1007
Open this publication in new window or tab >>Corpus callosum atrophy in MS is halted by autologous haematopoietic stem cell transplantation
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2017 (English)In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 23, p. 1006-1007Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
SAGE PUBLICATIONS LTD, 2017
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-345575 (URN)000413730206044 ()
Conference
7th Joint European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS)-Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS), OCT 25-28, 2017, Paris, FRANCE
Available from: 2018-03-12 Created: 2018-03-12 Last updated: 2018-03-12Bibliographically approved
Fagius, J., Feresiadou, A., Larsson, E.-M. & Burman, J. (2017). Discontinuation of disease modifying treatments in middle aged multiple sclerosis patients: First line drugs vs natalizumab. Multiple Sclerosis and Related Disorders, 12, 82-87, Article ID S2211-0348(17)30010-X.
Open this publication in new window or tab >>Discontinuation of disease modifying treatments in middle aged multiple sclerosis patients: First line drugs vs natalizumab
2017 (English)In: Multiple Sclerosis and Related Disorders, ISSN 2211-0348, E-ISSN 2211-0356, Vol. 12, p. 82-87, article id S2211-0348(17)30010-XArticle in journal (Refereed) Published
Abstract [en]

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.

Keywords
Multiple sclerosis, Natalizumab discontinuation, Rebound, Treatment discontinuation
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-317425 (URN)10.1016/j.msard.2017.01.009 (DOI)000396908400017 ()28283113 (PubMedID)
Available from: 2017-03-14 Created: 2017-03-14 Last updated: 2018-09-04Bibliographically approved
Fagius, J., Burman, J., Feresiadou, A. & Larsson, E.-M. (2015). Severe relapses and rebound activity after natalizumab discontinuation in MS patients with more than five years of treatment with stable disease course. Paper presented at 31st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), OCT 07-10, 2015, Barcelona, SPAIN. Multiple Sclerosis, 21, 297-297
Open this publication in new window or tab >>Severe relapses and rebound activity after natalizumab discontinuation in MS patients with more than five years of treatment with stable disease course
2015 (English)In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 21, p. 297-297Article in journal, Meeting abstract (Other academic) Published
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-276952 (URN)000365729400509 ()
Conference
31st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), OCT 07-10, 2015, Barcelona, SPAIN
Available from: 2016-02-23 Created: 2016-02-16 Last updated: 2017-11-30Bibliographically approved
Burman, J., Zetterberg, H., Fransson, M., Loskog, A. S., Raininko, R. & Fagius, J. (2014). Assessing tissue damage in multiple sclerosis: a biomarker approach. Acta Neurologica Scandinavica, 130(2), 81-89
Open this publication in new window or tab >>Assessing tissue damage in multiple sclerosis: a biomarker approach
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2014 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 130, no 2, p. 81-89Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES:

Magnetic resonance imaging (MRI) of the brain and spinal cord is the gold standard for assessing disease activity in multiple sclerosis (MS). MRI is an excellent instrument for determination of accumulated damage to the brain and spinal cord, but tells us little about ongoing tissue damage. In this study, biomarkers of oligodendrocyte, axonal and astrocyte injury were related to MRI and clinical findings and used to assess tissue damage in MS.

MATERIALS AND METHODS:

Cerebrospinal fluid from 44 patients with relapsing-remitting MS, 20 with secondary progressive MS and 15 controls were investigated with ELISA to determine levels of myelin basic protein (MBP), neurofilament light (NFL) and glial fibrillary acidic protein (GFAp). Patients underwent MRI of the brain and spinal cord, and gadolinium enhancing lesions, T1 lesions and T2 lesions were counted.

RESULTS:

Patients in clinical relapse and patients with nonsymptomatic gadolinium enhancing lesions had high levels of MBP and NFL, indicating ongoing damage to oligodendrocytes and axons. The level of MBP dropped quickly within a week from the onset of a relapse, whereas NFL remained elevated for several weeks and GFAp slowly rose during the course of a relapse. Relapsing-remitting MS patients without gadolinium enhancing lesions had values of MBP, NFL and GFAp similar to controls, while patients with secondary progressive disease had moderately increased values of all biomarkers.

CONCLUSIONS:

Analysis of MBP, NFL and GFAp provides direct means to measure tissue damage and is a useful addition to our methods for evaluation of MS.

National Category
Neurosciences Neurology
Research subject
Clinical Immunology
Identifiers
urn:nbn:se:uu:diva-219571 (URN)10.1111/ane.12239 (DOI)000339951900006 ()24571714 (PubMedID)
Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2018-01-11Bibliographically approved
Burman, J., Iacobaeus, E., Svenningsson, A., Lycke, J., Gunnarsson, M., Nilsson, P., . . . Fagius, J. (2014). Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. Journal of Neurology, Neurosurgery and Psychiatry, 85(10), 1116-1121
Open this publication in new window or tab >>Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience
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2014 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 85, no 10, p. 1116-1121Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-223632 (URN)10.1136/jnnp-2013-307207 (DOI)000344456000228 ()24554104 (PubMedID)
Available from: 2014-04-23 Created: 2014-04-23 Last updated: 2017-12-05Bibliographically approved
Fagius, J. & Burman, J. (2014). Normal outcome of pregnancy with ongoing treatment with natalizumab. Acta Neurologica Scandinavica, 129(6), e27-e29
Open this publication in new window or tab >>Normal outcome of pregnancy with ongoing treatment with natalizumab
2014 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 129, no 6, p. e27-e29Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Treatment of multiple sclerosis (MS) with natalizumab during pregnancy is not recommended due to potential risks for the foetus. Despite strong advice accidental pregnancies occur.

CASE: A 32-year old woman with MS since the age of 26 was treated with natalizumab since January 2008. Treatment was stopped April 2011 due to pregnancy plans, but was restarted following an MS relapse. The patient was thoroughly informed about potential foetal risks, but nevertheless she one year later disclosed that she was pregnant in gestational week 15. Treatment was continued, since the first trimester had passed. The pregnancy course was normal and a healthy daughter was born at full gestational term.

CONCLUSIONS: This is the second known case where natalizumab treatment continued throughout the whole gestational period.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-223633 (URN)10.1111/ane.12222 (DOI)000333851500001 ()24527849 (PubMedID)
Available from: 2014-04-23 Created: 2014-04-23 Last updated: 2017-12-05Bibliographically approved
Burman, J., Svensson, E., Fransson, M., Loskog, A. S., Zetterberg, H., Raininko, R., . . . Mangsbo, S. M. (2014). The cerebrospinal fluid cytokine signature of multiple sclerosis: A homogenous response that does not conform to the Th1/Th2/Th17 convention. Journal of Neuroimmunology, 277(1-2), 153-159
Open this publication in new window or tab >>The cerebrospinal fluid cytokine signature of multiple sclerosis: A homogenous response that does not conform to the Th1/Th2/Th17 convention
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2014 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 277, no 1-2, p. 153-159Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-239312 (URN)10.1016/j.jneuroim.2014.10.005 (DOI)000347663100019 ()25457841 (PubMedID)
Available from: 2014-12-22 Created: 2014-12-22 Last updated: 2017-12-05Bibliographically approved
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