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  • 1.
    de Flon, Pierre
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Treatment with the monoclonal antibody rituximab in Multiple Sclerosis: a study based on an academic clinical trial2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Multiple sclerosis (MS) is a chronic, inflammatory disease, affecting the central nervous system. A growing number of disease modifying treatment alternatives entails a need for an individualised risk-benefit- convenience analysis in the counselling of patients and methods to monitor the treatment effect, including markers for subclinical inflammation. Today, MRI and the biomarker neurofilament light chain (NFL) in cerebrospinal fluid (CSF- NFL) are commonly used. The development of new techniques for analysing NFL in very low concentrations in serum or plasma provides a promising opportunity for a less invasive method. Rituximab is a chimeric monoclonal antibody with B- cell depleting properties vastly used in rheumatological disease and certain haematological malignancies. Phase II studies have shown a beneficial effect on inflammation also in MS, the detailed mechanisms of action yet to be explained.

    Aims: The aims of this thesis were to evaluate rituximab as a treatment alternative in relapsing remitting MS (RRMS) by describing the clinical effect and patient related outcome measures after a switch of therapy from first-line injectables to rituximab and to explore possible immunological mechanisms of B cell depletion as well as to evaluate the use of neurofilament in plasma (p-NFL) as an end-point in a clinical trial setting.

    Methods: The thesis is based on the open-label phase II multicentre clinical trial Switch-To-RItuXimab in MS (STRIX-MS; EudraCT 2010-023021-38), in which 75 patients completed a therapy switch from first-line injectables to rituximab, and, to some part, the extended follow-up study, STRIX-MS extension (EudraCT 2013-002378-26). The disease modifying effect was evaluated by regular clinical evaluations, MRI and analyses of CSF-NFL. The clinical outcome was evaluated by the EDSS and SDMT scales. The questionnaires MSIS-29, FSMC and TSQM were used for the evaluation of patient related outcome measures. Immunological mechanisms of the B cell depletion were explored by the analysis of a broad panel of cyto- and chemokines in CSF by an electrochemiluminiscens method before and after therapy switch, and in comparison to healthy controls. The concentration of p-NFL was measured by an in-house NF-light assay on the Simoa platform with a Homebrew kit and explored for the use as a clinical trial end-point.

    Results: During the follow-up, signs of inflammatory activity decreased. Both the mean number of Gd enhancing lesions (0.03 vs 0.36, p=0.029) and the number of new or enlarged T2 lesions were reduced (0.01 vs 0.28, p=0.01). The mean concentration of CSF-NFL was reduced during the first year (491 vs 387, p=0.01). The corresponding reduction in plasma did not reach the level of statistical significance. The rating of overall treatment satisfaction improved significantly (6.3 vs 4.8, scale range 1-7, p<0.001). In the explorative immunological study, the immunological profile was altered after therapy switch with the most prominent reduction observed in the concentrations of IP-10 and IL-12/23p40.

    Conclusions: The results indicate a disease modifying effect of rituximab in line with other studies and provide support for a superior treatment satisfaction with rituximab as compared with injectable therapies. However, the lack of control group hampers the possibility to draw definite conclusions on the therapy effect. The immunological effects of B cell depletion need to be further explored.

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  • 2.
    de Flon, Pierre
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gunnarsson, Martin
    Laurell, Katarina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Söderström, Lars
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Lindqvist, Thomas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Krauss, Wolfgang
    Dring, Ann
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bergman, Joakim
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Reduced inflammation in relapsing-remitting multiple sclerosis after therapy switch to rituximab2016In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 87, no 2, p. 141-147Article in journal (Refereed)
    Abstract [en]

    Objective: To describe the effects of switching treatment from ongoing first-line injectable therapies to rituximab on inflammatory activity measured by MRI and levels of CSF neurofilament light chain (CSF-NFL) in a cohort of patients with clinically stable relapsing-remitting multiple sclerosis (RRMS).

    Method: Seventy-five patients with clinically stable RRMS treated with the first-line injectables interferon-β (IFN-β) and glatiramer acetate (GA) at 3 Swedish centers were switched to rituximab in this open-label phase II multicenter study. After a run-in period of 3 months, 2 IV doses of 1,000 mg rituximab were given 2 weeks apart followed by repeated clinical assessment, MRI, and CSF-NFL for 24 months.

    Results: The mean cumulated number of gadolinium-enhancing lesions per patient at months 3 and 6 after treatment shift to rituximab was reduced compared to the run-in period (0.028 vs 0.36, p = 0.029). During the first year after treatment shift, the mean number of new or enlarged T2 lesions per patient was reduced (0.01 vs 0.28, p = 0.004) and mean CSF-NFL levels were reduced by 21% (p = 0.01).

    Conclusions: For patients with RRMS, a treatment switch from IFN or GA to rituximab is associated with reduced inflammatory activity measured by MRI and CSF-NFL.

    Classification of evidence: This study provides Class IV evidence that rituximab has an equal or superior effect in reducing inflammatory activity in RRMS measured by MRI and CSF-NFL compared to first-line injectables during the first year after treatment shift.

  • 3.
    de Flon, Pierre
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Laurell, Katarina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Blennow, Kaj
    Söderström, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Zetterberg, Henrik
    Gunnarsson, Martin
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Clinical Sciences, Karolinska Institute Danderyd Hospital, Stockholm, Sweden.
    Comparison of plasma and cerebrospinal fluid neurofilament light in a multiple sclerosis trial2019In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 139, no 5, p. 462-468Article in journal (Refereed)
    Abstract [en]

    Objective: The main objective of this study was to evaluate the axonal component neurofilament light protein (NFL) in plasma and cerebrospinal fluid (CSF) as an outcome measure in a clinical trial on disease-modifying treatments in multiple sclerosis.

    Materials and methods: Seventy-five patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) participating in the clinical trial "Switch-To RItuXimab in MS" (STRIX-MS) were switched to rituximab from first-line injectable therapy and then followed up for 2 years. Thirty patients from the extension trial (STRIX-MS extension), accepting repeated lumbar punctures, were followed up for an additional 3 years. Plasma and CSF samples were collected yearly during the follow-up. NFL concentration in plasma was measured by an in-house NF-light assay on the Simoa platform with a Homebrew kit. NFL concentration in CSF was measured by sandwich ELISA.

    Results: The mean levels of NFL, in both CSF and plasma, were low. The reduction of CSF-NFL was 25% during the first year of follow-up (from a mean of 471 [SD 393] to 354 [SD 174] pg/mL; P = 0.006) and was statistically significant. The corresponding reduction in plasma NFL was 18% (from 9.73 [SD 7.04] to 7.94 [SD 3.10] pg/mL; P = 0.055) and did not reach statistical significance.

    Conclusion: This study indicates that NFL in plasma is less sensitive as an endpoint in group comparisons than NFL in CSF. Given that plasma NFL is far easier to access, it is a promising and awaited method but further studies are needed to optimize the use in clinical trials.

  • 4.
    de Flon, Pierre
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Laurell, Katarina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Blennow, Kaj
    Department of Psychiatry and Neurochemistry; Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 3 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Söderström, Lars
    Unit of Research, Education and Development, Region Jämtland Härjedalen, Sweden.
    Zetterberg, Henrik
    Department of Psychiatry and Neurochemistry; Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 3 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden 4 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK 5 UK Dementia Research Institute at UCL, London, UK.
    Gunnarsson, Martin
    Department of Neurology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Svenningsson, Anders
    Department of Clinical Sciences, Karolinska Institute Danderyd Hospital, Stockholm, Sweden.
    Comparison of plasma and CSF Neurofilament light as outcome in a multiple sclerosis trialManuscript (preprint) (Other academic)
    Abstract [en]

    Objective: The main objective of this study was to evaluate the axonal component neurofilament light protein (NFL) in plasma and cerebrospinal fluid (CSF) as an outcome measure in a clinical trial on disease-modifying treatments in multiple sclerosis.

    Method: Seventy-five patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) participating in the clinical trial “Switch-To RItuXimab in MS” (STRIX-MS) were switched to rituximab from first-line injectable therapy and then followed for two years. Thirty patients from the extension trial (STRIX-MS extension), accepting repeated lumbar punctures, were followed for an additional three years. Plasma and CSF samples were collected yearly during the follow-up. NFL concentration in plasma was measured by an in-house NF-light assay on the Simoa platform with a Homebrew kit. NFL concentration in CSF was measured by sandwich ELISA.

    Results: The mean levels of NFL, in both CSF and plasma, were low. The reduction of CSF-NFL with 25% during the first year of follow-up (from a mean of 471 (SD 393) to 354 (SD 174) pg/mL; p=0.006) was statistically significant. The corresponding reduction in plasma-NFL was 18% (from 9.73 (SD 7.04) to 7.94 (SD 3.10) pg/mL; p=0.055) and did not reach the level of statistical significance.

    Conclusion: This study indicates that NFL in plasma is less sensitive as an endpoint in group comparisons than NFL in CSF. Given that plasma NFL is far easier to access, it is a promising and awaited method but further studies are needed to optimise the use in clinical trials.

  • 5.
    de Flon, Pierre
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Neurology, Östersund Hospital, Östersund, Sweden.
    Laurell, Katarina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Söderström, Lars
    Gunnarsson, Martin
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Improved treatment satisfaction after switching therapy to rituximab in relapsing-remitting MS2017In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 23, no 9, p. 1249-1257Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: New disease-modifying treatment strategies in multiple sclerosis offer possibilities for individualised treatment. In this study, we evaluated patient-reported outcome measures before and after a switch in therapy from first-line injectable treatments to rituximab.

    METHOD: A total of 75 patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) receiving ongoing first-line injectable treatment at three Swedish centres had their treatment switched to rituximab in this open-label phase II multicentre study. Assessment of treatment satisfaction, patient-perceived impact of the disease on daily life, fatigue, cognitive symptoms and disease progression was performed 3 months before and at the time of the treatment shift and then for a subsequent 2-year period.

    RESULTS: The overall treatment satisfaction rating improved significantly from a mean of 4.8 (scale range: 1-7), while on injectable therapies, to a mean of 6.3 after 1 year of rituximab treatment ( p < 0.001). This improvement was sustained after 2 years. There was no significant change in scores for patient-perceived impact of disease, fatigue or disease progression.

    CONCLUSION: A shift in therapy from first-line injectables to rituximab in a cohort of clinically stable RRMS patients was followed by improved treatment satisfaction. This is clinically relevant as it may influence long-term adherence to immunomodulating therapy.

  • 6.
    de Flon, Pierre
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Soderstrom, L.
    Laurell, Katarina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gunnarsson, M.
    Svenningsson, A.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Clinical Sciences, Karolinska Institute, Stockholm, Sweden.
    Changes of cerebrospinal fluid cytokine profile as a result of switching from first line MS-therapies to rituximab2016In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 22, p. 622-622Article in journal (Refereed)
  • 7.
    de Flon, Pierre
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Söderström, Lars
    Laurell, Katarina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Dring, Ann
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gunnarsson, Martin
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Dept of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm.
    Immunological profile in cerebrospinal fluid of patients with multiple sclerosis after treatment switch to rituximab and compared with healthy controls2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 2, article id e0192516Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate changes in the cerebrospinal fluid (CSF) immunological profile after treatment switch from first-line injectables to rituximab in patients with relapsing-remitting MS (RRMS), and to compare the profile in MS patients with healthy controls (HC).

    METHOD: Cerebrospinal fluid from 70 patients with clinically stable RRMS and 55 HC was analysed by a multiplex electrochemiluminescence method for a broad panel of cytokines and immunoactive substances before, and over a two-year period after, treatment switch to rituximab. After quality assessment of data, using a predefined algorithm, 14 analytes were included in the final analysis.

    RESULTS: Ten of the 14 analytes differed significantly in MS patients compared with HC at baseline. Levels of IP-10 (CXCL10), IL-12/23p40, IL-6, sVCAM1, IL-15, sICAM1 and IL-8 (CXCL8) decreased significantly after treatment switch to rituximab. The cytokines IP-10 and IL-12/IL-23p40 displayed the largest difference versus HC at baseline and also the largest relative reduction after therapy switch to rituximab.

    CONCLUSION: We found significant changes in the immunological profile after therapy switch to rituximab in RRMS in the direction towards the values of HC. IP-10 and IL12/IL-23p40 deserve further studies as part of the immunopathogenesis of MS as well as for the mode of action of rituximab in MS.

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