Treatment with the monoclonal antibody rituximab in Multiple Sclerosis: a study based on an academic clinical trial

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Fältnamn	Indikatorer	Metadata
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001		oai:DiVA.org:umu-145875
003		SwePub
008		180326s2018 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
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024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1458752 URI
040		a (SwePub)umu
041		a engb eng
042		9 SwePub
072	7	a vet2 swepub-contenttype
072	7	a dok2 swepub-publicationtype
100	1	a de Flon, Pierre,d 1966-u Umeå universitet,Klinisk neurovetenskap4 aut0 (Swepub:umu)pide0005
245	1 0	a Treatment with the monoclonal antibody rituximab in Multiple Sclerosis :b a study based on an academic clinical trial
264	1	a Umeå :b Umeå universitet,c 2018
300		a 50 s.
338		a electronic2 rdacarrier
490	0	a Umeå University medical dissertations,x 0346-6612 ;v 1951
520		a 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.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Neurologi0 (SwePub)302072 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Neurology0 (SwePub)302072 hsv//eng
653		a Multiple sclerosis
653		a Rituximab
653		a Cytokines
653		a Immunological profile
653		a Neurofilament light
653		a Treatment satisfaction
653		a neurologi
653		a Neurology
700	1	a Svenningsson, Anders,c Professoru Umeå universitet,Klinisk neurovetenskap,Department of Clinical Sciences, Karolinska Institute Danderyd Hospital, Stockholm, Sweden4 ths0 (Swepub:umu)ansv0041
700	1	a Gunnarsson, Martin,c Docentu Department of Neurology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden4 ths
700	1	a Laurell, Katarina,c Docentu Umeå universitet,Klinisk neurovetenskap4 ths0 (Swepub:umu)kala0094
700	1	a Fredrikson, Sten,c Professoru Institutionen för Klinisk Neurovetenskap, Karolinska Institutet, Karolinska Universitetssjukhuset Huddinge, Sverige4 opn
710	2	a Umeå universitetb Klinisk neurovetenskap4 org
856	4	u https://umu.diva-portal.org/smash/get/diva2:1193059/FULLTEXT01.pdfx primaryx Raw objecty fulltext
856	4	u https://umu.diva-portal.org/smash/get/diva2:1193059/FULLTEXT02.pdfy spikblad
856	4	u https://umu.diva-portal.org/smash/get/diva2:1193059/ERRATA01.pdfy errata
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-145875

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