| 1. |
- Wickström, Anne, 1961-
(författare)
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Work ability in multiple sclerosis : the impact of immunomodulating treatments and adjusted working conditions
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease affecting the central nervous system (CNS) and is considered to be of autoimmune origin. The prevalence in Sweden is estimated to be about 1 in 500. The inflammation leads to demyelination as well as neurodegeneration and with time the patients often suffer from increasing neurological disability. The young age of onset makes MS one of the major causes of reduced ability to work in the Western society. Several factors in the disease affect the work ability. One important factor is ongoing inflammatory activity conferring risk to develop tissue damage and disability. Previous studies have indicated that fatigue, mobility and cognitive problems are the primary symptoms preventing individuals with MS to remain in employment. However, the possibility to adapt both tasks and the workplace, the possibility for sedentary work and flexible working hours also have great influence to keep the individual in employment.The purpose of the thesis was to investigate how factors in the disease, immunomodulating treatments and work requirements influence the ability to work and study in people with MS.Methods: A MS specific questionnaire was used in one retrospective and one prospective study to compare the work ability before and after start of the second-generation immunomodulating drug natalizumab. The number of working hours per week and the degree of sick leave before and after one year of treatment was calculated. The effect of disease-specific and workrelated factors on work ability was evaluated. The treatment effect on fatigue and walking ability was correlated to work ability. In addition, a healtheconomic calculation was performed to estimate the cost-benefit of the treatment. The degree of sickness absence was evaluated in a cross-sectional study of two MS-populations; one historical that never was exposed to immunomodulating drugs and the other consisted of individuals with MS that was diagnosed after the introduction of immunomodulating drugs. Furthermore, work ability was studied in two MS-populations, one southern and one northern cohort of Sweden, for the latter population more active immunomodulating treatment and work-promoting measures have been practiced. The data was collected using the instrument WAQ-MS. Results Paper I: After one year of treatment with natalizumab the average working hours per week had increased with 3.3 hours, corresponding to an economic value of 3216 euro per person per year. Paper II and III: After initiation of treatment with natalizumab, in an active phase of relapsing-remitting MS, the patients improved their working ability after one year from 31 % to 60 % (p<0.001) and reduced their sickness benefit correspondingly (p<0.001) in relation to their total employment rate. They also reported improved physical and cognitive ability in relation to their requirements. Short disease duration, younger age and lower Expanded Disability Status Scale (EDSS) grade at treatment onset predicted a positive effect on work ability and also improvement of walking ability correlated significantly with reduced sick leave. Paper IV: The proportion of individuals without any kind of sickness absence was higher in the MS population being exposed to disease modifying drugs compared to the unexposed population (66 % vs 38 %) (p<0.001). In addition, the proportion of patients with full-time sickness absence was higher in the unexposed compared to the exposed population (32 % vs 16 %) (p<0.001). The median EDSS was lower in the exposed compared to the unexposed MS population (p<0.001). Paper V: The proportion of MS patients who participated in the work force or studied was significantly higher in the northern cohort, where they had been exposed to more work promoting measures, compared with the southern cohort (p=0.022). MS patients in the northern cohort had significantly lower physical and cognitive requirements in their occupations, more adapted work conditions and could work more hours per week compared with the southern cohort. The EDSS level explained 12 % of the working ability in the northern cohort and 21 % in the southern cohort.Conclusion Our results indicate that patients in the inflammatory phase of the disease may retain their work ability several years after disease onset if they are subjected to effective anti-inflammatory treatment regimens from disease onset. Furthermore, work ability may be additionally improved by adjusted working conditions even in the progressive phase of the disease. It is obvious that these results have implications in a socioeconomic perspective as well as for the individual patients as improved quality of life due to retained work-life participation. Long-term follow-up of our data is required to determine whether these positive effects are durable over longer time-periods.
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| 2. |
- Bergman, Joakim, 1989-
(författare)
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Studies of the Biology of Intrathecal Treatment in Progressive MS
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Multiple Sclerosis (MS) is a chronic, inflammatory, autoimmune disease, affecting the central nervous system (CNS). About 85% of afflicted present with a relapsing-remitting form of the disease (RRMS), for which a breakthrough in treatment was made in 2008 with rituximab, an antibody directed towards CD20, a surface antigen on B-cells. These findings also contributed to cementing the importance of the B-cell’s role in MS pathophysiology. However, MS also exist as a progressive phenotype, affecting most MS patients either from onset or after a transition from RRMS, and for progressive MS the same treatment effect of anti-CD20 has not been observed. Still, studies have found follicle-like structures containing B-cells in meninges and subarachnoid space of the cortex in progressive MS brains, supporting the involvement of B-cells. Evidence also support the existence of a chronic, low-grade inflammatory process compartmentalised within the CNS that correlates with the progressive phase of MS, which may present a treatment barrier towards anti-CD20. Peripherally administrated therapeutic antibodies cross the intact blood-brain barrier with low efficiency with only 0.1-0.5% of the plasma concentration occurring in the cerebrospinal fluid (CSF). Intrathecal (IT) administration circumvents the blood-brain barrier, presenting an opportunity to better target the CNS B-cells.Aims: To evaluate the safety and feasibility of intrathecal anti-CD20 therapy with rituximab in progressive MS, its effect on disease progression through clinical parameters, and impact on biomarkers in CSF. Furthermore, this thesis aimed to evaluate the effect on biomarkers representative of cell injury related to insertion of a ventricular catheter for drug administration and to examine the interstitial milieu in the brain through microdialysis (MD).Methods: The thesis is based on the open-label, phase IIb, multicentre clinical trial Intrathecal Treatment Trial in Progressive Multiple Sclerosis (ITT-PMS; EudraCT 2008-002626-11), in which 23 participants received IT treatment with rituximab, and the extended follow-up study, ITT-PMS extension (EudraCT 2012-000721-53). All participants received a ventricular catheter and an Ommaya reservoir for drug administration through a neurosurgical procedure, and 10 participants received a MD catheter in parallel to the ventricular catheter for 10 days. The treatment effect was evaluated by regular clinical evaluations and analyses of CSF. The clinical outcome was evaluated through walking and upper-limb function tests, and by clinical evaluation scales. Levels of selected CSF biomarkers were analysed from the same time-points as the clinical evaluations.Results: After the completion of the extension trial, one clinical parameter (cognitive performance) showed improvement but could most likely be explained by a learning effect. Worsening of walking speed was observed, while the remaining clinical parameters showed no change. Two severe adverse events occurred in the form of low-virulent bacterial meningitis caused by Propionibacterium, but both were treated effectively with antibiotics without residual symptoms. A ‘spike’ was noticed in the level of lumbar CSF neurofilament light (NFL) following surgery but returned to pre-surgery baseline within 6-12 months. No change was observed for any of the other lumbar CSF biomarkers. No meaningful correlation of protein levels was observed when comparing MD samples, ventricular CSF, and lumbar CSF.Conclusions: Intrathecal treatment through intraventricular administration was well tolerated but not without risks. A continued progression was observed in gait impairment. The insertion of the ventricular catheter caused white matter injury, measured through an increase in NFL in lumbar CSF, in direct association with the surgical procedure. No impact was observed on other CSF biomarkers. There was a poor correlation between different CNS compartments regarding protein levels, arguing for caution in drawing conclusions about brain pathophysiology from lumbar CSF samples.
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| 3. |
- de Flon, Pierre, 1966-
(författare)
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Treatment with the monoclonal antibody rituximab in Multiple Sclerosis : a study based on an academic clinical trial
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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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| 4. |
- Bergquist, Filip, et al.
(författare)
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Pharmacokinetics of Intravenously (DIZ101), Subcutaneously (DIZ102), and Intestinally (LCIG) Infused Levodopa in Advanced Parkinson Disease
- 2022
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Ingår i: Neurology. - : Lippincott, Williams & Wilkins. - 0028-3878 .- 1526-632X. ; 99:10, s. E965-E976
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives Intestinal levodopa/carbidopa gel infusion (LCIG) is superior to oral treatment in advanced Parkinson disease. The primary objective of this trial was to investigate whether continuous subcutaneous or intravenous infusion with a continuously buffered acidic levodopa/carbidopa solution yields steady-state plasma concentrations of levodopa that are equivalent in magnitude, and noninferior in variability, to those obtained with LCIG in patients with advanced Parkinson disease. Methods A concentrated acidic levodopa/carbidopa (8:1) solution buffered continuously and administered intravenously (DIZ101) or subcutaneously (DIZ102) was compared with an approved LCIG in a randomized, 3-period crossover, open-label, multicenter trial. Formulations were infused for 16 hours to patients with Parkinson disease who were using LCIG as their regular treatment. Patients were recruited from several university neurology clinics but came to the same phase I unit for treatment. Pharmacokinetic variables and safety including dermal tolerance are reported. The primary outcomes were bioequivalence and noninferior variability of DIZ101 and DIZ102 vs LCIG with respect to levodopa plasma concentrations. Results With dosing adjusted to estimated bioavailability, DIZ101 and DIZ102 produced levodopa plasma levels within standard bioequivalence limits compared with LCIG in the 18 participants who received all treatments. Although the levodopa bioavailability for DIZ102 was complete, it was 80% for LCIG. Therapeutic concentrations of levodopa were reached as quickly with subcutaneous administration of DIZ102 as with LCIG and remained stable throughout the infusions. Owing to poor uptake of LCIG, carbidopa levels in plasma were higher with DIZ101 and DIZ102 than with the former. All individuals receiving any of the treatments (n = 20) were included in the evaluation of safety and tolerability. Reactions at the infusion sites were mild and transient. Discussion It is feasible to rapidly achieve high and stable levodopa concentrations by means of continuous buffering of a subcutaneously administered acidic levodopa/carbidopa-containing solution.
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| 5. |
- Boström, Inger, 1946-
(författare)
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Epidemiological Studies of Multiple Sclerosis in Sweden with focus on the County of Värmland
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to study the frequency of MS in the suggested high-risk area of Värmland county by investigating the current prevalence and analyzing the development over time; secondly to investigate some aetiological factors – the pattern of industry, both in relation to MS in Värmland and in the whole country, and also to examine the possible relation between the distribution of MS and ALS, as it has previously shown a positive correlation in two studies; finally to analyze the women-to-men ratio of MS in Sweden because of international reports of an increasing ratio.Clinical data was collected from hospitals and other health care units in the county of Värmland, to calculate the prevalence ratio. The prevalence was 170.07 per 100,000 population on the prevalence day, 31 December 2002. The incidence rates analysed during ten years was 6.46 per 100,000 personyears (1991-1995) and 6.39 (1996-2000).The ecological study used data from the beginning of the 20th century on industries in Värmland and in all Sweden, which were correlated with the two MS prevalence studies (1925-1934 and 2002), and the mortality study on the time period 1952-1990. There was a statistical significant association between large sawmills and the prevalence 1925-1934 (p = 0.022). For all Sweden, wood-pulp factories and papermills correlated significantly with MS mortality 1952-1990 (p = <0.05).Collected data from Causes of death Register and from the Total Population Register were used when analysing mortality from ALS and MS. The previously shown correlation between ALS and MS mortality distribution in the Swedish counties was not confirmed in this study. However, the mean MS mortality rate was still highest in the county in Värmland. The mean MS mortality rates for whole Sweden was increased from 1.65 per 100,000 person-years (1952-1992) to 2.04 (1990-2010).For analysing sex ratio in MS, data from the Swedish Multiple Sclerosis Register and data from Total Population Register of the Swedish Statistics Office were used. These data was analysed by birth day cohort and by year of onset. The sex ratios in Sweden showed a stable women-to-men ratio.These investigations give indication that Värmland is a high-risk region of multiple sclerosis, and particularly the municipality of Säffle.We conclude that Värmland is a suitable area for continued epidemiological studies with both an environment and genetic focus.
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| 6. |
- Vågberg, Mattias, 1985-
(författare)
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Brain parenchymal fraction in healthy individuals and in clinical follow-up of multiple sclerosis
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Multiple sclerosis (MS) is an autoimmune disease characterised by inflammatory damage to the central nervous system (CNS). Accumulated CNS injury can be quantified as brain atrophy, definable as a reduction in brain parenchymal fraction (BPF). BPF correlate with disability in MS and is used routinely as an endpoint in clinical trials. In 2009/2010, a new MS clinical care program, that includes follow-up of BPF, was introduced at Umeå University Hospital (NUS). Levels of neurofilament light polypetide (NFL) and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) are markers of axonal and astrocytic injury, respectively, and also potential surrogate biomarkers for BPF decline. The goals of this thesis were to establish age-adjusted values of BPF in healthy individuals and to relate these to the BPF values from individuals with MS as well as to the levels of NFL and GFAP in CSF. Another goal was to investigate if expanded disability status scale (EDSS)-worsening could be predicted in a clinical MS cohort and if BPF measurements could contribute to such predictions. Methods A group of 111 healthy individuals volunteered to participate in the studies. A total of 106 of these underwent MRI with BPF measurements, 53 underwent lumbar puncture (LP) with measurement of NFL and GFAP and 48 underwent both MRI and LP. Three different automatic and one manual method were utilised to determine BPF. A literature search on BPF in healthy individuals was performed for the purpose of a systematic review. For studying disability progression in MS, all individuals with MS followed at NUS and included in the Swedish MS registry were included if they had matched data on BPF, EDSS and lesion load as part of clinical follow-up (n=278). Results BPF as well as NFL and GFAP levels in CSF were all associated with age. NFL was associated with BPF and GFAP, but only the association with GFAP was retained when adjusting for age. Significant differences were found between different methods for BPF determination. In the MS population, BPF was associated with EDSS. Only progressive disease course could predict EDSS worsening. Conclusion The data on BPF and levels of NFL and GFAP in CSF of healthy individuals can aid in the interpretation of these variables in the setting of MS. Knowledge on differences in BPF data from different methods for BPF determination can be useful in comparing data across studies, but also highlights the need for a commonly accepted gold standard. The correlation between GFAP and NFL levels in CSF may indicate an association between glial and axonal turnover that is independent of the aging effect on the brain. However, the low number of volunteers for LP precluded clear conclusions. An association between BPF and EDSS was seen in the MS group. The ability to predict EDSS worsening in the clinical MS cohort was limited.
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