| 941. |
- Kågström, S., et al.
(författare)
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A Swedish nationwide pharmaco-epidemiological and genetic study of the long-term safety and effectiveness of natalizumab (IMSE 1)
- 2018
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Ingår i: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 24:Suppl. 2, s. 699-700
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Natalizumab (NTZ) is a highly effective disease modulatory treatment for relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important for determination of long-term safety and effectiveness in a real-world setting. To this end the “Immunomodulation and Multiple Sclerosis Epidemiology Study 1” (IMSE 1) was initiated upon NTZ launch in Sweden (Aug 2006).Objective: To follow-up the long-term safety and effectiveness of NTZ in a real-world setting.Methods: In Sweden MS patients are registered in the nationwide Swedish Neuro Registry (NeuroReg). IMSE 1 includes patients starting NTZ treatment and data is collected from NeuroReg. Adverse events (AEs), JC-virus status (JCV) and clinical effectiveness measures are registered prospectively.Results: 3052 patients (72% female; 82% RRMS; mean age at treatment start 36 years; mean treatment duration 45.9 months) have been included in IMSE 1 from August 2006 until April 2018. A total of 1234 RRMS patients where included year ≥2011 (JCV test introduction) and had information on JCV (482 anti-JCV anti-bodies (JCV+), 752 JCV negative (JCV-)). 691 of these patients were currently treated with NZT at cutoff date, 88 (13%) of which were JCV+ with a mean JCV index at 1.1±1.1. A total of 612/1234 (49%) discontinued NTZ treatment at some time point of which 266/403 (66%) JCV+ discontinued due to JCV+. JCV- patients mainly discontinued due to pregnancy/planning pregnancy (78/209, 37%) and other reasons (57/209, 27%). The one and two-year drug survival rate was 79% and 45% for JCV+ and 90% and 82% for JCV-. The overall drug survival rate was 16% for JCV+ and 72% for JCV-. In patients with continuous NTZ treatment for ≥2 years (n=738), long lasting stabilization of disease activity was observed. From year 2006 until cutoff, 96 Serious AEs had been reported to the Swedish MPA and included 8 cases (1 fatal) of progressive multifocal leukoencephalopathy (PML), reported between 2008 and 2012. A total of 14 patients have died during or within 6 months after NTZ discontinuation, as reported in NeuroReg. None were reported to be associated to NTZ.Conclusions: NeuroReg functions well as a post-marketing drug surveillance platform, providing long-term data on drug effects and AEs. NTZ is generally well tolerated with sustained effective-ness. The introduction of JCV testing has led to fewer treated JCV+ patients, which likely explains a reduced incidence of PML.
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| 942. |
- Kågström, S., et al.
(författare)
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Efficacy and safety in patients treated with natalizumab for at least 10 years - real-world data from a swedish national surveillance study (IMSE 1)
- 2020
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Ingår i: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 26:3 Suppl., s. 279-280
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Natalizumab (NTZ) is a highly effective disease modulatory treatment for relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important for evalua-tion of long-term safety and effectiveness in a real-world setting. To this end, the “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 1) was initiated upon NTZ launch in Sweden (August 2006).Objectives: To follow-up the long-term effectiveness and safety of NTZ in a real-world setting, with focus on patients treated at least 10 years.Methods: IMSE 1 includes patients starting NTZ treatment and data is collected from the nationwide Swedish Neuro Registry (NeuroReg). Adverse events (AEs), JC-virus status (JCV) and clinical effectiveness measures are registered in NeuroReg pro-spectively. Effectiveness measures were assessed using the Wilcoxon Signed Rank Test.Results: A total of 3291 patients were included in the IMSE 1 study from August 2006 until June 2020 (72% female; mean age 36 years; 80% RRMS; mean treatment duration 50 months). 171/3291 patients (5%) had been treated for at least 120 months (73% female; men age 36 years; 87% RRMS; mean treatment duration 139 months). A total of 64% (110/171) were treated with interferons or glatiramer acetate prior to NTZ treatment. Over the duration of follow-up discontinued 21% (35/171) their NTZ treat-ment of which 46% (16/35) discontinued due to JCV positive (JCV+). In total, 27% (46/171) of these patients were JCV+ with a mean JCV index of 1.2±1.0 (4% missing data). The mean num-ber of relapses were reduced from 0.84 one year before NTZ treat-ment start to 0.00 during the first treatment year (12% missing data). All clinical effectiveness measures (Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Multiple Sclerosis Impact Scale (MSIS-29) and Symbol Digit Modalities Test (SDMT)) showed improvement in mean between baseline and 120 months. However, only MSSS, MSIS-29 psy-chological and SDMT were statistically significant. Over the entire observation time, 114 Serious AEs had been reported to the Swedish Medical Product Agency and included nine cases (2 fatal) of progressive multifocal leukoencephalopathy (PML) of which eight between year 2008 and 2012, and one in 2018. 17 patients died during or within 6 months of last NTZ infusion. None were judged to be directly associated with NTZ.Conclusions: NTZ is generally well tolerated with sustained effectiveness regarding cognitive, physical and psychological measures, as well as relapse-control.
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| 943. |
- Kågström, S., et al.
(författare)
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Improved clinical outcomes in patients treated with natalizumab for at least 8 years - real-world data from a Swedish national post-marketing surveillance study (IMSE 1)
- 2019
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Ingår i: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 25:Suppl. 2, s. 763-764
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Natalizumab (NTZ) is a highly effective disease modulatory treatment for relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important for evaluation of long-term safety and effectiveness in a real-world setting. To this end the “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 1) was initiated upon NTZ launch in Sweden (Aug 2006).Objective: To follow-up the long-term effectiveness and safety of NTZ in a real-world setting.Methods: In Sweden MS patients are registered in the nationwide Swedish Neuro Registry (NeuroReg). IMSE 1 includes patients starting NTZ treatment and data is collected from NeuroReg. Adverse events (AEs), JC-virus status (JCV) and clinical effec-tiveness measures are registered prospectively.Results: A total of 3141 patients were included in the IMSE 1 study from August 2006 until April 2019 (72% female; men age 35 years; 79% RRMS; mean treatment duration 50 months) and 288 had been treated for at least 96 months. 71% of these 288 patients (71% female; men age 37 years; 82% RRMS; mean treatment duration 118 months) were treated with interferons and glatiramer acetate prior NTZ. At some point of time, 31% (90/288) discontin-ued NTZ treatment of which 41% discontinued due to JCV posi-tive (JCV+). In total, 30% (86/288) of these patients were JCV+with a mean JCV index of 1.2±1.0 (6% missing data). Relapses before treatment were reduced from 388/1000 patient years to 54 during treatment, 62% were relapse-free and 17% had 1 relapse during the entire treatment period (12% missing data). All clinical effectiveness measures (Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Multiple Sclerosis Impact Scale (MSIS-29) and Symbol Digit Modalities Test (SDMT)) showed statistically significant improvement between baseline and 96 months. Over the entire observation time, 104 Serious AEs had been reported to the Swedish MPA and included 9 cases (2 fatal) of progressive multifocal leukoencephalopathy (PML) of which 8 between 2008 and 2012, and 1in 2018. 16 patients died during or within 6 months of last NTZ infusion. None were judged to be directly associated with NTZ.Conclusions: NTZ is generally well tolerated with sustained effectiveness regarding cognitive, physical and psychological measures, as well as relapse-control. Introduction of JCV testing has led to fewer treated JCV+ patients, which likely explains a drastic drop in the incidence of PML.
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| 944. |
- Kågström, S., et al.
(författare)
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Real-world data of peginterferon beta-1a from a swedish national post-marketing surveillance study (IMSE 6) - effectiveness and safety profile
- 2020
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Ingår i: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 26:3 Suppl., s. 302-302
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Subcutaneous peginterferon beta-1a (PegIFN) was approved for relapsing-remitting multiple sclerosis (RRMS) in Europe 2014. The clinical trial program showed that PegIFN reduced the relapse rate and proportion with disability progression compared to placebo. At its launch in Sweden, PegIFN was included in the Swedish “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 6), providing possibilities to track long-term effectiveness and safety in a population-based setting.Objectives: To follow-up the long-term effectiveness and safety of PegIFN treatment in Swedish patients in a real-world context.Methods: Data was obtained from the nationwide Swedish Neuro Registry (NeuroReg) between June 2015 and May 2020. Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve.Results: A total of 364 patients (78% female; 87% RRMS; mean age at treatments start 43 years) were followed up to 57 months (mean 20 months), of which 200 (55%) patients had been treated for at least 12 months. The majority of the patients had switched from other injectables (164 patients, 45%) or were treatment naïve (90 patients, 25%) prior to treatment with PegIFN. Over the dura-tion of the follow-up, 68% (247/364) patients discontinued their PegIFN treatment for various reasons (60% adverse events, 24% lack of effect) and switched mainly to rituximab (105 patients, 43%). The overall drug survival was 32%, 40% for men and 30% for women. The one- and two-year drug survival rate was 57% and 40%, respectively. The mean number of relapses were reduced from 0.35 one year before treatment start to 0.11 one year after (35% missing data). All clinical effectiveness measures (Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life – 5-Dimension test (EQ-5D), Visual Analogue Score (VAS) and Symbol Digit Modalities Test (SDMT)) remained stable. Statistically significant changes were observed in SDMT (p=0.027). A total number of 18 adverse events (6 serious) were reported to Swedish Medical Product Agency.Conclusions: These findings are consistent with PegIFN being a safe disease modifying treatment, however, a relatively high pro-portion of patients switched due to adverse events. All clinical effectiveness measures remained stable in patients treated with PegIFN for at least 12 months in this nationwide population-based real-world study. Longer follow up is needed to address the long-term effectiveness.
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| 945. |
- Kågström, S., et al.
(författare)
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Real-world longitudinal data of peginterferon beta-1a from a Swedish national post-marketing surveillance study (IMSE 6) - efficacy and safety profile
- 2018
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Ingår i: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 24:Suppl. 2, s. 927-928
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Subcutaneous peginterferon beta-1a (PegIFN) was approved for relapsing-remitting multiple sclerosis (RRMS) in Europe 2014. Phase II and III studies have shown that PegIFN reduces relapse rate and reduces the tendency to deteriorate disabilities. However, the long-term safety is important, therefore PegINF is included in the Swedish “Immunomodulation and Multiple Sclerosis Epidemiology Study 6” (IMSE 6). Which characterizes the real-world profile of PegIFN, including efficacy, safety, tolerability and patient outcome parameters.Objectives: To follow-up the long-term safety and effectiveness of PegIFN in a real-world setting.Methods: Approximately 60 collaborating neurology clinics continuously recruited PegIFN patients and documented clinical and demographic data in the nationwide Swedish Neuro Registry (NeuroReg). Data were obtained from NeuroReg between June 2015 and April 2018 for the IMSE 6 study.Results: A total of 324 patients (78% female; 88% RRMS; mean age at treatments start 43 years) were followed up to 34 months (mean 15 months) with 26% treatment naïve and 49% switched from other injectables. Mean duration from initial symptom(s) to treatment start was 114 months, and 69 months from MS diagnosis to treatment start. In total, 169 patients discontinued for vari-ous reasons (60% adverse events, 24% lack of effect) and switched mainly to rituximab (63 patients, 37%). The discontinuation rate at 12 months was 42.6%. Relapses before treatment were reduced from 207 to 130/1000 patient years during treatment. With 55% having no relapse and 9% having 1 relapse during treatment period (35% missing data). After 12 months, all clinical effectiveness measures (Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5-Dimension test (EQ-5D), Visual Analogue Score (VAS), and the mean Symbol Digit Modalities Test (SDMT)) remained stable. A total number of 9 adverse events (6 serious: 1 gastrointestinal disorder, 2 general disorder and administrations site, 2 skin, 1 reproductive) were reported to Swedish Medical Product Agency (MPA).Conclusions: NeuroReg proves to function well as a post-marketing drug surveillance platform, providing data regarding drug effectiveness and AEs. This real-world study presentation from IMSE 6 shows a stable efficacy and safety profile in long-term clinical use.
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| 946. |
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| 947. |
- Lagerström, Malin C., et al.
(författare)
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High affinity agonistic metal ion binding sites within the melanocortin 4 receptor illustrate conformational change of transmembrane region 3
- 2003
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Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 278:51, s. 51521-51526
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Tidskriftsartikel (refereegranskat)abstract
- We created a molecular model of the human melanocortin 4 receptor (MC4R) and introduced a series of His residues into the receptor protein to form metal ion binding sites. We were able to insert micromolar affinity binding sites for zinc between transmembrane region (TM) 2 and TM3 where the metal ion alone was able to activate this peptide binding G-protein-coupled receptor. The exact conformation of the metal ion interactions allowed us to predict the orientation of the helices, and remodeling of the receptor protein indicated that Glu100 and Ile104 in TM2 and Asp122 and Ile125 in TM3 are directed toward a putative area of activation of the receptor. The molecular model suggests that a rotation of TM3 may be important for activation of the MC4R. Previous models of G-protein-coupled receptors have suggested that unlocking of a stabilizing interaction between the DRY motif, in the cytosolic part of TM3, and TM6 is important for the activation process. We suggest that this unlocking process may be facilitated through creation of a new interaction between TM3 and TM2 in the MC4R.
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| 948. |
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| 949. |
- Lahmann, PH, et al.
(författare)
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Long-term weight change and breast cancer risk: the European prospective investigation into cancer and nutrition (EPIC)
- 2005
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 93:5, s. 582-589
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Tidskriftsartikel (refereegranskat)abstract
- We examined prospectively the association between weight change during adulthood and breast cancer risk, using data on 1358 incident cases that developed during 5.8 years of follow-up among 40 429 premenopausal and 57 923 postmenopausal women from six European countries, taking part in the European prospective investigation into cancer and nutrition study. Multivariate Cox regression models were used to calculate hazard ratios according to weight change ( kg), defined as the weight difference between age at enrolment and age 20 adjusted for other risk factors. Changes in weight were not associated with premenopausal breast cancer risk. In postmenopausal women, weight gain was positively associated with breast cancer risk only among noncurrent hormone replacement therapy (HRT) users (P-trend <= 0.0002). Compared to women with a stable weight ( 72 kg), the relative risk for women who gained 15 - 20 kg was 1.50 (95% confidence interval (CI) 1.06 - 2.13). The pooled RR per weight gain increment of 5 kg was 1.08 ( 95% CI 1.04 - 1.12). Weight gain was not associated with breast cancer risk in current HRT users, although, overall, these women experienced a much higher risk of breast cancer compared with nonusers. Our findings suggest that large adult weight gain was a significant predictor of breast cancer in postmenopausal women not taking exogenous hormones.
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| 950. |
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