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Background: Treatment of neuromyelitis optica spectrum disorder (NMOSD) has so far been based on retrospective case series. The results of six randomized clinical trials including five different monoclonal antibodies targeting four molecules and three distinct pathophysiological pathways have recently been published. Methods: Literature search on clinical trials and case studies in NMOSD up to July 10. 2020. Results: We review mechanism of action, efficacy and side effects, and consequences for reproductive health from traditional immunosuppressants and monoclonal antibodies including rituximab, inebilizumab, eculizumab, tocilizumab and satralizumab. Conclusion: In NMOSD patients with antibodies against aquaporin 4, monoclonal antibodies that deplete B cells (rituximab and inebilizumab) or interfere with interleukin 6 signaling (tocilizumab and satralizumab) or complement activation (eculizumab) have superior efficacy compared to placebo. Tocilizumab and rituximab were also superior to azathioprine in head-to-head studies. Rituximab, tocilizumab and to some extent eculizumab have well-known safety profiles for other inflammatory diseases, and rituximab and azathioprine may be safe during pregnancy. [ABSTRACT FROM AUTHOR]

The special nature of amyotrophic lateral sclerosis (ALS) and tracheostomy with invasive ventilation (TIV) leads to challenges that can be difficult in two senses: not only to handle well, but also to discuss with patients and other involved stakeholders. Because of the delicate nature of interpersonal relations and communication in ALS, some of the downsides to TIV may almost take on a nature of taboo, making them difficult to raise for open discussion. Yet these ethical challenges are important to be aware of, not only for health professionals and managers but, arguably, also for patients and next of kin. They are important also for a wider professional and societal debate about whether and to whom TIV should be offered. In this paper we highlight and examine ethical challenges in TIV for ALS, with a special emphasis on those that are hard to discuss openly and that therefore might fail to be addressed. The analysis is structured by the four core principles of healthcare ethics: beneficence, nonmaleficence, respect for patient autonomy, and justice. [ABSTRACT FROM AUTHOR]

Increasing female: male ratio in multiple sclerosis (MS) has been assigned to cohort effects, with females in more recent birth cohorts possibly being more exposed or vulnerable to environmental risk factors than males. We collected MS mortality data in Norway from 1951 to 2015 from The Norwegian Cause of Death registry. Age-Period-Cohort analysis was conducted using log-linear Poisson models, including sex interaction terms. MS was registered as the underlying, contributing or direct cause in 6060 deaths. MS associated mortality remained stable with a slight preponderance among males until after 1980, and have since increased preferentially among females. Throughout the study period the mean annual increase was 1.25% for females and 0.3% for males (p < 0.0001). Age-period-cohort analysis revealed limited evidence of cohort effects for the gender differences; the best fitting model only included gender-age and gender-period interaction terms. The period effect evened out for males in the last three decades but increased for females, especially among the oldest age-groups. In conclusion, the increased female: male mortality ratio in MS associated mortality is driven mainly by increased mortality among females in the three last decades, particularly in the older age groups. It is best explained by disproportional period effects, providing evidence of time-varying external factors including improved access to diagnosis among females. [ABSTRACT FROM AUTHOR]

Background: Knowledge concerning exposure to abuse in adulthood and in pregnancy in people with multiple sclerosis (MS) is sparse. Objective: To determine the occurrence of adult abuse and abuse in relation to pregnancy in women with MS and their risk of revictimization (repeated abuse as adults after childhood abuse). Methods: This cross-sectional study comprised pregnant women from the Norwegian Mother, Father and Child Cohort study. Information on abuse was acquired through self-completed questionnaires. We used logistic regression to estimate adjusted odds ratios (aORs) with 95% confidence intervals (CIs). Results: We identified 106 women with MS at enrollment through linkage with national health registries. The reference group consisted of 77,278 women without MS. Twenty-seven women (26%) with MS reported any adult abuse compared to 15,491 women (20%) without MS, aOR 1.33 (0.85–2.09). Twenty-two (21%) women with MS reported systematic emotional abuse compared to 13% without MS, aOR 1.75 (1.08–2.83). Ten women (10%) with MS reported sexual abuse, compared to 6% without MS, aOR 1.72 (0.89–3.33). More women with MS reported rape as an adult, aOR 2.37 (1.02–5.49). Women with MS had higher risk of revictimization as adults, after childhood abuse, aOR 2.23 (1.22–4.10). The risk of abuse during pregnancy or 6 months preceding pregnancy was similar between the groups. Conclusions: Women with MS had increased occurrence of systematic emotional abuse, rape, and revictimization as adults, compared to women without MS. [ABSTRACT FROM AUTHOR]

Introduction: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study.ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing–remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs.At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [− 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion.ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions.Clinical Trials Registration: Substudy of ENSEMBLE (NCT03085810). Registration: March 21, 2017.Methods: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study.ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing–remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs.At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [− 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion.ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions.Clinical Trials Registration: Substudy of ENSEMBLE (NCT03085810). Registration: March 21, 2017.Results: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study.ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing–remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs.At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [− 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion.ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions.Clinical Trials Registration: Substudy of ENSEMBLE (NCT03085810). Registration: March 21, 2017.Conclusion: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study.ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing–remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs.At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [− 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion.ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions.Clinical Trials Registration: Substudy of ENSEMBLE (NCT03085810). Registration: March 21, 2017. [ABSTRACT FROM AUTHOR]

Recent studies suggest that the incidence and mortality of amyotrophic lateral sclerosis (ALS) are increasing. Changing environmental factors could influence disease risk differently throughout life span, and also between genders, birth cohorts, and seasons of birth. We aimed at describing long-term ALS mortality trends in Norway between 1951 and 2014 using age-period-cohort analysis. The Norwegian Cause of Death Registry provided ALS mortality data that were age- and sex-adjusted through direct standardization. Poisson regression analyses were used for identification of mortality trends and potential month of birth effects. We identified 5345 ALS cases, of which 54.7 % were men. ALS mortality increased throughout the whole period ( p < 0.001), with a mean annual increase of 1.14 %. The increase was confined to those older than 60 years, but rates consistently dropped amongst the absolute oldest. The increase was mainly driven by birth cohort effects that increased from 1860 until 1934 ( p < 0.001). No month of birth effect or change in sex ratio was found. The continuous increase in ALS mortality since 1951 is best explained by the long-term changes in exposure to risk factors or in case ascertainment, affecting men and women equally in the generations born since 1860 and at least into 1934. [ABSTRACT FROM AUTHOR]

Observational studies have suggested that vitamin D may reduce inflammation in relapsing-remitting multiple sclerosis (RRMS), but this has not been clearly confirmed in randomized controlled trials. To further explore the possible anti-inflammatory effects of vitamin D in RRMS, we examined the effect of high-dose oral vitamin D on eleven markers of systemic inflammation in 68 RRMS patients enrolled in a double-blinded randomized placebo-controlled trial of vitamin D supplementation (20,000 IU/week) (NCT00785473). Serum inflammation markers and 25-hydroxyvitamin D (25(OH)D) were measured at baseline and week 96, and no restrictions were set on additional standard immunomodulatory treatment for RRMS. The mean 25(OH)D level rose from 56 ± 29 to 123 ± 34 nmol/L among patients receiving vitamin D supplementation, whereas only a minor increase from 57 ± 22 to 63 ± 24 nmol/L was seen in the placebo group. However, no significant differences appeared between the vitamin D group and the placebo group for any of the inflammation markers. Patients on immunomodulatory therapy had significantly higher levels of interleukin-1 receptor antagonist and chemokine (C-X-C motif) ligand 16 than patients without immunomodulatory treatment, but there were no clear synergistic effects between immunomodulatory therapy and vitamin D supplementation on any of the inflammation markers. The rise in 25(OH)D levels after vitamin D supplementation was unaffected by immunomodulatory treatment. We conclude that in this study of RRMS patients, high-dose oral vitamin D supplementation prominently increased serum 25(OH)D levels without affecting markers of systemic inflammation, while a more anti-inflammatory phenotype was found among patients on immunomodulatory treatment. [ABSTRACT FROM AUTHOR]

A remarkable increase in female to male ratio of multiple sclerosis (MS) is recognised in high incidence areas. Norway is a high-risk area for MS, spanning latitudes 58-71°N. We studied whether the sex ratio has changed over time and whether it differs by clinical phenotype or by latitude. Population-based epidemiological data and data from the Norwegian MS Registry on patients born from 1930 to 1979 were combined in this study. Place of birth was retrieved from the Norwegian Population Registry and information on clinical subtypes was obtained from the Norwegian MS Registry. The female to male ratio ranged from 1.7 to 2.7 (median 2.0) in 5,469 patients born in Norway, and increased slightly by 5-year blocks of year of birth ( p = 0.043). The sex ratio was 2.6:1 in 825 patients born 1970-1979, which is significantly higher than in those born 1930-1969 ( p < 0.001). In patients with relapsing remitting onset, the sex ratio was 2.4:1, while it was 1.1:1 in those with primary progressive disease. The sex ratio did not differ between the south, the middle and the north of the country. The overall sex ratio of MS is strongly determined by cases with relapsing remitting onset. We did not observe the remarkable increase in sex ratios of MS reported from other high-risk areas. The high sex ratio in the youngest birth cohorts may change as an increasing proportion of cases in this age group is being diagnosed. Sex ratio was not associated with latitude. [ABSTRACT FROM AUTHOR]