We report two cases of neuromyelitis optica spectrum disorder (NMOSD) who were misdiagnosed as multiple sclerosis (MS) and developed catastrophic relapses following initiation of dimethyl fumarate. ...Both patients developed a severe myelitis extending from the cervical cord to the medulla with significant cord swelling, resulting in complete quadriplegia and respiratory difficulties, in addition to severe bilateral visual loss in one patient. It is of note that both catastrophic relapses occurred 2 and 3 months following initiation of dimethyl fumarate.
To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort.
Using data from the MSBase Registry, we included pregnancies conceived after 31 Dec 2010 from women ...with relapsing-remitting MS or clinically isolated syndrome. Predictors of intrapartum relapse, and postpartum relapse and disability progression were determined by clustered logistic regression or Cox regression analyses.
We included 1998 pregnancies from 1619 women with MS. Preconception annualized relapse rate (ARR) was 0.29 (95% CI 0.27-0.32), fell to 0.19 (0.14-0.24) in third trimester, and increased to 0.59 (0.51-0.67) in early postpartum. Among women who used fingolimod or natalizumab, ARR before pregnancy was 0.37 (0.28-0.49) and 0.29 (0.22-0.37), respectively, and increased during pregnancy. Intrapartum ARR decreased with preconception dimethyl fumarate use. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (OR 0.76 per month 0.60-0.95, p=0.017). DMT re-initiation with natalizumab protected against postpartum relapse (HR 0.11 0.04-0.32, p<0.0001). Breastfeeding women were less likely to relapse (HR 0.61 0.41-0.91, p=0.016). 5.6% of pregnancies were followed by confirmed disability progression, predicted by higher relapse activity in pregnancy and postpartum.
Intrapartum and postpartum relapse probabilities increased among women with MS after natalizumab or fingolimod cessation. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 34 weeks gestation, with early re-initiation after delivery is an effective option to minimize relapse risks. Strategies of DMT use have to be balanced against potential fetal/neonatal complications.
•Extending the dosing interval of NTZ might decrease the risk of PML.•We assessed the effect of extended interval dosing (EID) ranging from 5–8 weeks on the efficacy of NTZ.•We reviewed 85 patients ...treated with NTZ at two MS centers in the Middle East.•Shifting to EID has no negative effect on relapse rate, EDSS and MRI activity.
It is postulated that extending the dosing interval of natalizumab (NTZ) from 4 to 5–8 weeks might decrease the risk of progressive multifocal leukoencephalopathy (PML). The aim of this study was to assess the effect of extended interval dosing (EID) on the therapeutic efficacy of natalizumab.
We reviewed 85 patients treated at two MS centers in the Middle East with natalizumab for at least 6 months using EID. Patients were shifted after an initial treatment period at standard interval dosing (SID) to an EID ranging from 5–8 weeks.
The mean treatment duration on SID and EID was 15.4 ± 11.9 and 11.8 ± 7.0 months, respectively. By the end of SID and EID treatment 95.3% and 93.9% of patients were free of relapses (P = 0.41) with an annualized relapse rate (ARR) of 0.0006 and 0.001 respectively (P = 0.42). The mean EDSS at the end of SID and EID periods was 2.56 ± 1.62 and 2.59 ± 1.61 respectively (P = 0.84). A total of 97.6% and 94.7% of patients had no enhancing lesions on MRI during the SID and EID periods respectively (P = 0.18). There were no cases of PML and the rate of infections was lower during the EID period.
In patients treated with natalizumab, shifting from SID to EID has no negative effect on efficacy as evidenced by relapse rate, disability progression and MRI activity.
To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy.
This was a retrospective cohort study from 2 large observational MS ...registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation.
A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80).
The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different therapies. These results suggest that untreated intervals should be minimized after stopping antitrafficking therapies (natalizumab and fingolimod).
This study provides Class III that disease reactivation occurs within months of discontinuation of MS disease-modifying therapies. The risk of disease activity is reduced by commencement of a subsequent therapy.
Objective. To evaluate the efficacy and safety of rituximab in multiple sclerosis in a clinical practice setting. Methods. Clinical data for all adult patients with multiple sclerosis (MS) treated ...with off-label rituximab at a single MS center in Lebanon between March 2008 and April 2017 were retrospectively collected from medical charts. The main efficacy outcomes assessed were annualized relapse rate (ARR) and proportion of patients free from relapses, disability progression, or magnetic resonance imaging (MRI) activity. Results. A total of 89 rituximab-treated patients were included: 59 relapsing-remitting MS (RRMS) and 30 progressive MS (PMS). Patients were treated with 1000 or 2000 mg rituximab IV every 6–12 months for a mean duration of 22.2 ± 24.8 months. The subjects were 65.2% females with a mean age of 40.5 ± 12.3 years and a mean disease duration of 7.9 ± 6.2 years. During treatment, the ARR decreased from 1.07 at baseline to 0.11 in RRMS (p<0.0001) and from 0.25 to 0.16 in PMS patients (p=0.593). The mean Expanded Disability Status Scale (EDSS) remained unchanged in both RRMS and PMS patients. Between baseline and the last follow-up, the percent of patients free from any new MRI lesions increased from 18.6% to 92.6% in the RRMS group and from 43.3% to 82% in the PMS group. No evidence of disease activity (NEDA) was achieved in 74% of patients at 1 year of treatment. A total of 64 adverse events (AEs) (71.9%) were recorded with the most common being infusion-related reactions in 25.8% of patients, all mild in nature. Two of our rituximab-treated patients experienced serious AEs requiring surgical interventions: pyoderma gangrenosum vaginalis with perianal abscess and fistula and an increase in the size of a meningioma. No case of progressive multifocal leukoencephalopathy (PML) was detected. Conclusion. In our real-world cohort, rituximab was well-tolerated and effective in reducing relapse rate and disability progression in relapsing-remitting and progressive MS patients.
The severity of multiple sclerosis (MS) varies widely among individuals. Understanding the determinants of this heterogeneity will help clinicians optimize the management of MS. The aim of this study ...was to investigate the association between latitude of residence, UV B radiation (UVB) exposure, and the severity of MS.
This observational study used the MSBase registry data. The included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry (date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and ≥1 Expanded Disability Status Scale score recorded). The latitude of each study center and cumulative annualized UVB dose at study center (calculated from National Aeronautics and Space Administration's Total Ozone Mapping Spectrometer) at ages 6 and 18 years and the year of disability assessment were calculated. Disease severity was quantified with Multiple Sclerosis Severity Score (MSSS). Quadratic regression was used to model the associations between latitude, UVB, and MSSS.
The 46,128 patients who contributed 453,208 visits and a cumulative follow-up of 351,196 patient-years (70% women, mean age 39.2 ± 12 years, resident between latitudes 19°35' and 56°16') were included in this study. Latitude showed a nonlinear association with MS severity. In latitudes <40°, more severe disease was associated with higher latitudes (β = 0.08, 95% CI 0.04-0.12). For example, this translates into a mean difference of 1.3 points of MSSS between patients living in Madrid and Copenhagen. No such association was observed in latitudes <40° (β = -0.02, 95% CI -0.06 to 0.03). The overall disability accrual was faster in those with a lower level of estimated UVB exposure before the age of 6 years (β = - 0.5, 95% CI -0.6 to 0.4) and 18 years (β = - 0.6, 95% CI -0.7 to 0.4), as well as with lower lifetime UVB exposure at the time of disability assessment (β = -1.0, 95% CI -1.1 to 0.9).
In temperate zones, MS severity is associated with latitude. This association is mainly, but not exclusively, driven by UVB exposure contributing to both MS susceptibility and severity.
•Patients with multiple sclerosis (MS) should be vaccinated against COVID-19.•COVID-19 Vaccines are safe to use in MS patients treated with DMTs.•The effectiveness of vaccination may be affected by ...few of the DMTs.•To enhance vaccine efficacy, we may coordinate its timing with the timing of the DMT dose.
Patients with multiple sclerosis (MS) should be vaccinated against COVID-19.
All COVID-19 vaccines are effective and do not appear to carry any additional risk for patients with MS. Patients with MS should get a COVID-19 vaccine as soon as it becomes available. The risks of COVID-19 disease outweigh any potential risks from the vaccine.
Even if vaccinated, patients with MS should continue to practice standard and recommended precautions against COVID-19, such as wearing a face mask, social distancing and washing hands.
There is no evidence that patients with MS are at higher risk of complications from the mRNA, non-replicating viral vector, inactivated virus or protein COVID-19 vaccines, compared to the general population.
COVID-19 Vaccines are safe to use in patients with MS treated with disease-modifying therapies (DMTs).
The effectiveness of vaccination may be affected by few of the DMTs but yet some protection is still provided.
For certain DMTs we may consider coordinating the timing of the vaccine with the timing of the DMT dose to increase vaccine efficacy.
Patients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses, and though patients with POMS usually recover from relapses ...better than adults, patients with POMS reach irreversible disability at a younger age than adult-onset patients. There have been few randomized, placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry.
This retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021. Patients were matched using inverse probability treatment weighting. The primary outcome was time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement.
A total of 1,218 patients with POMS were included in this analysis. Patients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMTs (hazard ratio HR, 0.49; 95% confidence interval CI, 0.29-0.83;
= 0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMTs (HR, 0.15; 95% CI 0.07-0.31;
< 0.001) or fingolimod (HR, 0.37; 95% CI 0.14-1.00;
= 0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting-adjusted patient populations were confirmed in multiple sensitivity analyses.
Our analyses of relapse risk suggest that natalizumab is more effective than fingolimod in the control of relapses in this population with high rates of new inflammatory activity, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. In addition, both fingolimod and natalizumab were more effective than first-line injectable therapies.
This study provides Class II evidence that patients with POMS treated with natalizumab had a lower risk of relapse than those with fingolimod.
The Middle East North Africa (MENA) region falls in the low-to-moderate multiple sclerosis (MS) prevalence zone, with prevalence rates slightly lower than Southern Europe but much higher than ...sub-Saharan Africa. However, there is clearly a trend toward increased MS prevalence over the last few decades, consistent with the globally rising prevalence of the disease. We analyzed all data collected from the MENACTRIMS (Middle East North Africa Committee for Treatment and Research in Multiple Sclerosis) registry by the end of December 2018. A total of 6885 patients were eligible for the study. Overall, the clinical phenotype of MS in the MENA region was not different from the Western phenotype except for earlier age at onset and a more aggressive clinical course leading to earlier disability.
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