Annualized Relapse Rate Research Articles

The Efficacy of Fingolimod and Interferons in Controlling Disability and Relapse Rate in Patients with Multiple Sclerosis: A Systematic Review and Meta-Analysis.

Fingolimod and interferons are used in the relapse form of multiple sclerosis (MS). The goal of this systematic review and meta-analysis was to evaluate the efficacy of fingolimod versus interferon in patients with MS. The systematic search was done in PubMed, Scopus, Embase, Web of Science, and Google Scholar. The references of included studies as well as conference abstracts were searched up to July 2021. The literature search revealed 8211 articles, and after deleting duplicates 5594 remained. For the meta-analysis, four studies were included. The standardized mean difference (SMD) of the Expanded Disability Status Scale (EDSS) after treatment (interferon vs fingolimod) was -0.06 (95% CI: -0.28, 0.17) (I2 = 80.2%, P = 0.002). The SMD of the annual relapse rate (ARR) after treatment (interferon - fingolimod) was -0.08 (95% CI: -0.53, 0.36) (I2 = 95.5%, P < 0.001). The SMD of the ARR after treatment and before treatment in the interferon group was - 1.45, (95% CI: -1.55, -1.36) (I2 = 0, P = 0.3). The SMD of ARR after treatment and before treatment in the fingolimod group was - 1.3, (95% CI: -1.94, -0.65) (I2 = 97.4%, P < 0.001). Conclusions: The results of this systematic review show that efficacy of interferon and fingolimod in controlling relapse rate and disability is similar.

CSF CXCL13 is elevated in patients with CIDP and may reflect higher disease activity

To evaluate B-cell involvement in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), 11 patients with CIDP, 8 patients with Guillain–Barré syndrome and 13 patients with idiopathic normal pressure hydrocephalus (iNPH) were studied. CSF cytokine and chemokine (IL-10, IL-15, TNF-α, TGF-β1, GM-CSF, BAFF, CXCL10, and CXCL13) levels were measured by ELISA. The CSF CXCL13 level was significantly higher in patients with CIDP than in those with iNPH. The CSF CXCL13 level was significantly higher in CIDP patients with higher annualized relapse rates and higher modified Rankin scale scores. The CSF CXCL13 level is elevated in CIDP, especially in those with higher disease activity.

Ocrelizumab exposure in relapsing-remitting multiple sclerosis: 10-year analysis of the phase 2 randomized clinical trial and its extension.

Open-label extension (OLE) studies help inform long-term safety and efficacy of disease-modifying therapies in multiple sclerosis (MS). We report exploratory analyses from a phase 2 trial on the longest follow-up to date of ocrelizumab-treated patients with relapsing-remitting MS (RRMS). The primary treatment period (PTP) comprised four 24-week treatment cycles; participants were randomized to double-blind ocrelizumab (2000mg or 600mg), placebo, or interferon β-1a (open label) for one cycle, then dose-blinded ocrelizumab 1000mg or 600mg for the remaining cycles. The PTP was followed by consecutive assessed and unassessed treatment-free periods (TFPs) and then the OLE (ocrelizumab 600mg every 24weeks). Safety and efficacy were prospectively assessed. Of 220 participants randomized, 183 (84%) completed the PTP. After the TFP, 103 entered OLE (median OLE ocrelizumab exposure 6.5years). Most common adverse events across all periods were infusion-related reactions. MRI activity, annualized relapse rate, and confirmed disability progression (CDP) rates remained low throughout. During the assessed TFP, there was a trend toward less and later B-cell repletion, and later CDP, for patients randomized to ocrelizumab; MRI activity was observed in 16.3% of patients, the earliest 24weeks after the last ocrelizumab dose. This is the longest follow-up of ocrelizumab-treated patients with RRMS, with no new safety signals emerging during an observation period from 2008 to 2020. Results reinforce the sustained efficacy of long-term ocrelizumab. Reduced disease activity was maintained following interruption of 6-month dosing cycles, with no evidence of rebound.

Diroximel fumarate in patients with relapsing–remitting multiple sclerosis: Final safety and efficacy results from the phase 3 EVOLVE-MS-1 study

Background: Diroximel fumarate (DRF) is approved for adults with relapsing–remitting multiple sclerosis (RRMS) in Europe and for relapsing forms of MS in the United States. DRF and dimethyl fumarate (DMF) yield bioequivalent exposure of the active metabolite monomethyl fumarate. Prior studies indicated fewer gastrointestinal (GI)-related adverse events (AEs) with DRF compared with DMF. Objective: To report final outcomes from EVOLVE-MS-1. Methods: EVOLVE-MS-1 was an open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in patients with RRMS. The primary endpoint was safety and tolerability; efficacy endpoints were exploratory. Results: Overall, 75.7% (800/1057) of patients completed the study; median exposure was 1.8 (range: 0.0–2.0) years. AEs occurred in 938 (88.7%) patients, mostly of mild (28.9%) or moderate (50.3%) severity. DRF was discontinued due to AEs in 85 (8.0%) patients, with < 2% discontinuing due to GI or flushing/flushing-related AEs. At Week 96, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (72.7%; p < 0.0001); adjusted annualized relapse rate was 0.13 (95% confidence interval: 0.11–0.15). Conclusion: DRF was generally well tolerated over 2 years, with few discontinuations due to AEs; radiological measures indicated decreased disease activity from baseline. These outcomes support DRF as a treatment option in patients with RRMS.

Effectiveness and Safety of Teriflunomide in Relapsing-Remitting Multiple Sclerosis and Improvements in Quality of Life: Results from the Real-World TERICARE Study.

Teriflunomide is a once-daily oral immunomodulator approved for relapsing forms of multiple sclerosis (MS) or relapsing-remitting multiple sclerosis (RRMS; depending on the local label), based on extensive evidence from clinical trials and a real-world setting on efficacy, tolerability and patient-reported benefits. The TERICARE study assessed the impact of teriflunomide treatment over 2years on health-related quality of life (HRQoL) and some of the most common and disabling symptoms of MS, such as fatigue and depression. This prospective observational study in Spain included RRMS patients treated with teriflunomide for ≤ 4weeks. The following patient-reported outcomes (PROs) were collected at baseline and every 6months for 2years: the 29-item Multiple Sclerosis Impact Scale version 2 (MSIS-29), the 21-item Modified Fatigue Impact Scale (MFIS-21), the Beck Depression Inventory (BDI-II), the Short Form (SF)-Qualiveen and theTreatment Satisfaction Questionnaire for Medication v1.4 (TSQM). Annualised relapse rate (ARR), disability progression according to the Expanded Disability Status Scale (EDSS), and no evidence of disease activity (NEDA-3) were also assessed. A total of 325 patients were analysed. Patients had a mean (SD) age of 43.2years (10.4), a mean baseline EDSS score of 1.75 (1.5), a mean number of relapses in the past 2years of 1.5 (0.7), and 64% had received prior disease-modifying therapy (DMT). Patients showed significant improvements in the psychological domain of MSIS-29 from 35.9 (26.6) at baseline to 29.4 (25.5) at 18months (p = 0.004) and 29.0 (24.6) at 24months (p = 0.002). Levels of fatigue and depression were also reduced. After 2years of treatment with teriflunomide, ARR was reduced to 0.17 (95% CI 0.14-0.21) from the baseline of 0.42 (95% CI 0.38-0.48), representing a 60.1% reduction. Mean EDSS scores remained stable during the study, and 79.9% of patients showed no disability progression. 54.7% of patients achieved NEDA-3 in the first 12months, which increased to 61.4% during months 12-24. Patients reported increased satisfaction with treatment over the course of the study, regardless of whether they were DMT naive or not. Teriflunomide improves psychological aspects of HRQoL and maintains low levels of fatigue and depression. Treatment with teriflunomide over 2years is effective in reducing ARR and disability progression.

Multiple sclerosis in the elderly: a retrospective cohort study.

There is a lack of knowledge of disease course, prognosis, comorbidities and potential treatments of elderly MS patients. To characterize the disease course including disability progression and relapses, to quantify the use of DMTs and to identify comorbidities and risk factors for progression in elderly multiple sclerosis (MS) patients. This is a retrospective study of 1200 Austrian MS patients older than 55years as of May 1st, 2017 representing roughly one-third of all the MS patients of this age in Austria. Data were collected from 15 MS centers including demographics, first symptom at onset, number of relapses, evolvement of disability, medication, and comorbidities. Median observation time was 17.1years with 957 (80%) relapsing and 243 (20%) progressive onsets. Average age at diagnosis was 45years with a female predominance of 71%. Three-hundred and twenty-six (27%) patients were never treated with a DMT, while most treated patients received interferons (496; 41%) at some point. At last follow-up, 420 (35%) patients were still treated with a DMT. No difference was found between treated and never-treated patients in terms of clinical outcome; however, patients with worse disability progression had significantly more DMT switches. Pyramidal onset, number of comorbidities, dementia, epilepsy, and psychiatric conditions as well as a higher number of relapses were associated with worse outcome. The risk of reaching EDSS 6 rose with every additional comorbidity by 22%. In late and very-late-onset MS (LOMS, VLOMS) time to diagnosis took nearly twice the time compared to adult and early onset (AEOMS). The overall annualized relapse rate (ARR) decreased over time and patients with AEOMS had significantly higher ARR compared to LOMS and VLOMS. Four percent of MS patients had five medications or more fulfilling criteria of polypharmacy and 20% of psychiatric drugs were administered without a matching diagnosis. In this study, we identified number of comorbidities, pyramidal and cerebellar signs, and a higher number of relapses as unfavorable prognostic factors in elderly MS patients filling gaps of knowledge in patients usually underrepresented in clinical trials and may guide future therapeutic studies.

Real-world treatment patterns and effectiveness of cladribine tablets in patients with relapsing forms of multiple sclerosis in the United States

BackgroundReal-world evidence on the use of cladribine tablets (CladT) for relapsing forms of multiple sclerosis (RMS) in the United States is emerging. The objective of this study was to assess the real-world treatment patterns and effectiveness of CladT in RMS. MethodsAdults with RMS initiating CladT were selected from the Symphony Integrated Dataverse. Baseline and follow-up periods were the 12 months before and 24 months after CladT initiation (index date). Switching to another disease-modifying therapy (DMT) and number of CladT courses were described during follow-up. Annualized relapse rate (ARR), MS disease severity, Expanded Disability Status Scale-Derived Disability Indicators (EDSS-DDI), corticosteroid use, and healthcare resource utilization (HRU) were described during Years 1 and 2 of follow-up and compared with baseline. ResultsA total of 539 CladT-treated patients were included (mean age: 49.9 years; 77.6 % female). Over the 2-year follow-up, 91 % and 59 % of patients had one and two CladT courses, respectively, and 7 % of patients had evidence of switching to another DMT. ARR, MS disease severity score, and corticosteroid use decreased significantly during follow-up compared with baseline, while EDSS-DDI remained stable. All-cause and MS-related HRU decreased during follow-up. ConclusionCladT-treated patients with RMS had low switch rates, reduced ARR, disease severity, corticosteroid use, and HRU.

Real-life safety and effectiveness outcomes of teriflunomide in patients with relapsing–remitting multiple sclerosis: The TERICAM study

Introduction and objectiveTeriflunomide is an oral immunomodulatory agent approved for the treatment of relapsing–remitting multiple sclerosis (RRMS). We examined teriflunomide outcomes in patients with RRMS under clinical practice conditions in Spain. Material and methodsNon-interventional, retrospective study at 15 sites in the Autonomous Region of Madrid and nearby regions. Effectiveness (relapses, EDSS, gadolinium-enhancing T1 lesions and new/enlarged T2-weighted lesions), safety (adverse events), and reasons for discontinuation during the 24 months after teriflunomide initiation were reported. ResultsA total of 776 patients were included (mean [SD] age was 43.3 (9.8) years; 69.3% were female). Two-thirds (67.7%) of patients had received a prior treatment, with beta-interferons or glatiramer acetate (BRACE) as the most frequent (93.5%) treatment. After 24 months, teriflunomide significantly reduced the annualized relapse rate (ARR) by 72% (mean [95% confidence interval] 0.12 [0.10, 0.14] vs 0.43 [0.40, 0.47] at baseline; P<.0001) and 81.8% of patients were relapse-free. The number of patients with gadolinium-enhancing T1 lesions and new/enlarged lesions on T2 was also reduced after 24 months of teriflunomide treatment (P<.001). Mean EDSS (SD) score was 1.9 (1.5) at teriflunomide initiation and 2.0 (1.6) at month 24. Half of patients (n=388) reported at least 1 adverse event (AE; gastrointestinal disorders: 26.2%; hair thinning: 25%; and elevation of ALT values: 12.9%). Most patients (91.5%) did not show fatigue increase during teriflunomide treatment. Among patients who discontinued treatment (n=262; 34.2%), the most common reasons were lack of effectiveness (58.0%), AEs (31.9%; n=82), and pregnancy desire (6.6%; n=17). ConclusionsMost RRMS patients treated with teriflunomide in clinical practice had received prior treatments. Teriflunomide resulted in decreased clinical and radiological activity and disability stabilization. AE frequency and type were in line with prior reports. Most patients did not experience fatigue increases after teriflunomide initiation.

Briumvi: a breakthrough in the treatment of relapsing multiple sclerosis: a review.

Multiple sclerosis (MS) is a chronic systemic autoimmune disorder characterized by plaques of demyelination, autoimmune inflammation, and astrocytic gliosis. The primary cells involved in the pathophysiology of MS are T cells. However, B cells have recently been implicated in the pathophysiology of the disease. Therefore, researchers have been exploring B cell therapy as an alternative treatment option for MS. B cell therapy is based on the targeted depletion of CD20-positive B cells. Rituximab, ocrelizumab, and ofatumumab are anti-CD20 antibodies already approved. Briumvi, the fourth type of anti-CD20 antibody was approved by FDA in December 2022, for the treatment of relapsing types of MS, including relapsing-remitting multiple sclerosis, active secondary progressive multiple sclerosis, and clinically isolated syndromes after the drug was tested in two randomized, double-blind, phase III, ULTIMATE I, and II trials which compared Briumvi (ublituximab) with Aubiago (teriflunomide). Ublituximab was found to have a much lower annual relapse rate in the ULTIMATE II trials than teriflunomide. Briumvi is a chimeric recombinant IgG1 monoclonal antibody directed against human CD20 with potential antineoplastic activity. Its mechanism of action involves several distinct processes that collectively lead to the depletion of B cells and suppression of the immune response. The primary mode of action of Briumvi is its high-affinity binding to CD20. Infusion-related reactions are the most common side effects encountered following intravenous administration of ublituximab.

Clinical Pharmacokinetics of Ponesimod, a Selective S1P1 Receptor Modulator, in the Treatment of Multiple Sclerosis.

Ponesimod, a selective, rapidly reversible, and orally active, sphingosine-1 phosphate receptor (S1P) modulator, is indicated for the treatment of relapsing-remitting multiple sclerosis (RRMS). The clinical pharmacokinetics (PK) and pharmacodynamics (PD) of ponesimod was studied in 16 phase I, one phase II, and one phase III clinical studies. Ponesimod population PK was characterized by an open two-compartment disposition model with a terminal half-life of 33h (accumulation factor of 2- to 2.6-fold), and fast and almost complete oral absorption (absolute oral bioavailability: 84%), reaching peak plasma and blood concentrations within 2-4h. Ponesimod is highly metabolized, and the parent compound along with its two major (non-clinically active) metabolites are mainly excreted in the feces (recovery: 57.3-79.6%) and to a lesser extent in the urine (recovery: 10.3-18.4%). Additionally, the population PKPD model characterized the ponesimod effects on heart rate: a transient, dose-dependent decrease in heart rate in the first days of dosing, that is mitigated by administering the first doses of ponesimod treatment using a gradual up-titration schedule, before reaching the daily maintenance dose of 20mg. This selected maintenance dose has been shown to be superior in reducing annualized relapse rate (ARR) when compared with teriflunomide in a pivotal phase III study. Furthermore, a dose-dependent reduction of peripheral lymphocyte counts that is sustained with continued daily oral dosing of ponesimod and is rapidly (4-7days) reversible upon drug discontinuation has been characterized with an indirect response model.

A five-year observational prospective mono-center study of the efficacy of alemtuzumab in a real-world cohort of patients with multiple sclerosis.

Alemtuzumab (ALZ) is a pulsed immune reconstitution therapy for multiple sclerosis (MS). To assess basic characteristics, therapeutic effects, and prognostic biomarkers on clinical and imaging parameters of disease activity for relapsing-remitting MS (RRMS) patients selected for ALZ, in a real-world long-term setting. Fifty-one RRMS patients [female = 31; mean age 36 (standard deviation 7.1) years; median expanded disability status scale (EDSS) 2 (interquartile range (IQR) 1.5)] initiating ALZ treatment, were consecutively included. Patients were assessed at baseline and thereafter annually for 5 years with clinical measures, symbol digit modality test (SDMT), and magnetic resonance imaging (MRI). Concentrations of glial fibrillary acidic protein (GFAP), reflecting astrogliosis, and neurofilament light (NfL), reflecting axonal damage, were measured in cerebrospinal fluid (CSF) and serum samples collected at baseline and after 2 years in CSF, and annually in serum. Control subjects were symptomatic controls (SCs, n = 27), who were examined at baseline and after 5 years without evidence of neurological disease. While the mean annualized relapse rate was significantly reduced from baseline at each year of follow-up, disability was essentially maintained at a median EDSS of 1.5 and IQR between 1.13 and 2.25. New MRI activity was recorded in 26 patients (53%) over 5 years. The proportion of patients who achieved no evidence of disease activity (NEDA-3), 6-months confirmed disability worsening (CDW), and 6-months confirmed disability improvement (CDI) at 5 years were 33, 31, and 31%, respectively. The SDMT score was reduced for patients (p < 0.001), but unchanged for SCs. ALZ treatment did not change GFAP levels, whereas there was a significant decrease for RRMS patients in median CSF and serum NfL levels at follow-up [CSF month 24: 456 pg./mL (IQR 285.4) (p = 0.05); serum month 24: 6.7 pg/mL (IQR 4.7) (p < 0.01); serum month 60: 7.2 pg/mL (IQR 4.7) (p < 0.01)], compared to baseline [CSF: 1014 pg/mL (IQR 2832.5); serum 8.6 pg/mL (IQR 17.4)]. In this real-world mono-center population, we observed a progression-free survival of 69%, cumulative NEDA-3 of 33%, and reduced NfL levels, over a five-year follow-up. This confirms ALZ as an effective pulsed immune reconstitution therapy that significantly reduces neuro axonal loss, and therefore has the potential to reduce long-term neurological disability. ALZ did not appear to affect astrogliosis.

Efficacy and safety of four-year ofatumumab treatment in relapsing multiple sclerosis: The ALITHIOS open-label extension

Background: Ofatumumab has demonstrated superior efficacy and favorable safety for up to 2.5 years versus teriflunomide in relapsing multiple sclerosis (RMS). Objective: Further characterize efficacy and safety of ofatumumab in RMS. Methods: Efficacy set: patients randomized to ofatumumab/teriflunomide in ASCLEPIOS I/II (core). Safety set: patients who received ⩾ 1 dose of ofatumumab in ASCLEPIOS I/II, APLIOS, APOLITOS (all core), or ALITHIOS (umbrella open-label extension). Patients received continuous ofatumumab or were newly switched from teriflunomide. Data cut-off: 25 September 2021. Results: In the efficacy set (n = 1882), the continuous ofatumumab group had a low annualized relapse rate (ARR 0.05 (95% confidence interval: 0.04–0.07)), low numbers of gadolinium-enhancing (Gd+) T1 lesions (0.01 lesions/scan) and fewer new/enlarging T2 lesions (annualized rate 0.08). Overall, 78.8% met three-parameter “no evidence of disease activity” criteria through 4 years. Switching from teriflunomide led to reduced ARR, risk of confirmed disability worsening (CDW), new/enlarging T2 lesions, Gd+ T1 lesions, and serum neurofilament light chain. In the continuous and newly switched ofatumumab groups, cumulative 3- and 6-month CDW rates remained low. In the safety set (n = 1969), the most frequently reported adverse events were infections and infestations (58.35%). No new safety signals were identified. Conclusion: Ofatumumab has a favorable longer-term benefit–risk profile in RMS. Trial registry: ALITHIOS (NCT03650114): https://clinicaltrials.gov/ct2/show/NCT03650114

Impact of menopause on relapse rate and disability level in patients with multiple sclerosis (MS): a systematic review and meta-analysis

BackgroundMenopause is a physiologic phase in women’s lives. Findings regarding multiple sclerosis (MS) course through menopause are diverse. So, we designed this systematic review and meta-analysis to estimate the impact of menopause on relapse rate, and disability status in women with MS.MethodsPubMed, Scopus, EMBASE, Web of Science, and google scholar were systematically searched by two independent researchers on January 1st, 2023. They also evaluated conference abstracts, and references of the included studies. In addition, data regarding the total number of participants, name of the first author of the publication, publication year, country of origin, disease duration, disease type, annual relapse rate, and Expanded Disability Status Scale (EDSS) before and after menopause were recorded.ResultsA literature search revealed 1024 records. Twenty-one full texts were evaluated, and finally, four studies were included for meta-analysis. Mean ARR before menopause ranged between 0.21 and 0.37, and after menopause ranged between 0.13 and 0.08. The SMD of mean ARR ranged between − 1.04, and − 0.29, while the pooled SMD was estimated as -0.52(95% CI: -0.88, -0.15) (I2 = 73.6%, P = 0.02). The mean EDSS before menopause ranged between 1.5 and 2, and after menopause ranged between 2 and 3.1. The SMD of EDSS ranged between 0.46, and 0.71. The pooled SMD of EDSS change (after menopause-before menopause) estimated as 0.56(95% CI: 0.38, 0.73)(I2 = 0, P = 0.4).ConclusionThe result of this systematic review and meta-analysis show that menopause can be associated with relapse rate reduction, unlike increase in disease-related disability in women with MS.

Side effects following vaccination in multiple sclerosis: a prospective, multi-centre cohort study

Vaccines play a crucial role in preventing infections in patients with multiple sclerosis (MS), although concerns have been raised about potential worsening of the underlying disease. To investigate this, we conducted a prospective, multicentre, non-randomized observational study assessing changes in disease activity, safety, and clinical tolerability of vaccination in 222 MS patients on disease-modifying drugs. The majority of patients were female (76.6%) and 89.6% had relapsing–remitting MS. The vaccines administered were primarily seasonal influenza (56.3%) or tetanus-based vaccines (33.8%). Disease activity, as measured by annualized relapse rate, decreased significantly from 0.64 the year prior to vaccination to 0.38 in the following year. Moreover, the extended disability status scale remained stable within six months after vaccination in comparison to pre-vaccination values. Side effects were reported in 19.2% of vaccinated subjects, most commonly local side effects (65.2%) or flu-like symptoms (34.8%). Our findings suggest that standard non-live vaccines are safe and well-tolerated in MS patients and do not negatively impact disease activity.

Epidemiologic and clinical characteristics of neuromyelitis optica spectrum disorder patients, A seven years follow-up study from Iran.

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a rare neuroinflammatory disease characterized by recurrent relapses. The most common signs are myelitis and optic neuritis. It can also present by cerebral or brain stem syndromes. There are still many challenges in its diagnosis and treatment, and long-term follow-up studies are needed to see the disease course over time. We established an electronic registration system of NMOSD patients starting from October 2015 in Kashani hospital, Isfahan, Iran. Every suspected patient was documented and included in the follow-up system to survey their disease course. Anti-aquaporine 4 (AQP4) antibody checked for all by cell-based assay method. All information such as demographic and clinical data and laboratory and MRI findings were documented. Participants were followed up for any relapses, new paraclinical tests and drug changes. This study is based on the definite NMOSD cases (according to the 2015 criteria) characteristics and clinical course during 7 years of registration. The study included 173 NMOSD cases and 56 ones were seropositive for AQP4 Ab. Their mean age was 40.02±11.11 years (45.78 in the seropositive group). The mean age at disease onset was about 30.16 years. The mean time of follow-up by our registration system is 55.84±18.94 months (54.82 months in seropositive ones). The annual relapse rate is estimated as 0.47±0.36. Long extended transvers myelitis (LETM) was present in the baseline MRI of 77 patients (44.5%), while 32 of them did not show any related clinical symptoms. 124 patients revealed an abnormality in the first brain MRI. 27 individuals suffer hypothyroidism as the most common comorbid disease. The disease seems to be more prevalent in the west and southwest areas of Isfahan province. The mean age of onset is higher than Multiple Sclerosis (MS) patients, but there are notable pediatric cases too. It should also be noticed that cervical LETM can be asymptomatic at first. Brain MRI abnormalities are frequently observed. The disease is more prevalent in the geographical areas where showing high MS prevalence.

Role of serostatus in pediatric neuromyelitis optica spectrum disorders: A nationwide multicentric study.

Neuromyelitis optica spectrum disorders (NMOSD) are immune-mediated inflammatory disorders of the central nervous system (CNS) mostly presenting as optic neuritis and acute myelitis. NMOSD can be associated with seropositivity for aquaporin 4 antibody (AQP4 IgG), myelin oligodendrocyte glycoprotein antibody (MOG IgG), or can be seronegative for both. In this study, we retrospectively examined our seropositive and seronegative pediatric NMOSD patients. Data were collected from all participating centres nationwide. Patients diagnosed with NMOSD were divided into three subgroups according to serology: AQP4 IgG NMOSD, MOG IgG NMOSD, and double seronegative (DN) NMOSD. Patients with at least six months of follow-up were compared statistically. The study included 45 patients, 29 female and 16 male (ratio:1.8), mean age 15.16±4.93 (range 5.5-27) years. Age at onset, clinical manifestations, and cerebrospinal fluid findings were similar between AQP4 IgG NMOSD (n=17), MOG IgG NMOSD (n=10), and DN NMOSD (n=18) groups. A polyphasic course was more frequent in the AQP4 IgG and MOG IgG NMOSD groups than DN NMOSD (p=0.007). The annualized relapse rate and rate of disability were similar between groups. Most common types of disability were related to optic pathway and spinal cord involvement. Rituximab in AQP4 IgG NMOSD, intravenous immunoglobulin in MOG IgG NMOSD, and azathioprine in DN NMOSD were usually preferred for maintenance treatment. In our series with a considerable number of double seronegatives, the three major serological groups of NMOSD were indistinguishable based on clinical and laboratory findings at initial presentation. Their outcome is similar in terms of disability, but seropositive patients should be more closely followed-up for relapses.

Meta‐analysis of the use of Ofatumumab in the treatment of relapsing‐remitting multiple sclerosis

AbstractBackgroundOfatumumab is the first monoclonal antibody developed specifically for treating relapsed multiple sclerosis (RMS). This disease (Multiple Sclerosis) includes relapsing–remitting multiple sclerosis (RRMS), a chronic autoimmune illness that affects the central nervous system (CNS), including the brain and spinal cord. The purpose of this study is to determine whether Ofatumumab is efficacious and safe in the treatment of relapsing–remitting multiple sclerosis.MethodsAn analysis of studies comparing Ofatumumab with placebo in people with relapsing‐remitting multiple sclerosis was done in accordance with PRISMA guidelines. We looked up information in MEDLINE, SciSearch, BIOSIS Previews, Derwent Drug File, Embase, and International Pharmaceutical Abstracts. In patients with relapsing–remitting multiple sclerosis, randomized double‐blind and non‐randomized trials contrasting Ofatumumab with placebo were found by two independent investigators. Utilizing Review Manager 5.4.1, data were examined. The main results were total gadolinium‐enhancing (Gd+) T1 lesions, annualized relapse rate, and new or expanding total T2 lesions. Secondary outcomes concentrated on general adverse events and adverse events related to infections.ResultsThree studies were included involving 334 patients, and the meta‐analysis indicated that Ofatumumab showed good efficacy and safety in patients with relapsing forms of multiple sclerosis. The annual rate of relapse was significantly reduced by Ofatumumab (OR 0.51; 95% CI 0.27, 0.98; P = 0.04). Ofatumumab reduced the number of gadolinium‐enhancing (Gd+) T1 lesions per scan (Mean difference −0.59; 95% CI −0.63, −0.55; P &lt; 0.05). Ofatumumab treatment decreased new or enlarging total T2 lesions significantly (Mean difference −1.03; 95% CI −1.29, −0.76; P &lt; 0.05). Infection‐related adverse effects were seen more frequently with Ofatumumab shown by the odd ratio 0.48; 95% CI 0.22, 1.04; P = 0.06. Infection is, thus, a major limitation to its use.ConclusionThe meta‐analysis indicated that Ofatumumab is efficacious and safe for patients with relapsing forms of multiple sclerosis.

Impact of adherence to disease modifying therapies on long-term clinical and economic outcomes in multiple sclerosis: A claims analysis of real-world data.

Multiple sclerosis (MS) is a chronic neurodegenerative inflammatory disease that requires long-term commitment to treatment for optimal outcomes. A variety of disease-modifying therapies (DMTs) are now available that reduce relapses and delay disease progression in people with MS. However, adherence remains a significant issue, with a variety of mental, physical, and emotional factors contributing to non-adherence. In a large number of studies, non-adherence has been associated with worse clinical outcomes (relapses and disease severity), a higher economic burden, and loss of work productivity. However, many of these studies were short-term (1-2 years) or cross-sectional studies; thus, more data are needed on the long-term clinical and economic impacts of DMT non-adherence. The objective of this study was to determine the longer-term impact of adherence to DMTs on disease activity and healthcare resource utilization (HCRU) in people with MS. The study hypothesis was that non-adherence to DMTs would be associated long-term with worse clinical outcomes and a higher economic burden. A retrospective administrative claims analysis of the US MarketScan® Commercial database (2011-2017) in individuals (18-65 years) with MS (based on International Classification of Disease coding) was conducted. Adherence was classified by proportion of days covered (PDC) ≥0.8 and non-adherence by PDC <0.8; sensitivity analyses helped further categorize as moderately (PDC ≥0.6-<0.8) or highly (PDC <0.6) non-adherent. Cohorts were matched using propensity score matching. Time to first relapse, annualized relapse rate (ARR), time to use of assistive devices (cane/walker or wheelchair), and annual HCRU (inpatient, emergency room [ER], outpatient, and MRI visits and costs) were compared between cohorts. 10,248 MS cases were identified; 58% met adherence criteria, and 42% met non-adherence criteria. Mean follow-up from diagnosis or first DMT claim was 5.3 years. Adherent individuals had a longer time to first relapse (hazard ratio [HR] 0.83; 95% confidence interval [CI]: 0.77-0.90; p<0.0001), a lower ARR (0.13vs. 0.18, respectively; rate ratio [RR] 0.75 [95% CI: 0.71-0.79]; p<0.0001), and longer lag times to cane/walker use (HR 0.79 [95% CI: 0.66-0.94]; p=0.0067) and wheelchair use (HR 0.68 [95% CI: 0.55-0.83]; p=0.0002) than non-adherent individuals. Adherent individuals had fewer annual inpatient and ER visits and lower total costs than those who were non-adherent (p<0.0001). Sensitivity analyses showed that differences in disease activity and HCRU were generally more pronounced between matched adherent and highly non-adherent pairs than between matched adherent and moderately non-adherent pairs. Significant differences in MS disease activity and HCRU were observed based on adherence to DMTs. Our study underscores the negative impact of non-adherence to DMTs on long-term clinical and economic outcomes in MS.

Use of follow-on fingolimod for multiple sclerosis: Analysis of effectiveness and patient reported outcomes in a real-world clinical setting.

Follow-on disease modifying therapies (FO-DMTs) do not always require Phase III studies. There are concerns that cheaper FO-DMTs are only used to reduce healthcare costs. However, the well-being of people with MS (pwMS) should be a priority. We aimed to evaluate the efficacy, safety and treatment satisfaction of one of the FO- Fingolimod (FTY) used in Turkey with the approval of Turkish Ministry of Health. PwMS under FTY were recruited from 13 centers and real-world data and answers of satisfaction and adherence statements of pwMS on FTY treatment were analyzed. Data of 239 pwMS were obtained. The duration of FTY treatment was 2.5±0.8 (1-4) years in pwMS who were included in the study and whose treatment continued for at least one year. Significant decreases in annual relapse rate (p<0.001), Expanded Disability Status Scale (p<0.001) and neuroimaging findings (p<0.001) were observed. While 64% of the patients were satisfied and 71.5% were found to adherent with this FO-FTY. This multicenter retrospective study found that the efficacy, safety and treatment adherence of a prescribed FO-FTY were consistent with the results of real-world studies. Studies including real-world data may provide guidance to address issues related to FO-FTY use.

Brain Atrophy as an Outcome of Disease-Modifying Therapy for Remitting-Relapsing Multiple Sclerosis.

Currently, clinical trials of DMTs strive to determine their effect on neuroinflammation and neurodegeneration. We aimed to determine the impact of currently used DMTs on brain atrophy and disability in RRMS. The main goal of this review is to evaluate the neuroprotective potential of MS therapy and assess its impact on disability. We performed a systematic analysis of clinical trials that used brain atrophy as an outcome or performed post hoc analysis of volumetric MRI parameters to assess the neuroprotective potential of applied therapies. Trials between 2008 and 2019 that included published results of brain parenchymal fraction (BPF) change and brain volume loss (BVL) in the period from baseline to week 96 or longer were considered. Twelve from 146 clinical trials met the inclusion criteria and were incorporated into the analysis. DMTs that presented a large reduction in BVL also exhibited robust effects on clinical disability worsening, e.g., alemtuzumab with a 42% risk reduction in 6-month confirmed disability accumulation (p = 0.0084), ocrelizumab with a 40% risk reduction in 6-month confirmed disability progression (p = 0.003), and other DMTs (cladribine and teriflunomide) with moderate influence on brain atrophy were also associated with a marked impact on disability worsening. Dimethyl fumarate (DEFINE) and fingolimod (FREEDOMS I) initially exhibited significant effect on BVL; however, this effect was not confirmed in further clinical trials: CONFIRM and FREEDOMS II, respectively. Peg-IFN-β1a shows a modest effect on BVL and disability worsening. Our results show that BVL in one of the components of clinical disability worsening, together with other variables (lesion volume and annualized relapse rate). Standardization of atrophy measurement technique as well as harmonization of disability worsening and progression criteria in further clinical trials are of utmost importance as they enable a reliable comparison of neuroprotective potential of DMTs.