Active Magnetic Resonance Imaging Lesions Research Articles

New directions in ocrelizumab therapy in multiple sclerosis: higher doses and subcutaneous therapy

Ocrelizumab is the first anti-CD20 monoclonal antibody approved for the treatment of relapsing and primary progressive multiple sclerosis. Ocrelizumab is administered intravenously (i.v.) at a dose of 600 mg every six months. It is a highly effective drug strongly inhibiting inflammatory changes in the central nervous system, which nearly completely prevents the development of new active magnetic resonance imaging lesions and clinical relapses. Pharmacokinetic studies and data from post hoc analyses of ocrelizumab pivotal studies suggest that a higher dose than the current dose level might have a stronger therapeutic impact. These results revealed that higher ocrelizumab exposure dependent on lower body mass correlated with increased B cell depletion and reduced risk of disability progression independent of relapse activity (PIRA). In addition, higher ocrelizumab exposure showed a correlation with decreased development of new and enlarging T2 magnetic resonance imaging lesions. Two randomised studies are currently under way to compare the efficacy and safety of the standard i.v. dose of 600 mg versus higher doses (1,200 mg or 1,800 mg) in multiple sclerosis patients. Another new direction in the development of ocrelizumab therapy in multiple sclerosis is subcutaneous (s.c.) drug administration. Recent data from the OCARINA study revealed that s.c. ocrelizumab was not inferior to the i.v. administration with respect to pharmacokinetics, magnetic resonance imaging activity, and clinical relapses. The safety of s.c. ocrelizumab was found to be comparable to the i.v. form, with a higher rate of mild local injection reactions.

Efficacy and safety of inebilizumab in Asian participants with neuromyelitis optica spectrum disorder: Subgroup analyses of the N-MOmentum study.

Inebilizumab, an anti-CD19 B cell-depleting antibody, reduced the risk of a neuromyelitis optica spectrum disorder (NMOSD) attack, disability worsening, magnetic resonance imaging (MRI) lesion activity, and disease-related hospitalizations in participants with NMOSD in the N-MOmentum study (NCT02200770). However, the efficacy and safety outcomes of inebilizumab specific to an Asian population were not fully reported. Therefore, subgroup analyses of the N-MOmentum study were conducted post hoc to evaluate the efficacy and safety of inebilizumab in Asian participants with NMOSD. The N-MOmentum study was a multicenter, double-blind, randomized, placebo-controlled phase 2/3 trial with an open-label extension period (OLP). In the subgroup analyses, data from Asian participants from the N-MOmentum study were compared with those of non-Asian participants. Eligible participants were randomly allocated (3:1) to receive 300mg intravenous (IV) inebilizumab or placebo on Days 1 and 15. Participants who had an NMOSD attack or completed the randomized controlled period (RCP) could enter the OLP, where they received inebilizumab for ≥2 years. All participants who entered the OLP received inebilizumab 300mg IV every 6 months. Overall, 230 participants received treatment (174 received inebilizumab and 56 received placebo), of whom 47 were Asian (39 received inebilizumab and 8 received placebo). Baseline characteristics were similar between the Asian and non-Asian subgroups, except for disease duration, annualized relapse rate prior to randomization in this study, and previous maintenance therapy. In the Asian subgroup, the risk of NMOSD attacks was reduced with inebilizumab versus placebo (hazard ratio, 0.202) and the attack-free rate at 28 weeks was 82.1% with inebilizumab versus 37.5% with placebo, in the 6-month RCP. NMOSD attack rates were comparable between the Asian and non-Asian subgroups. In the Asian subgroup, the rates of Expanded Disability Status Scale worsening from baseline, active MRI lesions, and disease-related hospitalizations tended to be lower in the inebilizumab group than in the placebo group; similar results were shown in the non-Asian subgroup. For long-term efficacy and safety (RCP and OLP), the annualized adjudicated NMOSD attack rate in Asian participants treated with inebilizumab was reduced (0.096) compared with that at baseline (1.04), with a mean follow-up period of inebilizumab treatment of 3.38 years, which was consistent with the results in the non-Asian subgroup. The risk of NMOSD attack decreased with prolonged duration of treatment in both the inebilizumab/inebilizumab and placebo/inebilizumab groups in the Asian and non-Asian subgroups. The incidence of treatment-emergent adverse events (TEAEs) was similar between the Asian and non-Asian subgroups. In the Asian and non-Asian subgroups, 15.2% and 35.2% of participants, respectively, had at least one serious TEAE and/or Grade ≥3 TEAE during long-term therapy. No deaths occurred in the Asian subgroup whereas three deaths occurred in the non-Asian subgroup. Inebilizumab reduced the risk of an NMOSD attack, progression of disability, MRI lesion activity, and disease-related hospitalizations in Asian participants with NMOSD. The efficacy of inebilizumab in reducing NMOSD attacks continued without any unexpected safety signals or concerns during long-term use in Asian participants.

Clinical and fringe benefits of rituximab in multiple sclerosis treatment in a poor resource setting: Case series and cost analysis.

Multiple sclerosis (MS) is an inflammatory demyelinating condition of the central nervous system that leads to neurological disability and a poor quality of life (QoL). Rituximab has been used off-label in many countries to treat MS because of its high efficacy and affordability. However, there is no evidence of its effectiveness in Thailand. Therefore, the objective of this study was to evaluate the efficacy and additional benefits of rituximab in Thai patients with MS. This was a prospective cohort study of patients diagnosed with MS who started treatment with rituximab between November 1, 2020, and October 31, 2022. Patients with MS eligible for the study received intravenous rituximab with a starting dose of 1000mg at the first visit and another 1000mg dose 2 weeks later. Thereafter, 1000mg rituximab was administered every 6 months until the end of the study. The primary outcome was the annualized relapse rate (ARR). In addition, magnetic resonance imaging (MRI) activity of the gadolinium-enhancing lesion, QoL, number of hospital visits, and treatment costs were considered secondary outcomes. Ten patients diagnosed with relapsing-remitting multiple sclerosis were included in the study. The median ARR markedly decreased from 2.14 (0-4) to 0 (0-0.5) (p=0.005). The median Expanded Disability Status Scale score improved from 3.25 (1.5-6.0) to 1 (1-4) (p=0.005). The median number of enhancing lesions decreased from 1 (0-7) to 0 (0-3) (p=0.017). In addition, the median EuroQoL 5 Dimension 5 Level score, indicating QoL, improved from 0.7 (0.41-0.85) to 0.88 (0.68-1.00) (p=0.005). The median number of outpatient department visits significantly decreased from 6 (4-12) to 3 (2-5) (p=0.009). Hospitalization or inpatient department visits diminished from 1 (0-2) to 0 (0-1) (p=0.007). The total direct medical cost of rituximab treatment was not significantly different from that of the pre-treatment condition: 70,891 THB (65,391-116,358) VS 66,961 THB (33,927-109,248) or 1,904 USD (1,756-3,125 USD) VS 1,798 USD (911-2,934) (p=0.173). Rituximab was effective in the treatment of MS in Thailand. The use of rituximab reduced the number of relapses, reduced disability, decreased the number of active MRI lesions, and improved QoL. Moreover, the benefit of rituximab in treating MS in Thailand surpasses the current cost of treatment.

A randomized study of natalizumab dosing regimens for relapsing–remitting multiple sclerosis

Background: REFINE was an exploratory, dose- and frequency-blinded, prospective, randomized, dose-ranging study in relapsing–remitting multiple sclerosis (RRMS) patients. Objective: To examine the efficacy, safety, and tolerability of natalizumab administered via various regimens in RRMS patients. Methods: Clinically stable RRMS patients previously treated with 300 mg natalizumab intravenously for ⩾12 months were randomized to one of six natalizumab regimens over 60 weeks: 300 mg administered intravenously or subcutaneously every 4 weeks (Q4W), 300 mg intravenously or subcutaneously every 12 weeks (Q12W), or 150 mg intravenously or subcutaneously Q12W. The primary endpoint was the mean cumulative number of combined unique active magnetic resonance imaging (MRI) lesions at week 60. Results: In total, 290 patients were enrolled. All Q12W dosing arms were associated with increased clinical and MRI disease activity and closed early; ⩾39.5% of patients in each Q12W arm met rescue criteria. In the 300 mg intravenous and subcutaneous Q4 W arms, the mean cumulative number of combined unique active MRI lesions was 0.23 and 0.02, respectively; annualized relapse rates were 0.07 and 0.08, respectively; and trough natalizumab serum levels and α4-integrin saturation were comparable. Conclusion: Natalizumab 300 mg subcutaneous Q4W was comparable to 300 mg intravenous Q4W dosing with respect to efficacy, pharmacokinetics/pharmacodynamics, and safety.

Inflammatory activity following motor progression due to critical CNS demyelinating lesions

Background: New inflammatory activity is of unclear frequency and clinical significance in progressive multiple sclerosis (MS); it is uncertain in patient cohorts with motor progression due to critical demyelinating lesions. Objectives: The aim of this study is to determine the likelihood of central nervous system (CNS) inflammatory activity, assessed by new clinical relapses or active magnetic resonance imaging (MRI) lesions, following onset of motor progression due to critical demyelinating lesions. Methods: Patients with progressive upper motor neuron impairment for ⩾1 year attributable to critical demyelinating lesions with single CNS lesion (progressive solitary sclerosis (PSS)), 2 to 5 total CNS demyelinating lesions (progressive “pauci-sclerosis” (PPS)), or >5 CNS demyelinating lesions and progressive exclusively unilateral monoparesis or hemiparesis (PUHMS) were identified. Clinical data were reviewed for acute MS relapses, and subsequent MRI was reviewed for active T1-gadolinium-enhancing or T2-demyelinating lesions. Results: None of the 91 patients (22 PSS, 40 PPS, 29 PUHMS) identified experienced clinical relapses over a median clinical follow-up of 93 months (range: 12–518 months). Nine patients (10%) developed active lesions over median 84 months radiologic follow-up (range: 12–518 months). Active lesions occurred in 24% PUHMS, 5% PSS, and 3% PPS cohorts. Conclusion: New inflammatory activity, defined by active lesions and clinical relapses following motor progression in patients with critical demyelinating lesions, is low. Disease-modifying therapies that reduce demyelinating relapses and active MRI lesions are of uncertain benefit in these cohorts.

Effect of interferon-β1α therapy on multiple sclerosis based on gadolinium-enhancing or active T2 magnetic resonance imaging outcomes: a meta-analysis

Objectives: Interferon-beta1alpha (IFN-β1α) is widely used to modify the course of relapsing-remitting multiple sclerosis. However, many patients have relapses. The purpose of this study was to evaluate magnetic resonance imaging (MRI) as a predictor of IFN-β1α treatment efficacy in patients with MS.Methods: PubMed, Embase, and the Cochrane Library were searched to identify eligible studies. Manual searches were also conducted. All eligible trials included MS patients who received IFN-β1α based on gadolinium-enhancing or active T2 MRI lesions for determination of relapse rates.Results: Of 499 identified studies, we included 10 trials reporting data on 6,037 MS patients. IFN-β1α therapy significantly reduced the risk of relapse (RR: 0.87; 95% confidence intervals (CI): 0.76–0.99; p = 0.032). Furthermore, baseline median T2 lesion volume was found to be related to IFN-β1α therapy and relapse (p = 0.018). Subgroup analysis suggested that IFN-β1α therapy was associated with reduced risk of relapse (RR: 0.82; 95%CI: 0.71–0.94; p = 0.005 versus placebo). However, there was no significant difference in the risk of relapse compared to treatment with low dose IFN-β1α (RR: 0.93; 95%CI: 0.80–1.08; p = 0.337) or glatiramer acetate (RR: 0.93; 95%CI: 0.77–1.14; p = 0.506). Finally, IFN-β1α therapy significantly increased the risk of injection-site disorders, influenza-like syndrome, and alanine transferase elevation.Discussion: Effects of IFN-β1α therapy are associated with a statistically significant impact on baseline median T2 lesion volume. However, the safety outcomes are significantly worse in patients who receive IFN-β1α therapy.

Lack of magnetic resonance imaging lesion activity as a treatment target in multiple sclerosis: An evaluation using electronically collected outcomes

BackgroundThe appropriate treatment target in multiple sclerosis (MS) is unclear. Lack of magnetic resonance imaging (MRI) lesion activity, a component of the no evidence of disease activity concept, has been proposed as a treatment target in MS. We used our MS database to investigate whether aggressively pursuing MRI stability by changing disease modifying therapy (DMT) when MRI activity is observed leads to better clinical and imaging outcomes. MethodsThe Knowledge Program (KP) is a database linked to our electronic medical record allowing capture of patient and clinician reported outcomes. Through KP query and chart review, we identified all relapsing-remitting MS patients visiting between 1 January 2008 and 31 December 2014 with active MRIs despite DMT. Propensity modeling based on demographic and disease characteristics was used to match DMT switchers to non-switchers. KP and MRI outcomes were compared 18 months after the active MRI using mixed-effects linear regression models. ResultsWe identified 417 patients who met criteria for our analysis. After propensity matching, 78 switchers and 91 non-switchers were analyzed. There was no difference in clinical or radiologic outcomes between these groups at 18 months. ConclusionsWe did not find a short-term benefit of changing DMT to pursue MRI stability.

Activity of secukinumab, an anti-IL-17A antibody, on brain lesions in RRMS: results from a randomized, proof-of-concept study.

The objective of this study was to assess the effect of secukinumab, a monoclonal antibody that inhibits interleukin (IL)-17A, on number of new active brain magnetic resonance imaging (MRI) lesions in subjects with relapsing-remitting multiple sclerosis (MS). Subjects (N=73) were randomized 1:1 to secukinumab 10mg/kg or placebo by intravenous infusion at weeks 0, 2, 4, 8, 12, 16, and 20. MRI scans were obtained within 30days prior to randomization, on a monthly basis during the treatment period, and at study completion. The primary endpoint was the cumulative number of combined unique active lesions (CUAL) observed on brain MRI scans from week 4 to week 24. Compared with placebo, secukinumab non-significantly reduced the number of CUAL observed on 4-weekly MRI from week 4 to 24 (primary endpoint) by 49% (95% CI -10 to 77%; P=0.087) and significantly reduced the number of cumulative new gadolinium-enhancing T1 lesions by 67% (31-84%, P=0.003). CUAL reductions were progressively greater from week 4 (1%) to week 16 (49%) and persisted until end-study (50%). There were no serious adverse events; the adverse event rate was comparable to placebo (53 versus 49%), although mild-to-moderate infection was somewhat more frequent (37 versus 23%). This proof-of-concept study provides the first evidence that blocking IL-17A with an antibody may reduce MRI lesion activity in MS. Further studies are needed to confirm this finding and determine the magnitude of effect.

Lack of Magnetic Resonance Imaging Lesion Activity as a Treatment Target in Multiple Sclerosis: An Evaluation Using Electronically Collected Outcomes (P2.141)

Lack of Magnetic Resonance Imaging Lesion Activity as a Treatment Target in Multiple Sclerosis: An Evaluation Using Electronically Collected Outcomes (P2.141)

Therapeutic Intervention in Multiple Sclerosis with Alpha B-Crystallin: A Randomized Controlled Phase IIa Trial

As a molecular chaperone and activator of Toll-like receptor 2-mediated protective responses by microglia and macrophages, the small heat shock protein alpha B-crystallin (HspB5) exerts therapeutic effects in different animal models for neuroinflammation, including the model for multiple sclerosis (MS). Yet, HspB5 can also stimulate human antigen-specific memory T cells to release IFN-γ, a cytokine with well-documented detrimental effects during MS. In this study, we explored in a Phase IIa randomized clinical trial the therapeutic application of HspB5 in relapsing-remitting MS (RR-MS), using intravenous doses sufficient to support its protective effects, but too low to trigger pathogenic memory T-cell responses. These sub-immunogenic doses were selected based on in vitro analysis of the dose-response profile of human T cells and macrophages to HspB5, and on the immunological effects of HspB5 in healthy humans as established in a preparatory Phase I study. In a 48-week randomized, placebo-controlled, double-blind Phase IIa trial, three bimonthly intravenous injections of 7.5, 12.5 or 17.5 mg HspB5 were found to be safe and well tolerated in RR-MS patients. While predefined clinical endpoints did not differ significantly between the relatively small groups of MS patients treated with either HspB5 or placebo, repeated administration especially of the lower doses of HspB5 led to a progressive decline in MS lesion activity as monitored by magnetic resonance imaging (MRI), which was not seen in the placebo group. Exploratory linear regression analysis revealed this decline to be significant in the combined group receiving either of the two lower doses, and to result in a 76% reduction in both number and total volumes of active MRI lesions at 9 months into the study. These data provide the first indication for clinical benefit resulting from intervention in RR-MS with HspB5. Trial Registration: ClinicalTrials.gov Phase I: NCT02442557; Phase IIa: NCT02442570

Long-term Therapy With Interleukin 6 Receptor Blockade in Highly Active Neuromyelitis Optica Spectrum Disorder.

Neuromyelitis optica (NMO) is characterized by disabling relapses of optic neuritis and myelitis and the presence of aquaporin 4 antibodies (AQP4-abs). Interleukin 6, which is significantly elevated in serum and cerebrospinal fluid of patients with NMO, induces AQP4-ab production by plasmablasts and represents a novel therapeutic target. To evaluate the long-term safety and efficacy of tocilizumab, a humanized antibody targeting the interleukin 6 receptor, in NMO and NMO spectrum disorder. Retrospective observational study with 10 to 51 months of follow-up between December 2010 and February 2015, in neurology departments at tertiary referral centers. Participants were 8 female patients of white race/ethnicity with highly active AQP4-ab-seropositive NMO (n = 6) and NMO spectrum disorder (n = 2) whose disease had been resistant to previous medications, including B-cell depletion, and who switched to tocilizumab (6-8 mg/kg of body weight per dose). Annualized relapse rate, Expanded Disability Status Scale score, spinal cord and brain magnetic resonance imaging, AQP4-ab titers, pain levels (numerical rating scale), and adverse effects. Patients were followed up for a mean (SD) of 30.9 (15.9) months after switching to tocilizumab. Two of eight patients received add-on therapy with monthly corticosteroid pulses (temporary) or azathioprine, respectively. During tocilizumab treatment, the median annualized relapse rate significantly decreased from 4.0 (interquartile range, 3.0-5.0) in the year before tocilizumab therapy to 0.4 (interquartile range, 0.0-0.8) (P = .008), and the median Expanded Disability Status Scale score significantly decreased from 7.3 (interquartile range, 5.4-8.4) to 5.5 (interquartile range, 2.6-6.5) (P = .03). Active magnetic resonance imaging lesions were seen in 6 of 8 patients at tocilizumab initiation and in 1 of 8 patients at the last magnetic resonance imaging. Three patients remained relapse free during tocilizumab treatment. In 5 patients, a total of 8 relapses occurred, 4 within the first 2½ months of therapy. Five attacks were associated with delayed tocilizumab administration (≥40 days), and 6 attacks were associated with reduced tocilizumab dosage (6 vs 8 mg/kg). The AQP4-ab titers (P = .02) and pain levels (P = .02) dropped significantly during tocilizumab treatment. Adverse effects included moderate cholesterol elevation in 6 of 8 patients, infections in 4 of 8 patients, and deep venous thrombosis and neutropenia in one patient each. Prolonged tocilizumab therapy may be safe and effective from early treatment phases onward for otherwise therapy-resistant highly active NMO and NMO spectrum disorder. Relapse patterns indicate that adherence to a regular therapeutic regimen with monthly infusions of tocilizumab (8 mg/kg) may increase efficacy.

Treatment of Multiple Sclerosis – Relationship between Vitamin D and Interferon β-1b

There are many reports suggesting an association between vitamin D status and both the development of multiple sclerosis (MS) and its course. This relationship and the effects of vitamin D and interferon β-1b (IFNβ-1b) in the treatment of patients are reviewed in the BEtaferon/ Betaseron in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) and the Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose in multiple sclerosis (BEYOND) studies. In the BENEFIT study the average serum 25-hydroxyvitamin D (25[OH]D) levels strongly predicted MS disease activity and progression. The probability of clinically definite MS (CDMS) and magnetic resonance imaging (MRI) activity was lower in these clinically isolated syndrome (CIS) patients with 25(OH)D levels ≥50 nmol/L and in those starting with IFNβ -1b. Furthermore, there was a beneficial effect on relapse rate, occurrence of new active MRI lesions and disease progression for a 50 nmol/L increase in 25(OH)D levels. Similarly, in relapsing-remitting (RR) MS patients from the BEYOND study serum 25(OH)D levels were inversely associated with MRI markers of MS activity. Genetic analysis of patients from these studies indicated that there may be a benefit in monitoring and managing vitamin D levels in early MS patients treated with IFNβ-1b and a cumulative number of risk alleles predict lower 25(OH)D levels in CIS and RRMS patients. Further studies have suggested that some of the IFNβ-1b therapeutic effects on relapse could be mediated through modulation of vitamin D metabolism. Thus, there seems to be a benefit on clinical and MRI measures if patients are treated with both vitamin D and IFNβ-1b. There is a need to further evaluate this effect in clinical trials. The relationship between vitamin D and MS disease activity along with the effects of vitamin D and IFNβ-1b in the treatment of MS patients is reviewed.

MRI in the management of MS

Measures derived from conventional magnetic resonance imaging (MRI), including the number of active lesions, as well as the overall burden of T2-hyperintense and T1-hypointense lesions, and brain volume, have clear advantages over clinical assessment, including that they are more objective and more sensitive to multiple sclerosis (MS) related changes. For these reasons, conventional MRI has been incorporated into the diagnostic workup of patients with clinically isolated syndromes who are at risk of developing MS, and it is always recommended in patients with definite MS to monitor the course of the disease. Even though no standardized guidelines exist, follow-up brain MRI is advised whenever new diagnostic questions arise or new neurological symptoms develop, especially if suggestive of comorbid conditions. Patients about to start a new treatment or to change treatment should undergo a brain MRI scan. This MRI scan should then be repeated after 6–12 months to assess the effectiveness of the treatment regimen. In addition, conventional MRI-derived end-points have been used as primary and secondary outcome measures for monitoring MS clinical trials. The rationale for using conventional MRI metrics as surrogates for clinical outcomes is that the efficacy of a treatment in reducing relapses can be predicted at a trial level by its capacity to reduce active MRI lesions. In this context, the most widely used conventional MRI measures are those reflecting disease activity (new or enlarged T2 lesion counts, enhancing and new gadolinium-enhancing lesion counts, enhancing lesion volume measurement) and accumulated disease burden (T2 lesion load assessment). In the near future, it is likely that novel MR markers of MS evolution will be offered by non-conventional techniques and ultra-high field scanners.

Further investigation of safety monitoring guidelines based on magnetic resonance imaging lesion activity in multiple sclerosis clinical trials

We assess two modified guidelines for monitoring patient safety in multiple sclerosis (MS) trials. These guidelines flag patients with an increase in contrast enhancing lesion (CEL) count above a threshold over the CEL level 1–2 months earlier. We compare the new guidelines to the original guideline where the threshold is set according to the baseline by applying the guidelines to two previous studies. The odds ratios of a subsequent clinical relapse associated with meeting the CEL threshold based on the modified guidelines are similar to those based on the original guideline. There is a need for patient and cohort specific monitoring procedures.

Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis

To evaluate the extent to which treatment effect on brain atrophy is able to mediate, at the trial level, the treatment effect on disability progression in relapsing-remitting multiple sclerosis (RRMS). We collected all published randomized clinical trials in RRMS lasting at least 2 years and including as endpoints disability progression (defined as 6 or 3 months confirmed 1-point increase on the Expanded Disability Status Scale), active magnetic resonance imaging (MRI) lesions (defined as new/enlarging T2 lesions), and brain atrophy (defined as change in brain volume between month 24 and month 6-12). Treatment effects were expressed as relative reductions. A linear regression, weighted for trial size and duration, was used to assess the relationship between the treatment effects on MRI markers and on disability progression. Thirteen trials including >13,500 RRMS patients were included in the meta-analysis. Treatment effects on disability progression were correlated with treatment effects both on brain atrophy (R(2) = 0.48, p = 0.001) and on active MRI lesions (R(2) = 0.61, p < 0.001). When the effects on both MRI endpoints were included in a multivariate model, the correlation was higher (R(2) = 0.75, p < 0.001), and both variables were retained as independently related to the treatment effect on disability progression. In RRMS, the treatment effect on brain atrophy is correlated with the effect on disability progression over 2 years. This effect is independent of the effect of active MRI lesions on disability; the 2 MRI measures predict the treatment effect on disability more closely when used in combination.

Safety and efficacy of mitoxantrone in pediatric patients with aggressive multiple sclerosis

ObjectiveThe purpose of this study was to assess the safety and efficacy of mitoxantrone (MX) in pediatric patients with aggressive multiple sclerosis (MS). MethodsA retrospective analysis on pediatric MS patients treated with MX was performed with regards to demographic/clinical parameters and magnetic resonance imaging (MRI) findings. Results19 definite pediatric MS cases with mean ± SD age of 15.4 ± 2.8 years underwent 20 mg MX for control of their severe/frequent relapses, high EDSS score or new and active brain MRI lesions. After a median [IQR] follow-up period of 30[12–60] months, 14 cases (73%) were relapse free; the EDSS score decreased by at least 0.5 in 16 cases (84.2%); and gadolinium-enhancing lesion volume fell by 84.2% in 16 cases. Adverse events included nausea and vomiting, fatigue, alopecia, palpitation, cardiomyopathy and mild leukopenia. All adverse events were mild and transient. ConclusionOur results suggest MX is a good candidate for treatment of children with worsening RRMS and SPMS. Recommendations regarding patient selection, treatment administration, and close follow-up should be considered. Continuing research is needed to establish its efficacy and safety profile in a multinational collaboration with careful follow-up of adverse events.

Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing–remitting multiple sclerosis: subgroup analyses of the CONFIRM study

In the phase 3, randomized, placebo-controlled and active reference (glatiramer acetate) comparator CONFIRM study in patients with relapsing-remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) reduced the annualized relapse rate (ARR; primary endpoint), as well as the proportion of patients relapsed, magnetic resonance imaging lesion activity, and confirmed disability progression, compared with placebo. We investigated the clinical efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, Expanded Disability Status Scale score, T2 lesion volume, and gadolinium-enhancing lesions. BG-12 treatment demonstrated generally consistent benefits on relapse-related outcomes across patient subgroups, reflecting the positive findings in the overall CONFIRM study population. Treatment with BG-12 BID and TID reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in all subgroups analyzed. Reductions in ARR with BG-12 BID versus placebo ranged from 34% [rate ratio 0.664 (95% confidence interval 0.422-1.043)] to 53% [0.466 (0.313-0.694)] and from 13% [0.870 (0.551-1.373)] to 67% [0.334 (0.226-0.493)] with BG-12 TID versus placebo. Treatment with glatiramer acetate reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in most patient subgroups. The results of these analyses indicate that treatment with BG-12 is effective on relapses across a broad range of patients with relapsing-remitting multiple sclerosis with varied demographic and disease characteristics.

Mitoxantrone for multiple sclerosis

This is an updated Cochrane review of the previous published version.Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in multiple sclerosis (MS) patients. The main objective was to assess the efficacy and safety of MX compared to a control group in relapsing-remitting (RRMS), progressive relapsing (PRMS) and secondary progressive (SPMS) MS participants. We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (June 2012) and reference lists of articles. We also undertook handsearching and contacted trialists and pharmaceutical companies. Randomised, double-blinded, controlled trials (RCTs) comparing the administration of MX versus placebo or MX plus steroids treatment versus placebo plus steroids treatment were included. The review authors independently selected articles for inclusion. They independently extracted clinical, safety and magnetic resonance imaging (MRI) data, resolving disagreements by discussion. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using odds ratios (OR) with 95% confidence intervals (CI) for the binary outcomes and mean differences (MD) with 95% CI for the continuous outcomes. If heterogeneity was absent, a fixed-effect model was used. Three trials were selected and 221 participants were included in the analyses. MX reduced the progression of disability at two years follow-up (proportion of participants with six months confirmed progression of disability (OR 0.30, 95% CI 0.09 to 0.99 and MD -0.36, 95% CI- 0.70 to -0.02; P = 0.04)). Significant results were found regarding the reduction in annualised relapse rate (MD -0.85, 95% CI -1.47 to -0.23; P = 0.007), the proportion of patients free from relapses at one year (OR 7.13, 95% CI 2.06 to 24.61; P = 0.002) and two years (OR 2.82, 95% CI 1.54 to 5.19; P = 0.0008), and the number of patients with active MRI lesions at six months or one year only (OR 0.24, 95% CI 0.10 to 0.57; P = 0.001). Side effects reported in the trials (amenorrhoea, nausea and vomiting, alopecia and urinary tract infections) were more frequent in treated patients than in controls, while no major adverse events have been reported. These results should be considered with caution because of the heterogeneous characteristics of included trials in term of drug dosage, inclusion criteria and quality of included trials. Moreover, it was not possible to estimate the long-term efficacy and safety of MX. MX shows a significant but partial efficacy in reducing the risk of MS progression and the frequency of relapses in patients affected by worsening RRMS, PRMS and SPMS in the short-term follow-up (two years). No major neoplastic events or symptomatic cardiotoxicity related to MX have been reported; however studies with longer follow-up (not included in this review) have raised concerns about the risk of systolic disfunction (˜12%) and therapy-related acute leukaemias (0.8%), which are increasingly reported in the literature.MX should be limited to treating patients with worsening RRMS and SPMS and with evidence of persistent inflammatory activity after a careful assessment of the individual patients' risk and benefit profiles. Assessment should also consider the present availability of alternative therapies with less severe adverse events.

Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis

Until recently, all approved multiple sclerosis (MS) disease treatments were administered parenterally. Oral fingolimod was approved in September 2010 by the US Food and Drug Administration to reduce relapses and disability progression in relapsing forms of MS. In the clinical trials that led to approval, fingolimod reduced not only acute relapses and magnetic resonance imaging lesion activity but also disability progression and brain volume loss, suggesting preservation of tissue. Fingolimod's mechanism of action in MS is not known with certainty. Its active form, fingolimod-phosphate (fingolimod-P), is a sphingosine 1-phosphate receptor (S1PR) modulator that inhibits egress of lymphocytes from lymph nodes and their recirculation, potentially reducing trafficking of pathogenic cells into the central nervous system (CNS). Fingolimod also readily penetrates the CNS, and fingolimod-P formed in situ may have direct effects on neural cells. Fingolimod potently inhibits the MS animal model, experimental autoimmune encephalomyelitis, but is ineffective in mice with selective deficiency of the S1P₁ S1PR subtype on astrocytes despite normal expression in the immune compartment. These findings suggest that S1PR modulation by fingolimod in both the immune system and CNS, producing a combination of beneficial anti-inflammatory and possibly neuroprotective/reparative effects, may contribute to its efficacy in MS. In clinical trials, fingolimod was generally safe and well tolerated. Its interaction with S1PRs in a variety of tissues largely accounts for the reported adverse effects, which were seen more frequently with doses 2.5 to 10x the approved 0.5 mg dose. Fingolimod's unique mechanism of action distinguishes it from all other currently approved MS therapies.

Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis

The SENTINEL study showed that the addition of natalizumab improved outcomes for patients with relapsing multiple sclerosis (MS) who had experienced disease activity while receiving interferon beta-1a (IFNβ-1a) alone. Previously unreported secondary and tertiary magnetic resonance imaging (MRI) measures are presented here. Patients received natalizumab 300 mg ( n = 589) or placebo ( n = 582) intravenously every 4 weeks plus IFNβ-1a 30 µg intramuscularly once weekly. Annual MRI scans allowed comparison of a range of MRI end points versus baseline. Over 2 years, 67% of patients receiving natalizumab plus IFNβ-1a remained free of new or enlarging T2-lesions compared with 30% of patients receiving IFNβ-1a alone. The mean change from baseline in T2 lesion volume over 2 years decreased in patients receiving natalizumab plus IFNβ-1a and increased in those receiving IFNβ-1a alone (–277.5 mm 3 versus 525.6 mm 3; p < 0.001). Compared with IFNβ-1a alone, add-on natalizumab therapy resulted in a smaller increase in mean T1-hypointense lesion volume after 2 years (1821.3 mm 3 versus 2210.5 mm 3; p < 0.001), a smaller mean number of new T1-hypointense lesions over 2 years (2.3 versus 4.1; p < 0.001), and a slower rate of brain atrophy during the second year of therapy (–0.31% versus –0.40%; p = 0.020). Natalizumab add-on therapy reduced gadolinium-enhancing, T1-hypointense, and T2 MRI lesion activity and slowed brain atrophy progression in patients with relapsing MS who experienced disease activity despite treatment with IFNβ-1a alone.