Aggressive Multiple Sclerosis Research Articles

Aggressive Multiple Sclerosis: Clinical Phenotype and Treatment Within a Randomised Clinical Trial of Autologous Haematopoietic Stem Cell Transplantation vs High Efficacy Disease Modifying Treatment (P9-6.004)

Aggressive Multiple Sclerosis: Clinical Phenotype and Treatment Within a Randomised Clinical Trial of Autologous Haematopoietic Stem Cell Transplantation vs High Efficacy Disease Modifying Treatment (P9-6.004)

Matching proposed clinical and MRI criteria of aggressive multiple sclerosis to serum and cerebrospinal fluid markers of neuroaxonal and glial injury

BackgroundDefinitions of aggressive MS employ clinical and MR imaging criteria to identify highly active, rapidly progressing disease courses. However, the degree of overlap between clinical and radiological parameters and biochemical markers of CNS injury is not fully understood. Aim of this cross-sectional study was to match clinical and MR imaging hallmarks of aggressive MS to serum/CSF markers of neuroaxonal and astroglial injury (neurofilament light chain (sNfL, cNfL), and glial fibrillary acidic protein (sGFAP, cGFAP)).MethodsWe recruited 77 patients with relapsing–remitting MS (RRMS) and 22 patients with clinically isolated syndrome. NfL and GFAP levels in serum and CSF were assessed using a single-molecule-array HD-1-analyzer. A general linear model with each biomarker as a dependent variable was computed. Clinical and imaging criteria of aggressive MS, as recently proposed by the ECTRIMS Consensus Group, were modeled as independent variables. Other demographic, clinical or laboratory parameters, were modeled as covariates. Analyses were repeated in a homogenous subgroup, consisting only of newly diagnosed, treatment-naïve RRMS patients presenting with an acute relapse.ResultsAfter adjusting for covariates and multiplicity of testing, sNfL and cNfL concentrations were strongly associated with the presence of ≥2 gadolinium-enhancing lesions (psNfL = 0.00008; pcNfL = 0.004) as well as the presence of infratentorial lesions on MRI (psNfL = 0.0003; pcNfL < 0.004). No other clinical and imaging criteria of aggressive MS correlated significantly with NfL or GFAP in serum and CSF. In the more homogeneous subgroup, sNfL still was associated with the presence of ≥2 gadolinium-enhancing lesions (psNfL = 0.001), presence of more than 20 T2-lesions (psNfL = 0.049) as well as the presence of infratentorial lesions on MRI (psNfL = 0.034), while cNfL was associated with the presence of ≥2 gadolinium-enhancing lesions (psNfL = 0.011) and presence of more than 20 T2-lesions (psNfL = 0.029).ConclusionsAmong proposed risk factors for an aggressive disease course, MRI findings but not clinical characteristics correlated with sNfL and cNfL as a marker of neuroaxonal injury and should be given appropriate weight considering MS prognosis and therapy. No significant correlation was detected for GFAP alone.

Autologous hematopoietic stem cell transplantation for multiple sclerosis: Long-term follow-up data from Norway

Background: Autologous hematopoietic stem cell transplantation (HSCT) is a potent treatment option for patients with aggressive relapsing-remitting multiple sclerosis (RRMS). Objective: To evaluate long-term outcomes of HSCT in MS. Methods: National retrospective single-center observational study of patients with aggressive RRMS that underwent HSCT in Norway from January 2015 to January 2018. Criteria for receiving HSCT included at least two clinical relapses the last year while on disease modifying treatment (DMT). Results: In total, 29 patients, with a mean follow-up time of 70 months (standard deviation:14.3), were evaluated. Twenty patients (69%) had sustained no evidence of disease activity (NEDA-3) status, 24 (83%) were relapse-free, 23 (79%) free of magnetic resonance imaging (MRI) activity, and 26 (90%) free of progression. Number of patients working full-time increased from 1 (3%), before HSCT, to 10 (33%) after 2 years and 15 (52%) after 5 years. Conclusion: HSCT offers long-term disease-free survival with successively increasing work participation in patients with aggressive MS resistant to DMTs.

Experiences of being treated with autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: A qualitative interview study.

Autologous haematopoietic stem cell transplantation (AHSCT) is increasingly used as a treatment for aggressive multiple sclerosis (MS) and has the potential to induce long-term remission and resolution of disease activity. Despite the extensive research on treatment outcome after AHSCT, the experience of living with MS after AHSCT has not been previously described in the scientific literature. The aim of this study was to explore long-term lived experience of people with MS treated with AHSCT. To exclude selection bias, all persons treated with AHSCT for MS at Uppsala University Hospital, Sweden, between 2004 and 2007 (n = 10), were asked to participate in the study, and all accepted. Open-ended interviews were conducted, digitally recorded, transcribed verbatim, and then subjected to qualitative content analysis with an inductive approach. Five main themes emerged from the interviews: (I) being diagnosed with MS-an unpredictable existence; (II) a new treatment-a possibility for a new life; (III) AHSCT-a transition; (IV) reclaiming life; and (V) a bright future accompanied by insecurity. AHSCT was described by the participants in terms of a second chance and an opportunity for a new life. The treatment became a transition from a state of illness to a state of health, enabling a previous profound uncertainty to wane and normality to be restored. Although participants of different age and sex were included, the main limitation of this study is the relatively small number of participants. Also, the inclusion of persons from one centre alone could restrict transferability of the results. The results give a first insight into lived experience following a highly effective induction treatment for MS, and the experience of not having MS anymore. Underpinned by previously described outcome following AHSCT, the results of this study challenge the current view on MS as a chronic disease with no possible cure.

Therapeutic options in a patient with highly aggressive multiple sclerosis and genetic predisposition to autoimmune process: a clinical case

A clinical case of highly aggressive multiple sclerosis in a patient with a family history of demyelinating disease is presented. The effectiveness of early pathogenetic therapy by blocking the adhesion molecules of lymphocytes is demonstrated.

Kappa free light chains index in multiple sclerosis very long-term prognosis.

The role of the kappa-free light chain (kFLC) in the diagnosis of multiple sclerosis (MS) and, to a lesser extent, its role as a medium-term prognostic marker have been extensively studied. This study aimed to explore its potential as a long-term prognostic marker for MS. We performed an exploratory retrospective observational study by selecting patients systemically followed up in our MS unit with available cerebrospinal fluid and serum samples at the time of initial evaluation. Two groups were defined: benign MS (bMS), defined as patients with Expanded Disability Status Scale (EDSS) ≤ 3 at 10 years of follow-up, and aggressive MS (aMS), defined as patients with EDSS ≥ 6 at 15 years of follow-up. Clinical variables were collected, and the immunoglobulin G (IgG) index, kFLC index, and oligoclonal bands (OCB) were determined for all patients and compared between the groups. Twenty bMS and 15 aMS patients were included in this study. Sixty percent (21/35) were female, and the mean age at the time of the first symptom was 31.5 ± 9.45 years, with no statistical differences between groups. Median follow-up time was 19.8 years (Interquartile range, IQR 15.9-24.6). The median EDSS scores at the last follow-up were 1.5 and 7.5 in the bMS and the aMS group, respectively. No statistically significant differences were found in the kFLC index between the two groups (136.6 vs. 140.27, p=0.59). The IgG index was positive in 62.9% of patients (55% bMS vs. 73.3% aMS, p>0.05), and OCB was positive in 88.6% (90% bMS vs. 86.7% aMS, p>0.05). A significant positive correlation was found between IgG and kFLC indices (rs = 0.85, p<0.001). Given the absence of differences between the two groups with opposite disease courses, it is unlikely that the kFLC index is a reliable and powerful marker of long-term prognosis in MS.

Should autologous hematopoietic stem cell transplantation be offered as a first-line disease modifying therapy to patients with multiple sclerosis?

In multiple sclerosis (MS), progression independent of new focal inflammation may commence shortly after disease onset, and it is increasingly revealed that the risk of disability accrual is reduced by early use of high-efficacy disease-modifying therapies (HE-DMTs). People with aggressive MS may therefore benefit from early treatment with autologous haematopoietic stem cell transplantation (AHSCT), a procedure inducing maximal immunosuppression followed by immune reconstitution, demonstrated to be superior to DMTs in one randomized clinical trial. However, in current practice prior failure to HE-DMTs is typically required to establish the indication for AHSCT. In the present article, the available evidence on the potential role of AHSCT as first-line treatment in aggressive MS and the rationale for its early use will be summarized. Proposed definitions of aggressive MS that could help identifying MS patients eligible for early treatment with AHSCT will also be discussed.

Escalation Versus Induction/High-Efficacy Treatment Strategies for Relapsing Multiple Sclerosis: Which is Best for Patients?

After more than 2decades of recommending an escalating strategy for the treatment of most patients with multiple sclerosis, there has recently been considerable interest in the use of high-efficacy therapies in the early stage of the disease. Early intervention with induction/high-efficacy disease-modifying therapy may have the best risk-benefit profile for patients with relapsing-remitting multiple sclerosis who are young and have active disease, numerous focal T2 lesions on spinal and brain magnetic resonance imaging, and no irreversible disability. Although we have no curative treatment, at least seven classes of high-efficacy drugs are available, with two main strategies. The first strategy involves the use of high-efficacy drugs (e.g., natalizumab, sphingosine 1-phosphate receptor modulators, or anti-CD20 drugs) to achieve sustained immunosuppression. These can be used as a first-line therapy in many countries. The second strategy entails the use of one of the induction drugs (short-term use of mitoxantrone, alemtuzumab, cladribine, or autologous hematopoietic stem cell transplant) that are mainly recommended as a second-line or third-line treatment in patients with very active or aggressive multiple sclerosis disease. Early sustained immunosuppression exposes patients to heightened risks of infection and cancer proportionate to cumulative exposure, and induction drugs expose patients to similar risks during the initial post-treatment period, although these risks decrease over time. Their initial potential safety risks should now be revisited, taking account of long-term data and some major changes in their regimens: natalizumab with the long-term monitoring of John Cunningham virus; use of monthly courses of mitoxantrone with maximum cumulative doses of 36-72 mg/m2, followed by a safer disease-modifying drug; cladribine with only 2-weekly treatment courses required in years 1 and 2 and no systematic treatment for the following 2 years; alemtuzumab, whose safety and clinical impacts have now been documented for more than 6 years after the last infusion; and autologous haematopoietic stem cell transplant, which dramatically reduces transplantation-related mortality with a new regimen and guidelines. Escalation and induction/high-efficacy treatments need rigorous magnetic resonance imaging monitoring. Monitoring over the first few years, using the MAGNIMS score or American Academy of Neurology guidelines, considerably improves prediction accuracy and facilitates the selection of patients with relapsing-remitting multiple sclerosis requiring aggressive treatment.

Investigation of the safety of live attenuated varicella-zoster virus vaccination in patients with relapse-remitting multiple sclerosis treated with natalizumab: A case series and review of the literature.

It is generally recommended to avoid live attenuated vaccines in patients treated with high efficacy disease-modifying treatment (DMT). However, a delay in starting DMT in highly active or aggressive multiple sclerosis (MS) might lead to a significant disability. We aimed to report a case series of 16 highly active RRMS patients who received the live-attenuated varicella-zoster virus (VZV) vaccine during treatment with natalizumab. This retrospective case series was conducted between September 2015 and February 2022 at the MS Research Center of Sina and Qaem hospital, Tehran, Mashhad, Iran, to identify the outcome of highly active MS patients who received the live-attenuated VZV vaccine on natalizumab. Two males and 14 females were included in this study, with a mean age of 25.5±8.4-year-old. 10 patients were naïve cases of highly active MS, and six were escalated to natalizumab. The patients received two doses of live attenuated VZV vaccine after a mean of 6.72 cycles of natalizumab treatment. Except for the one who experienced mild chickenpox infection, no serious adverse event or disease activity was evident after vaccination. While our data do not confirm the safety of the live attenuated VZV vaccine in natalizumab recipients, it highlights the importance of case-by-case decision-making in MS management based on the risk-benefit assessment.

Cyclophosphamide for severe acute forms of central nervous system inflammatory disorders

Cyclophosphamide (CYC) may be an effective treatment in patients who fail first line therapy for severe central nervous system (CNS) inflammatory disorders including CNS vasculitis, neuromyelitis optica, autoimmune encephalitis, tumefactive and aggressive multiple sclerosis (MS). We performed a retrospective analysis of 46 patients treated with CYC after failing first line therapy for severe CNS inflammatory conditions. Primary outcomes included modified Rankin Scale (mRS) for patients classified into a non-MS group, Expanded Disability Status Score (EDSS) for MS patients, and Targeted Neurological Deficit score (TND) for all patients. Secondary outcome included neuroimaging studies following CYC treatment. By the second follow up period (average of 7 months) mRS in the non-MS group improved from 3.7 to 2.2 and EDSS in the MS group improved from 5.6 to 3.8. Average TND score at 7 months was 2.8 (mild-marked improvement). At first follow up (average 5.6 months), 76.2% (32/42) patients had either stable or improving imaging, and 83.3% (30/36) patients had stable or improving imaging at second follow up (average 13.6 months). Adverse events were reported by 31.9% of patients with most common being nausea and vomiting, headache, alopecia, and hyponatremia. Treatment with CYC can result in disease stabilization of severe CNS inflammatory diseases and is generally well tolerated.

Baseline predictors of disability worsening among patients wth a Clinically Isolated Syndrome. (P5-3.015)

Baseline predictors of disability worsening among patients wth a Clinically Isolated Syndrome. (P5-3.015)

Are highly active and aggressive multiple sclerosis the same entity?

Are highly active and aggressive multiple sclerosis the same entity?

Grey matter atrophy in patients with benign multiple sclerosis.

BackgroundBrain atrophy appears during the progression of multiple sclerosis (MS) and is associated with the disability caused by the disease.MethodsWe investigated global and regional grey matter (GM) and white matter (WM) volumes, WM lesion load, and corpus callosum index (CCI), in benign relapsing‐remitting MS (BRRMS, n = 35) with and without any treatment and compared those to aggressive relapsing‐remitting MS (ARRMS, n = 46). Structures were analyzed by using an automated MRI quantification tool (cNeuro®).ResultsThe total brain and cerebral WM volumes were larger in BRRMS than in ARRMS (p = .014, p = .017 respectively). In BRRMS, total brain volumes, regional GM volumes, and CCI were found similar whether or not disease‐modifying treatment (DMT) was used. The total (p = .033), as well as subcortical (p = .046) and deep WM (p = .041) lesion load volumes were larger in BRRMS patients without DMT. Cortical GM volumes did not differ between BRRMS and ARRMS, but the volumes of total brain tissue (p = .014) and thalami (p = .003) were larger in patients with BRRMS compared to ARRMS. A positive correlation was found between CCI and whole‐brain volume in both BRRMS (r = .73, p < .001) and ARRMS (r = .80, p < .01).ConclusionsThalamic volume is the most prominent measure to differentiate BRRMS and ARRMS. Validation of automated quantification of CCI provides an additional applicable MRI biomarker to detect brain atrophy in MS.

Early Predictors of Clinical and MRI Outcomes Using Least Absolute Shrinkage and Selection Operator (LASSO) in Multiple Sclerosis.

The objective of this study was to identify predictors in common between different clinical and magnetic resonance imaging (MRI) outcomes in multiple sclerosis (MS) by comparing predictive models. We analyzed 704 patients from our center seen at MS onset, measuring 37 baseline demographic, clinical, treatment, and MRI predictors, and 10-year outcomes. Our primary aim was identifying predictors in common among clinical outcomes: aggressive MS, benign MS, and secondary-progressive (SP)MS. We also investigated MRI outcomes: T2 lesion volume (T2LV) and brain parenchymal fraction (BPF). The performance of the full 37-predictor model was compared with a least absolute shrinkage and selection operator (LASSO)-selected model of predictors in common between each outcome by the area under the receiver operating characteristic curves (AUCs). The full 37-predictor model was highly predictive of clinical outcomes: in-sample AUC was 0.91 for aggressive MS, 0.81 for benign MS, and 0.81 for SPMS. After variable selection, 10 LASSO-selected predictors were in common between each clinical outcome: age, Expanded Disability Status Scale, pyramidal, cerebellar, sensory and bowel/bladder signs, timed 25-foot walk ≥6seconds, poor attack recovery, no sensory attacks, and time-to-treatment. This reduced model had comparable cross-validation AUC as the full 37-predictor model: 0.84 versus 0.81 for aggressive MS, 0.75 versus 0.73 for benign MS, and 0.76 versus 0.75 for SPMS, respectively. In contrast, 10-year MRI outcomes were more strongly influenced by initial T2LV and BPF than clinical outcomes. Early prognostication of MS is possible using LASSO modeling to identify a limited set of accessible clinical features. These predictive models can be clinically usable in treatment decision making once implemented into web-based calculators. ANN NEUROL 2022;92:87-96.

Natalizumab for multiple sclerosis: the dilemma of NOVA

Before natalizumab was approved for clinical use, management of aggressive multiple sclerosis was unsatisfactory and unspecific. Natalizumab, a monoclonal antibody to the α4β1 unit of the integrin receptor that inhibits leukocyte trafficking into the brain, has shown promise in the treatment of relapsing-remitting multiple sclerosis in phase 3 studies.1,2 Of note, natalizumab led to significant reductions in relapse occurrence, disability progression, and MRI outcomes, including new or newly enlarging T2 lesions, compared with placebo or interferon beta.

Comparison of Mitoxantrone versus Cyclophosphamide Treatment in Patients with Secondary Progressive Multiple Sclerosis

Objective: Mitoxantrone (Mtx) and cyclophosphamide (Cyc) have successfully been used in highly aggressive multiple sclerosis (MS) patients. This study aims to compare the efficacy of these drugs in patients with secondary progressive MS (pwSPMS).&#x0D; Method: Clinical data of pwSPMS treated with either Mtx or Cyc were collected retrospectively. The EDSS scores before, during, and after the drug was determined. The efficacy of the drug was evaluated according to the EDSS change after the completion of therapy. The variations in clinical benefit between the two groups were investigated, as well as the factors that influenced them.&#x0D; Results: Fifty-nine SPMS patients (29 Mtx, 30 Cyc) were included in our study. Mean treatment periods were 19.5±9.9 months for Mtx and 9.1±4.1 months for the Cyc group. Mean EDSS in Mtx and Cyc groups at the first dose were 6.2±0.7 and 6.3±0.8, respectively (p=0.42). The percentage of patients who benefited from treatment was 41.6% in the Mtx group and 43.0% in the Cyc group (p=0.54). However, Mtx was more effective in patients with younger age of disease onset (p=0.01).&#x0D; Conclusion: Immunosuppression with intravenous Mtx and Cyc may equally prevent progression in patients with SPMS. Additionally, Mtx may be more beneficial in MS patients with earlier disease onset.

Intermediate-Intensity Autologous Hematopoietic Stem Cell Transplantation Reduces Serum Neurofilament Light Chains and Brain Atrophy in Aggressive Multiple Sclerosis

BackgroundAutologous haematopoietic stem cell transplantation (AHSCT) is highly effective in reducing new inflammatory activity in aggressive multiple sclerosis (MS). A remarkable decrease of serum neurofilament light chains (sNfL) concentration, a marker of axonal damage, was reported in MS following high-intensity regimen AHSCT, but hints for potential neurotoxicity had emerged. sNfL and brain atrophy were therefore analysed in a cohort of patients with aggressive MS treated with intermediate-intensity AHSCT, exploring whether sNfL might be a reliable marker of disability progression independent from new inflammation (i.e. relapses and/or new/gadolinium-enhancing MRI focal lesions).MethodssNfL concentrations were measured using SIMOA methodology in peripheral blood from relapsing-remitting (RR-) or secondary-progressive (SP-) MS patients undergoing AHSCT (MS AHSCT), collected before transplant and at months 6 and 24 following the procedure. sNfL measured at a single timepoint in SP-MS patients not treated with AHSCT without recent inflammatory activity (SP-MS CTRL) and healthy subjects (HD) were used as controls. The rate of brain volume loss (AR-BVL) was also evaluated by MRI in MS AHSCT cases.ResultsThirty-eight MS AHSCT (28 RR-MS; 10 SP-MS), 22 SP-MS CTRL and 19 HD were included. Baseline median sNfL concentrations were remarkably higher in the MS AHSCT than in the SP-MS CTRL and HD groups (p = 0.005 and <0.0001, respectively), and levels correlated with recent inflammatory activity. After a marginal (not significant) median increase observed at month 6, at month 24 following AHSCT sNfL concentrations decreased compared to baseline by median 42.8 pg/mL (range 2.4–217.3; p = 0.039), reducing by at least 50% in 13 cases, and did not differ from SP-MS CTRL (p = 0.110) but were still higher than in HD (p < 0.0001). Post-AHSCT AR-BVL normalised in 55% of RR-MS and in 30% of SP-MS. The effectiveness and safety of AHSCT were aligned with the literature.ConclusionsNfL concentrations correlated with recent inflammatory activity and were massively and persistently reduced by intermediate-intensity AHSCT. Association with response to treatment assessed by clinical or MRI outcomes was not observed, suggesting a good sensitivity of sNfL for recent inflammatory activity but low sensitivity in detecting ongoing axonal damage independent from new focal inflammation.

Cerebrospinal Fluid IgM and Oligoclonal IgG Bands in Multiple Sclerosis: A Meta-Analysis of Prevalence and Prognosis.

The presence of intrathecal IgM synthesis (ITMS) has been associated with an aggressive multiple sclerosis (MS) clinical course. In the present systematic review, we aimed at assessing the prevalence of ITMS among different MS phenotypes. Moreover, we aimed at quantifying the risk of a second relapse in ITMS positive and oligoclonal IgG bands (OCGBs)-positive patients. We selected clinical studies reporting the ITMS prevalence assessed as oligoclonal IgM Bands (OCMBs), lipid-specific OCMBs (LS-OCMBs), and/or as an intrathecal IgM production > 0% (IgMLoc, Reiber formula). The overall prevalence of ITMS was higher in relapsing-remitting (RR) than clinically isolated syndrome (CIS) patients (40.1% versus 23.8%, p < 0.00001), while was in line with that detected in primary progressive MS (PPMS, 26.7%). Almost all patients (98%) with ITMS had also OCGBs. The risk of having a second relapse was higher in OCGBs positive patients (HR = 2.18, p = 0.007) but much higher in ITMS positive patients (HR = 3.62, p = 0.0005). This study revealed that the prevalence of ITMS is higher in RRMS patients. It suggests that the risk of having a second relapse, previously ascribed to OCGBs, may, to a certain extent, be related to the presence of intrathecal IgM.

Italian multicenter observational study on real-life experience with alemtuzumab in naïve patients with aggressive multiple sclerosis

Alemtuzumab (ALEM) is an anti-CD52 monoclonal antibody approved for the treatment of active Multiple Sclerosis(MS) which showed high efficacy also in the subgroup of highly-active patients. We aimed to evaluate efficacy/safety profile of ALEM-treatment in a population of aggressive MS naïve-patients.

Serum GFAP and NfL levels in benign relapsing-remitting multiple sclerosis

ObjectiveWe aimed to investigate serum glial fibrillary acidic protein (GFAP) and serum neurofilament light chain (NfL) levels as potential discriminative biomarkers between benign relapsing-remitting multiple sclerosis (BRRMS) and aggressive relapsing-remitting MS (ARRMS). MethodsSerum GFAP and NfL levels were analyzed in patients with BRRMS (n = 34), ARRMS (n = 29), and healthy controls (n = 14) by using Single Molecule Array (Simoa). Patients with ARRMS had been treated with highly effective disease-modifying treatments (DMT) (fingolimod or natalizumab). ResultsSerum GFAP levels in both BRRMS (median 210.19 pg/ml, IQR 163.69–287.19) and in ARRMS (median 188.60 pg/ml, IQR39.23–244.93) were significantly higher (p = 0.035 and p = 0.034, respectively) compared to healthy controls (median 117.93 pg/ml, IQR 60.28–183.83). Serum GFAP levels did not differ between BRRMS and ARRMS. There were no statistical differences in NfL levels between BRRMS, ARRMS and healthy controls. GFAP level was significantly higher (p = 0.04) in BRRMS without DMT (median 216.04 pg/ml, IQR 188.60–274.79) than in those BRRMS patients who had used DMT (median 196.26 pg/ml, IQR 133.33–325.54). ConclusionsWe found elevated levels of serum GFAP in both BRRMS and ARRMS compared to healthy controls, reflecting astrocytic activation. Serum NfL did not differ between BRRMS and ARRMS, probably due to the stable inflammatory phase of the disease and effective DMT use in ARRMS. Single serum NfL and GFAP measurements cannot separate a patient with BRRMS from effectively treated ARRMS after a long history of the disease, thus consecutive samples are needed in the follow-up.