Carolyn Bevan

Disease Activity Free Status: A New End Point for a New Era in Multiple Sclerosis Clinical Research?

Since the introduction of interferon beta-1b in 1993, the number of disease-modifying therapies for multiple sclerosis (MS) has grown at a remarkable pace. Currently there are 10 treatments approved by the US Food and Drug Administration, each with varying effects on important clinical and radiographic markers of disease activity. Multiple sclerosis is one of many immunemediated diseases in which significant advancements in disease modification have been made. Tumor necrosis factor inhibitors have revolutionized the treatment of rheumatologic diseases such as Crohn disease, psoriasis, and rheumatoid arthritis (RA). This therapeutic class has made sustained disease remission achievable in these rheumatologic diseases. In the case of RA, combinations of clinical and laboratory measures such as disease activity status became the standard by which treatment success is measured.1 In MS, the first clinical trial that explored a combined clinical and radiographic end point was the pivotal trial of natalizumab.2 In a post hoc analysis, natalizumab as compared with placebo was found to result in a greater proportion of patients with “disease activity free status” (DAFS), defined by the absence of clinical or radiographic activity. Since then, similar analyses have been applied to novel disease-modifying therapies in MS, including cladribine,3 fingolimod4,5 and dimethyl fumarate,6 as well as intramuscular interferon beta-1a and glatiramer acetate.7 Results from these studies are summarized in the Table. The DAFS measure is intuitively appealing and has been compared with disease remission in RA. However, there are important biological differences in the disease course of RA and MS that may limit such an interpretation. Rheumatoid arthritis is an inflammatory disease for which the treat-to-target approach inherently makes sense. In contrast, MS has both inflammatory as well as degenerative components. It is not known if applying a treat-to-target strategy to the inflammatory aspect of MS will have an effect on the degenerative processes that underlie disease progression. Because MS evolves over decades, the effect of DAFS on long-term disability has yet to be evaluated.

Spinal Cord Gray Matter Atrophy Correlates with Multiple Sclerosis Disability

In multiple sclerosis (MS), cerebral gray matter (GM) atrophy correlates more strongly than white matter (WM) atrophy with disability. The corresponding relationships in the spinal cord (SC) are unknown due to technical limitations in assessing SC GM atrophy. Using phase‐sensitive inversion recovery (PSIR) magnetic resonance imaging, we determined the association of the SC GM and SC WM areas with MS disability and disease type.

Spinal cord gray matter atrophy correlates with multiple sclerosis disability - eScholarship

In multiple sclerosis (MS), cerebral gray matter (GM) atrophy correlates more strongly than white matter (WM) atrophy with disability. The corresponding relationships in the spinal cord (SC) are unknown due to technical limitations in assessing SC GM atrophy. Using phase‐sensitive inversion recovery (PSIR) magnetic resonance imaging, we determined the association of the SC GM and SC WM areas with MS disability and disease type.

Long-term evolution of multiple sclerosis disability in the treatment era.

To characterize the accrual of long‐term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and magnetic resonance imaging (MRI) data used in clinical trials have long‐term prognostic value.

Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial

BACKGROUND Multiple sclerosis is a degenerative inflammatory disease of the CNS characterised by immune-mediated destruction of myelin and progressive neuroaxonal loss. Myelin in the CNS is a specialised extension of the oligodendrocyte plasma membrane and clemastine fumarate can stimulate differentiation of oligodendrocyte precursor cells in vitro, in animal models, and in human cells. We aimed to analyse the efficacy and safety of clemastine fumarate as a treatment for patients with multiple sclerosis. METHODS We did this single-centre, 150-day, double-blind, randomised, placebo-controlled, crossover trial (ReBUILD) in patients with relapsing multiple sclerosis with chronic demyelinating optic neuropathy on stable immunomodulatory therapy. Patients who fulfilled international panel criteria for diagnosis with disease duration of less than 15 years were eligible. Patients were randomly assigned (1:1) via block randomisation using a random number generator to receive either clemastine fumarate (5·36 mg orally twice daily) for 90 days followed by placebo for 60 days (group 1), or placebo for 90 days followed by clemastine fumarate (5·36 mg orally twice daily) for 60 days (group 2). The primary outcome was shortening of P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. We analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT02040298. FINDINGS Between Jan 1, 2014, and April 11, 2015, we randomly assigned 50 patients to group 1 (n=25) or group 2 (n=25). All patients completed the study. The primary efficacy endpoint was met with clemastine fumarate treatment, which reduced the latency delay by 1·7 ms/eye (95% CI 0·5-2·9; p=0·0048) when analysing the trial as a crossover. Clemastine fumarate treatment was associated with fatigue, but no serious adverse events were reported. INTERPRETATION To our knowledge, this is the first randomised controlled trial to document efficacy of a remyelinating drug for the treatment of chronic demyelinating injury in multiple sclerosis. Our findings suggest that myelin repair can be achieved even following prolonged damage. FUNDING University of California, San Francisco and the Rachleff Family.

Association between thoracic spinal cord gray matter atrophy and disability in multiple sclerosis

IMPORTANCE In multiple sclerosis (MS), upper cervical cord gray matter (GM) atrophy correlates more strongly with disability than does brain or cord white matter (WM) atrophy. The corresponding relationships in the thoracic cord are unknown owing to technical difficulties in assessing GM and WM compartments by conventional magnetic resonance imaging techniques. OBJECTIVES To investigate the associations between MS disability and disease type with lower thoracic cord GM and WM areas using phase-sensitive inversion recovery magnetic resonance imaging at 3 T, as well as to compare these relationships with those obtained at upper cervical levels. DESIGN, SETTING, AND PARTICIPANTS Between July 2013 and March 2014, a total of 142 patients with MS (aged 25-75 years; 86 women) and 20 healthy control individuals were included in this cross-sectional observational study conducted at an academic university hospital. MAIN OUTCOMES AND MEASURES Total cord areas (TCAs), GM areas, and WM areas at the disc levels C2/C3, C3/C4, T8/9, and T9/10. Area differences between groups were assessed, with age and sex as covariates. RESULTS Patients with relapsing MS (RMS) had smaller thoracic cord GM areas than did age- and sex-matched control individuals (mean differences [coefficient of variation (COV)]: 0.98 mm2 [9.2%]; P = .003 at T8/T9 and 0.93 mm2 [8.0%]; P = .01 at T9/T10); however, there were no significant differences in either the WM area or TCA. Patients with progressive MS showed smaller GM areas (mean differences [COV]: 1.02 mm2 [10.6%]; P < .001 at T8/T9 and 1.37 mm2 [13.2%]; P < .001 at T9/T10) and TCAs (mean differences [COV]: 3.66 mm2 [9.0%]; P < .001 at T8/T9 and 3.04 mm2 [7.2%]; P = .004 at T9/T10) compared with patients with RMS. All measurements (GM, WM, and TCA) were inversely correlated with Expanded Disability Status Scale score. Thoracic cord GM areas were correlated with lower limb function. In multivariable models (which also included cord WM areas and T2 lesion number, brain WM volumes, brain T1 and fluid-attenuated inversion recovery lesion loads, age, sex, and disease duration), cervical cord GM areas had the strongest correlation with Expanded Disability Status Scale score followed by thoracic cord GM area and brain GM volume. CONCLUSIONS AND RELEVANCE Thoracic cord GM atrophy can be detected in vivo in the absence of WM atrophy in RMS. This atrophy is more pronounced in progressive MS than RMS and correlates with disability and lower limb function. Our results indicate that remarkable cord GM atrophy is present at multiple cervical and lower thoracic levels and, therefore, may reflect widespread cord GM degeneration.

Association of MBP peptides with Hsp70 in normal appearing human white matter.

Multiple Sclerosis is an autoimmune disease directed against myelin proteins. The etiology of MS is poorly defined though, with no definitive causative agent yet identified. It has been hypothesized that MS may be a multifactorial disease resulting in the same end product: the destruction of myelin by the immune system. In this report we describe a potential role for heat shock proteins in the pathogenesis of MS. We isolated Hsp70 from the normal appearing white matter of both MS and normal human brain and found this was actively associated with, among other things, immunodominant MBP peptides. Hsp70-MBP peptide complexes prepared in vitro were shown to be highly immunogenic, with adjuvant-like effects stimulating MBP peptide-specific T cell lines to respond to normally sub-optimal concentrations of peptide. This demonstration of a specific interaction between Hsp70 and different MBP peptides, coupled with the adjuvanticity of this association is suggestive of a possible role for Hsp70 in the immunopathology associated with MS.

Precision medicine in chronic disease management: The multiple sclerosis BioScreen

We present a precision medicine application developed for multiple sclerosis (MS): the MS BioScreen. This new tool addresses the challenges of dynamic management of a complex chronic disease; the interaction of clinicians and patients with such a tool illustrates the extent to which translational digital medicine—that is, the application of information technology to medicine—has the potential to radically transform medical practice. We introduce 3 key evolutionary phases in displaying data to health care providers, patients, and researchers: visualization (accessing data), contextualization (understanding the data), and actionable interpretation (real‐time use of the data to assist decision making). Together, these form the stepping stones that are expected to accelerate standardization of data across platforms, promote evidence‐based medicine, support shared decision making, and ultimately lead to improved outcomes. Ann Neurol 2014;76:633–642

Therapeutic Management of Severe Relapses in Multiple Sclerosis

Opinion statementWhile not all multiple sclerosis (MS) relapses require treatment, relapses that are bothersome or that impair function should prompt consideration of timely treatment to restore function and minimize disability. Patients with suspected MS relapses should be evaluated to confirm the diagnosis, exclude other causes of neurological dysfunction, and identify potential triggers for relapse or pseudo-relapse, such as urinary tract infections, fever, or metabolic derangements. The diagnosis of an MS relapse is clinical, but MRI may be useful for confirmation and to evaluate for multifocal disease activity. High-dose oral or intravenous glucocorticoids, with or without an oral taper, are first-line therapy for MS relapses. Adrenocorticotropic hormone (ACTH) provides an alternative to glucocorticoid treatment but is currently much more expensive and does not have proven superiority. If the acute neurological deficits remain severe after steroid treatment, and particularly if there is persistent abnormal contrast-enhancement of the symptomatic lesion on repeat MRI, plasma exchange (PLEX) should be considered as an acute rescue therapy for relapse. In exceptional cases, particularly fulminant or tumefactive disease that fails to improve following treatment with steroids and PLEX, cytoxic agents such as cyclophosphamide or B cell-depleting regimens such as rituximab may be considered, although risk must be carefully weighed and the kinetics of such regimens indicate that they probably serve more to accelerate remission of disease activity than as an immediate relapse remedy. A single dose of natalizumab given as acute therapy for MS relapse was shown not to improve clinical outcomes in a randomized controlled trial. Attention to symptom management and promotion of neurorehabilitation are important aspects of MS relapse care. Neuroprotective and neuroreparative therapies remain under investigation, but are likely to become important complementary elements of relapse therapy in the future. Relapses serve as important indicators of MS disease activity. In the context of the emerging treatment paradigm of targeting freedom from evidence of MS disease activity, relapses should prompt consideration of transitioning to a disease-modifying treatment that may offer better efficacy.

Clonal relationships of CSF B cells in treatment-naive multiple sclerosis patients

A role of B cells in multiple sclerosis (MS) is well established, but there is limited understanding of their involvement during active disease. Here, we examined cerebrospinal fluid (CSF) and peripheral blood (PB) B cells in treatment-naive patients with MS or high-risk clinically isolated syndrome. Using flow cytometry, we found increased CSF lymphocytes with a disproportionate increase of B cells compared with T cells in patients with gadolinium-enhancing (Gd+) lesions on brain MRI. Ig gene heavy chain variable region (Ig-VH) repertoire sequencing of CSF and PB B cells revealed clonal relationships between intrathecal and peripheral B cell populations, which could be consistent with migration of B cells to and activation in the CNS in active MS. In addition, we found evidence for bystander immigration of B cells from the periphery, which could be supported by a CXCL13 gradient between CSF and blood. Understanding what triggers B cells to migrate and home to the CNS may ultimately aid in the rational selection of therapeutic strategies to limit progression in MS.