Misdiagnosis of multiple sclerosis (MS) (the incorrect assignment of a diagnosis of MS) remains a problem in contemporary clinical practice. Studies indicate that misdiagnosed patients are often ...exposed to prolonged unnecessary health care risks and morbidity. The recently published 2017 revision of the McDonald criteria for the diagnosis of MS provides an opportunity to consider the effect of these revisions on the problem of MS misdiagnosis. The 2017 McDonald criteria include several new recommendations to reduce potential for misdiagnoses. The criteria should be used for the types of patients in which validation studies were performed, specifically those patients who present with typical demyelinating syndromes. MRI lesion characteristics were defined for which McDonald criteria would be expected to perform with accuracy. However, 2017 revisions, which now include assessment for cortical lesions, and the inclusion of symptomatic lesions and positive oligoclonal bands for the fulfillment of diagnostic criteria, may have the potential to lead to misdiagnosis of MS if not applied appropriately. While the 2017 McDonald criteria integrate issues relating to MS misdiagnosis and incorporate specific recommendations for its prevention more prominently than prior criteria, the interpretation of clinical and radiologic assessments upon which these criteria depend will continue to allow misdiagnoses. In patients with atypical clinical presentations, the revised McDonald criteria may not be readily applied. In those situations, further evaluation or monitoring rather than immediate diagnosis of MS is prudent.
This scientific commentary refers to ‘Disease-modifying drugs can reduce disability progression in paediatric, adult and late-onset relapsing multiple sclerosis’, by Amato etal. ...(doi:10.1093/brain/awaa251).
The safety and efficacy of ocrelizumab in primary progressive multiple sclerosis were shown in the phase 3 ORATORIO trial. In this study, we assessed the effects of maintaining or switching to ...ocrelizumab therapy on measures of disease progression and safety in the open-label extension phase of ORATORIO.
ORATORIO was an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done at 182 study locations including academic centres, hospitals, and community speciality centres within 29 countries across the Americas, Australia, Europe, Israel, New Zealand, and Russia. Patients with primary progressive multiple sclerosis aged 18–55 years who had an Expanded Disability Status Scale (EDSS) score of 3·0–6·5 were eligible for enrolment. Those who had previous treatment with B-cell-targeted therapies or other immunosuppressive medications were excluded. Eligible participants were randomly assigned (2:1) to receive either intravenous infusion of 600 mg of ocrelizumab (two 300 mg infusions 14 days apart) or placebo every 24 weeks for at least 120 weeks until a prespecified number (n=253) of disability events occurred. After the double-blind phase, patients entered an extended controlled period of variable duration, during which they and investigators became aware of treatment allocation. Following this period, patients could enter an optional open-label extension, during which they continued ocrelizumab or switched from placebo to ocrelizumab. Time to onset of disability progression was confirmed at 24 weeks with four measures (ie, increase in EDSS score, ≥20% increase in time to complete the 9-Hole Peg Test 9HPT, ≥20% increase in time to perform the Timed 25-Foot Walk T25FW, and composite progression defined as the first confirmed occurrence of any of these three individual measures), as was time to requiring a wheelchair (EDSS ≥7). Conventional MRI measures were also analysed. The intention-to-treat population was used for the safety and efficacy analyses; all analyses, and their timings, were done post hoc. ORATORIO is registered with ClinicalTrials.gov, NCT01194570, and is ongoing.
From March 3, 2011, to Dec 27, 2012, 488 patients were randomly assigned to the ocrelizumab group and 244 to the placebo group. The extended controlled period started on July 24, 2015, and ended on April 27, 2016, when the last patient entered the open-label extension. Overall, 544 (74%) of 732 participants completed the double-blind period to week 144; 527 (97%) of 544 entered the open-label extension phase, of whom 451 (86%) are ongoing in the open-label extension. After at least 6·5 study years (48 weeks per study year) of follow-up, the proportion of patients with progression on disability measures was lower in those who initiated ocrelizumab early than in those initially receiving placebo for most of the measures of 24-week confirmed disability progression: EDSS, 51·7% vs 64·8% (difference 13·1% 95% CI 4·9–21·3; p=0·0018); 9HPT, 30·6% vs 43·1% (12·5% 4·1–20·9); p=0·0035); T25FW, 63·2% vs 70·7% (7·5% –0·3 to 15·2; p=0·058); composite progression, 73·2% vs 83·3% (10·1% 3·6–16·6; p=0·0023); and confirmed time to requiring a wheelchair, 11·5% vs 18·9% (7·4% 0·8–13·9; p=0·0274). At study end, the percentage change from baseline was lower in those who initiated ocrelizumab early than in those initially receiving placebo for T2 lesion volume (0·45% vs 13·00%, p<0·0001) and T1 hypointense lesion volume (36·68% vs 60·93%, p<0·0001). Over the entire period, in the ORATORIO all ocrelizumab exposure population, the rate of adverse events was 238·09 (95% CI 232·71–243·57) per 100 patient-years and serious adverse events was 12·63 (95% CI 11·41–13·94) per 100 patient-years; the most common serious adverse events were infections at 4·13 (95% CI 3·45–4·91) per 100 patient-years. No new safety signals emerged compared with the double-blind phase of ORATORIO.
Compared with patients switching from placebo, earlier and continuous ocrelizumab treatment provided sustained benefits on measures of disease progression over the 6·5 study years of follow-up. Although this study shows the benefit of earlier intervention with ocrelizumab in primary progressive disease, progression remains an important unmet need in multiple sclerosis. Further research should focus on how the potential benefits described in this study might be improved upon, particularly over longer time periods.
F Hoffmann-La Roche.
The original anti-CD20 therapy, rituximab, is used off-label in some countries, and results from a clinical trial (RIFUND-MS) by Anders Svenningsson and colleagues1 published in The Lancet Neurology ...help to fill a gap in our knowledge about how useful this monoclonal antibody might be for patients with relapsing-remitting multiple sclerosis. Because immunoglobulins are made by B cells and by plasma cells that differentiate from B cells, these cells became an early focus of multiple sclerosis immunological research. Relapses (the primary endpoint) occurred in three (3%) of the 98 patients eligible for primary outcome analysis in the rituximab group and 16 (16%) of 97 in the dimethyl fumarate group.1 In a post-hoc analysis, numbers of new and enlarged T2 lesions and contrast-enhancing lesions were significantly lower for rituximab than for dimethyl fumarate (mean 0·3 SD 0·7 vs 1·5 4·0 T2 lesions; mean 0·04 0·20 vs 0·26 0·70 contrast-enhancing lesions).1 However, limitations of the study include that patients and treating clinicians were not masked to treatment and that data on ethnic background of participants were not collected, so the applicability to populations elsewhere is unknown.
OBJECTIVETo assess over 3 years of follow-up the effects of maintaining or switching to ocrelizumab (OCR) therapy on clinical and MRI outcomes and safety measures in the open-label extension (OLE) ...phase of the pooled OPERAI/II studies in relapsing multiple sclerosis.
METHODSAfter 2 years of double-blind, controlled treatment, patients continued OCR (600 mg infusions every 24 weeks) or switched from interferon (IFN)-β-1a (44 μg 3 times weekly) to OCR when entering the OLE phase (3 years). Adjusted annualized relapse rate, time to onset of 24-week confirmed disability progression (CDP)/improvement (CDP), brain MRI activity (gadolinium-enhanced and new/enlarging T2 lesions), and percentage brain volume change were analyzed.
RESULTSOf patients entering the OLE phase, 88.6% completed year 5. The cumulative proportion with 24-week CDP was lower in patients who initiated OCR earlier vs patients initially receiving IFN-β-1a (16.1% vs 21.3% at year 5; p = 0.014). Patients continuing OCR maintained and those switching from IFN-β-1a to OCR attained near complete and sustained suppression of new brain MRI lesion activity from years 3–5. Over the OLE phase, patients continuing OCR exhibited less whole brain volume loss from double-blind study baseline vs those switching from IFN-β-1a (−1.87% vs −2.15% at year 5; p < 0.01). Adverse events were consistent with past reports and no new safety signals emerged with prolonged treatment.
CONCLUSIONCompared with patients switching from IFN-β-1a, earlier and continuous OCR treatment up to 5 years provided sustained benefit on clinical and MRI measures of disease progression.
CLASSIFICATION OF EVIDENCEThis study provides Class III evidence that earlier and continuous treatment with OCR provided sustained benefit on clinical and MRI outcomes of disease activity and progression compared with patients switching from IFN-β-1a. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in OLE.
CLINICAL TRIAL IDENTIFIERSNCT01247324/NCT01412333.
Axon injury/loss, demyelination and inflammation are the primary pathologies in multiple sclerosis lesions. Despite the prevailing notion that axon/neuron loss is the substrate of clinical ...progression of multiple sclerosis, the roles that these individual pathological processes play in multiple sclerosis progression remain to be defined. An imaging modality capable to effectively detect, differentiate and individually quantify axon injury/loss, demyelination and inflammation, would not only facilitate the understanding of the pathophysiology underlying multiple sclerosis progression, but also the assessment of treatments at the clinical trial and individual patient levels. In this report, the newly developed diffusion basis spectrum imaging was used to discriminate and quantify the underlying pathological components in multiple sclerosis white matter. Through the multiple-tensor modelling of diffusion weighted magnetic resonance imaging signals, diffusion basis spectrum imaging resolves inflammation-associated cellularity and vasogenic oedema in addition to accounting for partial volume effects resulting from cerebrospinal fluid contamination, and crossing fibres. Quantitative histological analysis of autopsied multiple sclerosis spinal cord specimens supported that diffusion basis spectrum imaging-determined cellularity, axon and myelin injury metrics closely correlated with those pathologies identified and quantified by conventional histological staining. We demonstrated in healthy control subjects that diffusion basis spectrum imaging rectified inaccurate assessments of diffusion properties of white matter tracts by diffusion tensor imaging in the presence of cerebrospinal fluid contamination and/or crossing fibres. In multiple sclerosis patients, we report that diffusion basis spectrum imaging quantitatively characterized the distinct pathologies underlying gadolinium-enhanced lesions, persistent black holes, non-enhanced lesions and non-black hole lesions, a task yet to be demonstrated by other neuroimaging approaches. Diffusion basis spectrum imaging-derived radial diffusivity (myelin integrity marker) and non-restricted isotropic diffusion fraction (oedema marker) correlated with magnetization transfer ratio, supporting previous reports that magnetization transfer ratio is sensitive not only to myelin integrity, but also to inflammation-associated oedema. Our results suggested that diffusion basis spectrum imaging-derived quantitative biomarkers are highly consistent with histology findings and hold promise to accurately characterize the heterogeneous white matter pathology in multiple sclerosis patients. Thus, diffusion basis spectrum imaging can potentially serve as a non-invasive outcome measure to assess treatment effects on the specific components of underlying pathology targeted by new multiple sclerosis therapies.
PDF
