Magnetic Resonance Imaging Disease Activity Research Articles

Autoimmune Pancreatitis Surveillance: A Simplified MRI Protocol Versus a Comprehensive Pancreatic MRI Protocol

Magnetic resonance imaging (MRI) has good diagnostic performance and causes no radiation damage, making it an ideal tool for the autoimmune pancreatitis (AIP) surveillance. However, its time cost is high. This study aimed to evaluate (1) whether a simplified protocol (SP) of MRI for AIP surveillance provides information equivalent to the comprehensive protocol (CP) and (2) the time cost reductions associated with using an SP. This retrospective single-institutional study included 40 patients with AIP with at least two contrast-enhanced MRI/magnetic resonance cholangiopancreatography studies. Two radiologists evaluated two imaging sets (CP/SP) per patient, independently. Intra- and inter-observer agreement in the evaluation of the pancreas and extrapancreatic organs involvement using the SP/CP in addition to the time cost differences between the SP and CP were assessed. Intra- and inter-rater reliability were assessed using Cohen's kappa test, intraclass correlations, or the weighted kappa test. The differences in time costs between the CP and SP were compared using the Mann-Whitney U test or Wilcoxon signed-rank test. The SP had strong intra- and inter-observer agreement with the CP in evaluating MRI parameters (κ＞0.60, moderate to excellent) and disease activity status (κ＞0.80, all excellent). The overall image acquisition time cost for the SP was 49.2% of the CP. For the two radiologists, the image interpretation time cost of the SP was reduced by approximately 35% and 27% compared to the CP. For AIP surveillance, SP MRI provides information consistent with the CP and is less time-consuming.

Single-cell profiling reveals preferential reduction of memory B cell subsets in cladribine patients that correlates with treatment response

Background: Cladribine is a highly effective immunotherapy that is applied in two short-term courses over 2 years and reduces relapse rate and disease progression in patients with relapsing multiple sclerosis (MS). Despite the short treatment period, cladribine has a long-lasting effect on disease activity even after recovery of lymphocyte counts, suggesting a yet undefined long-term immune modulating effect. Objectives: Our aim was to provide a more profound understanding of the detailed effects of cladribine, also with regard to the patients’ therapy response. Design: We performed an open-labeled, explorative, prospective, single-arm study, in which we examined the detailed lymphocyte subset development of MS patients who received cladribine treatment over 2 years. Methods: We performed in-depth profiling of the effects of cladribine on peripheral blood lymphocytes by flow cytometry, bulk RNA sequencing of sorted CD4+ T cells, CD8+ T cells, and CD19+ B cells as well as single-cell RNA sequencing of peripheral blood mononuclear cells in a total of 23 MS patients before and at different time points up to 24 months after cladribine treatment. Data were correlated with clinical and cranial magnetic resonance imaging (MRI) disease activity. Results: Flow cytometry revealed a predominant and sustained reduction of memory B cells compared to other B cell subsets after cladribine treatment, whereas T cell subsets were slightly reduced in a more uniform pattern. The overall transcriptional profile of total blood B cells exhibited reduced expression of proinflammatory and T cell activating genes, while single-cell transcriptomics revealed that gene expression within each B cell cluster did not change over time. Stable patients displayed stronger reductions of selected memory B cell clusters as compared to patients with clinical or cerebral MRI disease activity. Conclusion: We describe a pronounced and sustained effect of cladribine on the memory B cell compartment, and the resulting change in B cell subset composition causes a significant alteration of B cell transcriptional profiles resulting in reduced proinflammatory and T cell activating capacities. The extent of reduction in selected memory B cell clusters by cladribine may predict treatment response.

The reliability of Juvenile Arthritis Magnetic Resonance Imaging Scoring system in the evaluation of the shoulder joint in juvenile idiopathic arthritis.

We aimed to evaluate shoulder joint by magnetic resonance imaging (MRI) using the Juvenile Arthritis Magnetic Resonance Imaging Scoring (JAMRIS) system in children with juvenile idiopathic arthritis (JIA) and to compare clinical, laboratory parameters and disease activity scores with MRI parameters. A total of 32 shoulder joints of 20 patients (16 males, 4 females; mean age: 8.9±3.5 years; range, 2.5 to 14 years) with a known diagnosis of JIA and a clinical suspicion of shoulder joint involvement and underwent MRI were included. Reliability was determined by inter- and intra-observer correlation coefficients. Correlation of the clinical and laboratory parameters with JAMRIS scores was done using the non-parametric tests. Sensitivity of clinical examination to detect shoulder joint arthritis was also determined. Of the 32 joints, 27 joints in 17 patients showed MRI changes. Seven joints in five patients fulfilled the definition of clinical arthritis, all revealed MRI changes. In 25 joints without clinical arthritis, early and late MRI changes were seen in 19 (67%) and 12 (48%) joints, respectively. The inter- and intra-observer correlation coefficients for JAMRIS system were excellent. No correlation was found between MRI parameters, clinical, laboratory, and disease activity scores. The sensitivity of clinical examination to detect shoulder joint arthritis was 25.9%. The JAMRIS system is reliable and reproducible to determine shoulder joint inflammation in JIA. Detection of shoulder joint arthritis by clinical examination has a poor sensitivity.

Spinal Fluid Myeloid Microvesicles Predict Disease Course in Multiple Sclerosis.

In vivo measures of myeloid activity are promising biomarkers in multiple sclerosis. We previously demonstrated that cerebrospinal fluid (CSF) myeloid microvesicles are markers of microglial/macrophage activity and neuroinflammation in multiple sclerosis. Here, we aimed at investigating the diagnostic and prognostic value of myeloid microvesicles in a clinical setting. Six hundred one patients discharged with a diagnosis of neuroinflammatory, neurodegenerative, or no neurological disease were enrolled. Myeloid microvesicles were measured with flow cytometry as isolectin B4-positive events in fresh CSF. Clinical, demographical, and magnetic resonance imaging (MRI) data were collected at diagnosis (all patients) and during follow-up (n=176). CSF myeloid microvesicles were elevated in neuroinflammatory patients compared to the neurodegenerative and control groups. In multiple sclerosis, microvesicles were higher in patients with MRI disease activity and their concentration increased along with the number of enhancing lesions (p < 0.0001, Jonckheere-Terpstra test). CSF myeloid microvesicles were also higher in patients with higher disease activity in the month and year preceding diagnosis. Microvesicles excellently discriminated between the relapsing-remitting and control groups (receiver operator characteristic curve, area under the curve=0.939, p < 0.0001) and between radiologically isolated syndrome and unspecific brain lesions (0.942, p < 0.0001). Furthermore, microvesicles were independent predictors of prognosis for both the relapsing-remitting and progressive groups. Microvesicles independently predicted future disease activity in relapsing-remitting patients (hazard ratio [HR]=1.967, 95% confidence interval [CI] = 1.147-3.372), correcting for prognostic factors of standard clinical use. In the progressive group, microvesicles were independent predictors of disability accrual (HR=10.767, 95% CI=1.335-86.812). Our results confirm that CSF myeloid microvesicles are a clinically meaningful biomarker of neuroinflammation and microglial/macrophage activity in vivo. These findings may support a possible use in clinical practice during diagnostic workup and prognostic assessment. ANN NEUROL 2021;90:253-265.

P399 Higher anti-tumour necrosis factor-alpha drug levels are associated with improved radiological outcomes in patients with perianal fistulising Crohn’s disease: A retrospective multi-centre study

Abstract Background Higher anti-tumour necrosis factor-α (TNF) drug levels are associated with improved clinical fistula healing and closure in perianal fistulising Crohn’s disease (pfCD). It is hypothesised that higher drug levels will lead to improved healing on magnetic resonance imaging (MRI); but this is yet to be established. This study evaluated the association between anti-TNF drug levels and radiological outcomes in pfCD. Methods A multi-centre retrospective study (FISCAL), across 10 ANZ Inflammatory Bowel Disease Consortium sites. Patients with pfCD on stable maintenance dosing of infliximab or adalimumab, with drug levels within 6-months of a pelvic MRI from 2010 to 2020 were included. Patients receiving perianal fistula surgery between drug level and MRI were excluded. MRI disease activity was scored using the Van Assche Index (VAI), with an inflammatory sub-score (VAIinfl) derived from the VAI indices: hyperintensity on T2-weighted images, collections &amp;gt;3mm diameter, and rectal wall involvement. Primary endpoint was radiological healing (VAIinfl≤6). Secondary endpoint was radiological remission (VAIinfl=0). Drug level tertiles were correlated to changes in VAIinfl scores. ROC analyses were used to identify optimal target drug levels. Results Of 193 patients (infliximab, n=117; adalimumab, n=76), radiological healing was achieved in 47.0 and 44.7% and radiological remission in 17.1 and 15.8% of patients receiving infliximab and adalimumab, respectively. Patients with radiological healing had higher median drug levels compared to those with radiologically active disease (infliximab 6.0 vs 3.9µg/mL, P=0.03; adalimumab 9.1 vs 6.2µg/mL, P=0.02). Patients with radiological remission had higher median drug levels compared to those with radiologically active disease (infliximab 7.4 vs 3.9µg/mL, P&amp;lt;0.01; adalimumab 9.8 vs 6.2µg/mL, P=0.07). There was a significant incremental reduction in median VAIinfl with higher anti-TNF drug level tertiles, shown in Figure 1. By ROC analyses, the optimal trough infliximab levels for radiological healing and remission were 4.0µg/mL (sensitivity 69.1%, specificity 45.2%, AUC 0.62, P=0.03) and 6.5µg/mL (sensitivity 60.0%, specificity 72.2%, AUC 0.67, P=0.02), respectively. The optimal adalimumab levels for radiological healing and remission were 7.2µg/mL (sensitivity 67.6%, specificity 59.5%, AUC 0.65, P=0.03) and 9.7µg/mL (sensitivity 58.0%, specificity 70.0%, AUC 0.62, P=0.20), respectively. Conclusion In the largest study of its kind, higher anti-TNF drug levels were associated with improved MRI parameters as per the VAI in patients with pfCD; with an incremental improvement in MRI outcomes at higher anti-TNF drug level tertiles for both infliximab and adalimumab. Replication in prospective studies are awaited.

Switch from sequestering to anti-CD20 depleting treatment: disease activity outcomes during wash-out and in the first 6 months of ocrelizumab therapy

Objectives: Switching between treatments is an opportunity for patients with multiple sclerosis (MS) to ameliorate disease control or safety. The aim of this study was to investigate the impact of switching from fingolimod (FTY) or natalizumab (NTZ) to ocrelizumab (OCR) on disease activity. Methods: We retrospectively enrolled 165 patients treated with OCR from 11 MS centres. We assessed the association of demographic and clinical characteristics on relapse rate (RR) and activity on magnetic resonance imaging (MRI) during wash-out and after 6 months of treatment with OCR through univariable and multivariable negative binomial regression models. Results: We registered a total of 35 relapses during the wash-out period. Previous treatment with FTY, relapses in the previous year, and relapsing-remitting course were associated with higher RR. In the first 6 months of OCR, 12 patients had clinical or MRI disease activity. Higher Expanded Disability Status Scale (EDSS) and higher lymphocyte count at OCR start were associated with a reduced probability of relapse. Discussion and Conclusion: This study confirms that withdrawal from sequestering agents as FTY increases the risk of relapses in the wash-out period. Nevertheless, starting OCR before achieving complete immune reconstitution could limit its effectiveness in the first 6 months probably because trapped lymphocytes escape the CD20-mediated depletion.

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.

Lower lymphocyte counts and older age are associated with reduced multiple sclerosis disease activity during dimethyl fumarate treatment

Backgrounddelayed-release dimethyl fumarate (DMF) is a disease modifying therapy for relapsing–remitting multiple sclerosis (MS) with antioxidant and anti-inflammatory properties. The drug causes lymphocyte count reduction, which can lead to lymphopenia development during treatment. This is an important safety issue, due to infectious risk, mainly progressive multifocal leukoencephalopathy (PML). If the lymphocyte count influences the response to treatment is still a matter of debate, as there are contrasting contrasting data in the literature. Considering this, we aimed to identify DMF induced lymphopenia risk factors and to evaluate lymphopenia impact on MS disease activity in a real world setting. Methodsa retrospective study on 135 MS patients receiving DMF with a mean treatment duration of 32.3±15.9 months was performed. Baseline and follow-up demographic, clinical, magnetic resonance imaging (MRI) and laboratory data were collected. Results44 patients (32.6%) developed lymphopenia, with 11 (8.1%) grade 1, 23 (17.0%) grade 2 and 10 (7.4 %) grade 3. Older age and lower basal absolute lymphocyte count were found to be associated with lymphopenia development on a binary regression model (p<0.001 and p=0.009). When compared with non lymphopenic+lymphopenia grade 1 patients, those experiencing lymphopenia grade 2+3 had longer disease activity free survival (p<0.001), fewer clinical relapses (p=0.005) and lower MRI disease activity (p≤0.001). On Cox regression model, older age and lymphopenia grade 2+3 were found to be protective factors against disease activity (HR=0.966; 95% C.I.=0.942-0.992; p=0.009 for age; HR=0.137; 95% C.I.=0.043-0.439; p=0.001 for lymphopenia grade 2+3) and MRI disease activity (HR=0.968; 95% C.I.=0.941-0.997; p=0.030 for age; HR=0.142; 95% C.I.=0.034-0.591; p=0.007 for lymphopenia grade 2+3). Only lymphopenia grade 2+3 was found to be a predictor of clinical relapses (HR=0.970; 95% C.I.=0.936-1.005; p=0.095 for age; HR=0.115; 95% C.I.=0.016-0.854; p=0.034 for lymphopenia grade 2+3), with a protective effect. Conclusionolder age and lower basal lymphocyte count were found to be associated with lymphopenia development. Lymphopenia grade 2+3 and older age could be protective against clinical and radiologic disease activity during DMF treatment.

Dimethyl fumarate-induced lymphocyte count drop is related to clinical effectiveness in relapsing-remitting multiple sclerosis.

Dimethyl fumarate (DMF) causes a mean lymphocyte count drop of approximately 30% in relapsing-remitting multiple sclerosis (RRMS) patients. The relationship between this reduction and DMF effectiveness is controversial. The objective was to investigate if the decrease in absolute lymphocyte count (ALC) from baseline during DMF treatment is associated with clinical and magnetic resonance imaging (MRI) disease activity. A secondary aim was to evaluate ALC variations over time in a real-life cohort of DMF-treated patients. Demographic, laboratory, clinical and MRI data were collected in this observational multicentre study, conducted on RRMS patients treated with DMF for at least 6months. Multivariate Cox models were performed to evaluate the impact of 6-month ALC drop on time to no evidence of disease activity (NEDA-3) status loss. NEDA-3 is defined as absence of clinical relapses, MRI disease activity and confirmed disability progression. In all, 476 patients (312 females, age at DMF start 38.4±9.97years) were analysed up to 5-year follow-up. A greater lymphocyte decrease was associated with a lower risk of NEDA-3 status loss (hazard ratio 0.87, P=0.01). A worse outcome in patients with lower ALC drop (<11.5%), compared with higher tertiles (11.5%-40.5% and >40.5%), was observed (P=0.008). The nadir of ALC drop (-33.6%) and 35% of grade III lymphopaenia cases occurred after 12months of treatment. A higher lymphocyte count drop at 6months is related to better outcomes in DMF-treated patients. A careful ALC monitoring should be pursued up to 24months of treatment.

Diagnostic performance of sacroiliac joint MRI and added value of spine MRI to detect active spondyloarthritis

PurposeTo investigate the diagnostic performance of sacroiliac joint (SIJ) magnetic resonance imaging (MRI) and the incremental value of spine MRI to “predict” clinical disease activity in patients with axial spondyloarthritis (axSpA). Materials and methodsThis cross-sectional study included adult patients with known axSpA according to the SpondyloArthritis International Society (ASAS) classification criteria, radiological arm. MRI disease activity was scored semi-quantitatively for SIJ and total spine MRI in each patient. Two cut-off levels (≥ 1.3 and ≥ 2.1) for ankylosing spondylitis disease activity score with C-reactive protein (ASDAS-CRP) were considered for clinical disease activity categorization. MRI scores were first evaluated individually. Then, SIJ score was combined with the score from a spine segment (lumbar, cervical, thoracic or total spine) to build a bi-parametric model using a classification tree. Receiver operating characteristic (ROC) curves were constructed to evaluate the classification performance according to disease activity category of these models. ResultsForty-four patients (30 men, 14 women; mean age, 37 years±10 [SD] [range: 17–64 years]) with a mean disease duration of 5 years±8 (SD) (range: 0–35 years) were included. Thirty-six patients (36/44; 82%) had ASDAS-CRP≥1.3 and 27 patients (27/44; 61%) had ASDAS-CRP≥2.1. The most frequently involved spinal segment was mid-thoracic (T7-T8). The SIJ MRI score was an informative model to identify active axSpA (AUC≥0.7, regardless of the cut-off level on ASDAS-CRP). Performance of bi-parametric models based on “SIJ+thoracic spine” (for detecting patients with ASDAS-CRP≥1.3) or “SIJ+total spine” (for detecting patients with ASDAS-CRP≥2.1) outperformed that of the individual SIJ score (P<0.05). ConclusionThe combination of MRI of the SIJ and spine allows to accurately discriminate between active and inactive axSpA, outperforming SIJ MRI alone.

Natural Variation of Vitamin D and Neurofilament Light Chain in Relapsing-Remitting Multiple Sclerosis.

Background: High serum levels of 25-hydroxyvitamin D (25(OH)D) have been found among patients with a favorable disease course in relapsing-remitting MS (RRMS), indicating that this may limit clinical deterioration. Clinical deterioration in RRMS correlates with increasing serum levels of neurofilament light chain (NfL).Objectives: To examine the association between physiological variations in serum 25(OH)D and NfL levels in RRMS patients before and during disease modifying therapy (DMT).Material and Methods: Serum 25(OH)D and NfL concentrations were measured in 85 newly diagnosed RRMS patients enrolled in a 24-month randomized double-blinded placebo-controlled trial of ω-3 fatty acid supplementation without vitamin D. Patients were without DMT until interferon β-1a (IFN-β) initiation at study month 6. Longitudinal serum measurements and brain magnetic resonance imaging (MRI) were obtained. Associations between 25(OH)D and NfL levels were analyzed with linear regression models for the whole study period and the periods before and during IFN-β treatment. Analyses with adjustment for inflammatory MRI disease activity were also performed.Results: No significant associations were found between variations in 25(OH)D and NfL levels during the whole study period (p = 0.95), or the periods without (p = 0.78) or with (p = 0.33) IFN-β therapy. Patients with inflammatory MRI disease activity had significantly higher serum NfL levels than patients without inflammatory MRI disease activity [mean (SD) difference 12.6 (2.0) pg/mL, p < 0.01]. Adjustment for this did not change the relationship between 25(OH)D and NfL concentrations.Conclusion: Natural variations in serum 25(OH)D values do not seem to be associated with alterations in serum NfL concentrations in RRMS patients.

Serum levels of leptin and adiponectin are not associated with disease activity or treatment response in multiple sclerosis

Adipokines secreted by fatty tissue have inflammatory properties and are suggested biomarkers of MS disease activity. To assess this, 88 MS patients were followed with nine repeated measurements of leptin and adiponectin and 12 magnetic resonance imaging (MRI) scans for two years; six months without any immunomodulatory treatment followed by 18 months during interferon-beta (IFNB) treatment. Serum levels of leptin dropped and adiponectin increased upon initiation of IFNB-therapy, but were not associated with clinical or MRI disease activity or with treatment response. Our findings indicate that leptin and adiponectin are not useful as biomarkers of MS disease activity.

Efficacy of rituximab in refractory RRMS

Objective: To investigate the efficacy of rituximab as rescue therapy in patients with relapsing-remitting multiple sclerosis (RRMS) and persistent disease activity confirmed by magnetic resonance imaging (MRI) despite immunosuppressive disease-modifying therapy (DMT). Methods: In this observational nationwide retrospective multicenter study, we first identified 351 off-label rituximab-treated patients through a cohort of 15,984 RRMS patients. In this group, we identified patients with disease activity prior to rituximab confirmed by MRI (one or more new T2 lesion and/or gadolinium-enhancing lesion) despite immunosuppressive DMT (fingolimod, natalizumab, or mitoxantrone) with a follow-up after rituximab initiation longer than 6 months. Outcome data were collected from the French Observatory of Multiple Sclerosis (OFSEP) register and medical charts. Results: A total of 50 patients were identified. Median rituximab treatment duration was 1.1 (0.5–6.4) year. Mean annualized relapse rate significantly decreased from 0.8 during last immunosuppressive DMT to 0.18 after rituximab (p < 0.0001). While 72% of patients showed gadolinium-enhancing lesions on the last MRI performed during last immunosuppressive DMT, 8% of them showed gadolinium-enhancing lesions on the first MRI performed 6.1 (range 1.4–18.4) months after rituximab (p < 0.0001). Conclusion: This study provides level IV evidence that rituximab reduces clinical and MRI disease activity in patients with active RRMS despite immunosuppressive DMT.

Intercorrelation between MRI disease activity scores of the sacroiliac joints and the spine, and clinical disease activity indices in patients with axial spondyloarthritis

Intercorrelation between MRI disease activity scores of the sacroiliac joints and the spine, and clinical disease activity indices in patients with axial spondyloarthritis Hon Wai Lau,1 Chi Chiu Mok,2 Wun Cheung Samuel Chan,1 Ming Keung Yuen,1 On Chee Li1 1Department of Radiology, 2Department of Medicine, Tuen Mun Hospital, Tuen Mun, New Territories, Hong Kong Objective: To analyze the correlation between the magnetic resonance imaging (MRI) disease activity scores and the clinical disease activity indices (DAI) in Chinese patients with active axial spondyloarthritis (aSpA) that required biologics therapy. The correlation between MRI disease activity scores of the sacroiliac joints (SIJs) and the spine in these patients was also assessed.Methods: This was a cross-sectional study design in which adult patients who fulfilled the Assessment of SpondyloArthritis international Society classification criteria for aSpA and had active disease (Bath Ankylosing Spondylitis Disease Activity Index score &ge;4, persistent spinal pain despite nonsteroidal anti-inflammatory drugs therapy &gt;3 months) that required biologics therapy were included. The MRI disease activities were measured using the Spondyloarthritis Research Consortium of Canada (SPARCC) scores. Correlation between the SPARCC scores of the SIJs and the spine, and clinical DAI was calculated. Results: Fifty-seven patients (47 men and 10 women; mean age 37 &plusmn; 12 years) completed the study. There was no statistically significant correlation between the SPARCC scores and clinical DAI. The SPARCC score of the SIJs showed a positive correlation with the SPARCC score of the spine (r = 0.34, p &lt; 0.05). The thoracic discovertebral units (57%) were found to be more frequently associated with significant disease activity than the other levels of the spine. Conclusion: MRI can detect active inflammation which may not be reflected by clinical DAI. MRI should be performed in patients with aSpA to provide a more comprehensive assessment and to better reflect disease activity and severity. MRI findings of more severe sacroiliitis should prompt the radiologist to look for involvement in the entire spine, particularly in the thoracic region. Keywords: magnetic resonance imaging, MRI, SPARCC score, axial spondyloarthritis, ankylosing spondylitis, spondyloarthropathies, sacroiliitis

Once‐daily glatiramer acetate decreases magnetic resonance imaging disease activity in Japanese patients with relapsing–remitting multiple sclerosis

ObjectiveMultiple sclerosis (MS) prevalence, clinical patterns, and treatment responses vary between races and geographical latitudes. Glatiramer acetate (GA; Copaxone) has provided a safe, effective treatment option for relapsing–remitting MS patients in the USA, European nations, and other countries for decades. The objective of the present study was to assess the safety and efficacy of GA in reducing magnetic resonance imaging disease activity in Japanese patients with active relapsing–remitting MS.MethodsThis phase 2, multicenter, open‐label, single‐arm, 52‐week study measured the effect of GA 20 mg once‐daily on magnetic resonance imaging disease activity. GA efficacy was evaluated through week 36, and safety through week 52. The primary end‐point was change in the mean number of T1‐weighted gadolinium‐enhancing (GdE) lesions from pretreatment (weeks –8, –4 and baseline) to weeks 28, 32 and 36. Secondary end‐points included a change in mean number of new T2‐weighted lesions, GdE lesion and T2 lesion volumes, annualized relapse rate, and Expanded Disability Status Scale scores.ResultsGA therapy reduced the number of new GdE lesions by 65.66% (95% CI 33.19–82.35%). The number of new T2 lesions and GdE lesion volume were also reduced from pretreatment. The annualized relapse rate was reduced by 42% compared with the 1 year before treatment. Changes in T2 lesion volume and Expanded Disability Status Scale scores were favorable, but less pronounced. Most common adverse events were injection‐site reactions.ConclusionsThe present study confirmed the well‐established safety, tolerability and efficacy profile of GA in Japanese MS patients.

Peginterferon beta-1a improves MRI measures and increases the proportion of patients with no evidence of disease activity in relapsing-remitting multiple sclerosis: 2-year results from the ADVANCE randomized controlled trial

BackgroundSubcutaneous peginterferon beta-1a has previously been shown to reduce the number of T2-hyperintense and gadolinium-enhancing (Gd+) lesions over 2 years in patients with relapsing-remitting multiple sclerosis (RRMS), and to reduce T1-hypointense lesion formation and the proportion of patients showing evidence of disease activity, based on both clinical and radiological measures, compared with placebo over 1 year of treatment. The objectives of the current analyses were to evaluate T1 lesions and other magnetic resonance imaging (MRI) measures, including whole brain volume and magnetization transfer ratio (MTR) of normal appearing brain tissue (NABT), and the proportions of patients with no evidence of disease activity (NEDA), over 2 years.MethodsPatients enrolled in the ADVANCE study received continuous peginterferon beta-1a every 2 or 4 weeks for 2 years, or delayed treatment (placebo in Year 1; peginterferon beta-1a every 2 or 4 weeks in Year 2). MRI scans were performed at baseline and Weeks 24, 48, and 96. Proportions of patients with NEDA were calculated based on radiological criteria (absence of Gd + and new/newly-enlarging T2 lesions) and clinical criteria (no relapse or confirmed disability progression) separately and overall.ResultsPeginterferon beta-1a every 2 weeks significantly reduced the number and volume of T1-hypointense lesions compared with delayed treatment over 2 years. Changes in whole brain volume and MTR of NABT were suggestive of pseudoatrophy during the first 6 months of peginterferon beta-1a treatment, which subsequently began to resolve. Significantly more patients in the peginterferon beta-1a every 2 weeks group compared with the delayed treatment group met MRI-NEDA criteria (41% vs 21%; odds ratio [OR] 2.56; p < 0.0001), clinical-NEDA criteria (71% vs 57%; OR 1.90; p < 0.0001) and achieved overall-NEDA (37% vs 16%; OR 3.09; p < 0.0001).ConclusionPeginterferon beta-1a provides significant improvements in MRI measures and offers patients a good chance of remaining free from evidence of MRI, clinical and overall disease activity over a sustained 2-year period.Trial registrationClinicalTrials.gov: NCT00906399; Registered on: May 20, 2009.

The role of neutralizing antibodies to interferon-β as a biomarker of persistent MRI activity in multiple sclerosis: a 7-year observational study.

During interferon-β (IFN-β) therapy, up to 45% of patients may develop neutralizing antibodies (NAbs), associated with a decreased efficacy of the drug. We investigated in a real-life setting the impact of NAbs on magnetic resonance imaging (MRI) outcomes in a population of 567 IFN-β-treated relapsing-remitting (RR) multiple sclerosis (MS) patients up to 7years. We also evaluated NAbs' role as a biomarker of the persistence of MRI disease activity. Patients' sera were tested for NAbs' presence by cytopathic effect (CPE) assay every 6-12months. MRI scans were performed every 12months. Generalized hierarchical linear models accounting for within-patient correlation were used to analyze T1 gadolinium-enhancing and new T2 lesions. Moreover, further tests were carried out to assess the overall outcome difference from year 1 to year 7 according to NAb status and the possible interaction between NAb status and time of follow-up. Seventy-five patients (13.2%) became NAb positive (NAb+) during the follow-up. Considering T1 gadolinium-enhancing (GD+) lesions, we observed a significantly higher incidence in NAb+ patients (52%, p=0.0091). Also for new T2 lesions, we found a higher incidence in NAb+ patients (50%, p=0.0075). The negative impact of NAbs on the MRI outcomes considered did not change during the follow-up. Our 7-year results show the negative effect of NAbs on MRI measures of disease activity and confirm their role as a surrogate marker of IFN-β treatment efficacy.

Monoclonal antibody therapies for the treatment of relapsing-remitting multiple sclerosis: differentiating mechanisms and clinical outcomes.

Monoclonal antibody (mAb) therapies for relapsing-remitting multiple sclerosis (MS) target immune cells or other molecules involved in pathogenic pathways with extraordinary specificity. Natalizumab and alemtuzumab are the only two currently approved mAbs for the treatment of MS, having demonstrated significant reduction in clinical and magnetic resonance imaging disease activity and disability in clinical studies. Ocrelizumab and daclizumab are in the late stages of phase III trials, and several other mAbs are in the early stages of clinical evaluation. mAbs have distinct structural characteristics (e.g. chimeric, humanized, fully human) and unique targets (e.g. blocking interactions, induction of signal transduction by receptor binding, complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity) conferring different mechanisms of action in MS. Because of these differences, mAbs for MS do not constitute a single treatment class; each must be considered individually when selecting appropriate therapy. Furthermore, in reviewing the data from clinical studies of mAbs, attention should be drawn to use of different comparators (e.g. placebo or interferon β-1a) and study designs. Each mAb treatment has a unique administration schedule. In the decision to select the appropriate treatment for each individual MS patient, careful review of the benefits relative to risks of mAbs is balanced against the risk of development of MS-associated disability.

Therapeutic interference with leukocyte recirculation in multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated disease where T cells are thought to initiate an inflammatory reaction in the brain and spinal cord, resulting in demyelination and axonal pathology. Interfering with the activation and recruitment of immune cells reduces disease activity in MS. We review the mechanism of action and treatment effects of natalizumab and fingolimod, which interfere with the recruitment of pathogenic immune cells in MS. Fingolimod blocks the egress of activated lymphocytes from lymph nodes by binding to the sphingosine-1-phosphate (S1P) receptor 1, but may also have effects on S1P receptor-expressing cells within the central nervous system (CNS). Natalizumab reduces the migration of lymphocytes to the CNS by binding to the α4 integrin very late antigen 4. Fingolimod and natalizumab also have other effects, but these are less well understood. Both treatments are efficacious in reducing relapses, accumulation of persisting disability and magnetic resonance imaging disease activity. Both treatments are safe and well tolerated in the majority of patients, but due to a potential for serious side effects they are licensed as second line therapies or for treatment of highly active MS in most European countries. We conclude that fingolimod and natalizumab have well known effects on the migration of immune cells in MS and have substantial effects on disease activity in relapsing-remitting MS. Additional effects on disease progression, potential effects within the CNS and other effects on immune cells are still being clarified.

Cyclophosphamide Pulses Therapy after Natalizumab Discontinuation for Multiple Sclerosis: A Multicentre Study

Importance: Natalizumab discontinuation induces the recurrence of Multiple Sclerosis (MS) disease activity: Currently no therapeutic approach has been found able to abolish disease reactivation. Objective: To collect data from patients with MS switching from natalizumab to cyclophosphamide. Design: Retrospective multicentre study. Setting: Nine Multiple Sclerosis Centers in Italy. Participants: A total of 47 patients with clinically definite RR-MS switched to cyclophosphamide after natalizumab discontinuation. Two patients were excluded from the analysis because received less than 12 natalizumab infusions. The remaining 45 patients were subdivided into two main groups: Early Treatment (period of washout between natalizumab and cyclophosphamide 1 to 3 months), Late Treatment (washout between natalizumab and cyclophosphamide higher than 3 months). Intervention: Cyclophosphamide intravenous pulses after natalizumab discontinuation. Main outcome measure: Number of relapses, Expanded Disability Status Scale scores, number of new T2/fluidattenuated inversion recovery lesions and contrast-enhancing lesions on brain magnetic resonance imaging, rebound effect, adverse events. Results: In the Early Treatment group, only 3/23 patients (13%) experienced a clinical relapse and only 2 out of 13 (15%) patients showed brain Magnetic Resonance Imaging (MRI) activity at 3 months, while none developed MRI activity at 6 months after cyclophosphamide introduction. In the Late Treatment Group 12/22 patients (63%) had relapses during the washout period and 4/22 (40%) after the introduction of cyclophosphamide; MRI disease activity was shown in 5/9 (56%) at 3 months and in 5/14 (36%) at 6 months after cyclophosphamide introduction. Conclusions and relevance: These data show that cyclophosphamide could be able to reduce disease reactivation after natalizumab, in particular with a short washout period after natalizumab discontinuation. It can be suggested that a short period (3-6 months) of cyclophosphamide monthly pulses could be used as “re-induction” treatment in patients discontinuing natalizumab.