MRI Disease Activity Research Articles

Analysis of soluble interleukin-2 receptor as CSF biomarker for neurosarcoidosis.

ObjectiveTo systematically analyze soluble interleukin-2 receptor (sIL-2R) in CSF as a diagnostic and disease activity biomarker in patients with sarcoidosis involving the CNS (neurosarcoidosis).MethodssIL-2R was determined by chemiluminescent immunoassays in CSF/serum samples from patients with neurosarcoidosis (n = 23), MS (n = 19), neurotuberculosis (n = 8), viral (n = 18) and bacterial (n = 9) meningitis, cerebral lymphoma (n = 15), Guillain-Barré syndrome (n = 8), and 115 patients with noninflammatory neurologic diseases (NINDs) as controls. The sIL-2R index was calculated by dividing the CSF/serum sIL-2R quotient (QsIL-2R) through the CSF/serum albumin quotient (QAlb). sIL-2R quotient diagrams were established by plotting QsIL-2R against QAlb. sIL-2R levels were correlated with clinical, MRI, and CSF disease activity markers of neurosarcoidosis.ResultsPatients with neurosarcoidosis had higher CSF sIL-2R, QsIL-2R, and sIL-2R index values than patients with NINDs (p < 0.0001 for all pairwise group comparisons). sIL-2R quotient diagrams demonstrated an intrathecal sIL-2R synthesis in >50% of neurosarcoidosis samples. Similar findings were observed in viral/bacterial meningitis, CNS lymphoma, and, most pronounced, in neurotuberculosis, but not in patients with MS. CSF sIL-2R parameters were associated with clinical disease activity, leptomeningeal gadolinium enhancement, and the CSF white cell count in patients with neurosarcoidosis.ConclusionsCSF sIL-2R parameters are elevated in patients with neurosarcoidosis, but this finding is not specific for neurosarcoidosis. Nevertheless, CSF sIL-2R parameters may help distinguishing neurosarcoidosis from MS and are associated with clinical, radiologic, and CSF disease activity markers of neurosarcoidosis.Classification of evidenceThis study provides Class II evidence that CSF sIL-2R parameters distinguish neurosarcoidosis from NINDs and MS.

Alemtuzumab Maintains Efficacy on Clinical and MRI Disease Activity Outcomes, Including Slowing of Brain Volume Loss, Over 9 Years in RRMS Patients: CARE-MS II Follow-up (TOPAZ Study) (151)

Alemtuzumab Maintains Efficacy on Clinical and MRI Disease Activity Outcomes, Including Slowing of Brain Volume Loss, Over 9 Years in RRMS Patients: CARE-MS II Follow-up (TOPAZ Study) (151)

Event-Driven Immunoprofiling Predicts Return of Disease Activity in Alemtuzumab-Treated Multiple Sclerosis.

Background: Alemtuzumab is a highly effective drug for the treatment of multiple sclerosis (MS), characterized by specific patterns of depletion and repopulation. As an induction-like treatment concept, two mandatory infusion courses can inhibit long-term disease activity in the majority of patients, and additional courses can successfully manage subsequent re-emergence of disease activity. Currently, there are no biomarkers to identify patients with re-emergent disease activity requiring retreatment.Methods: In this study, we systematically characterized 16 MS patients commencing alemtuzumab. Clinical parameters, MRI and detailed immunoprofiling were conducted every 3 months for up to 84 months.Results: Alemtuzumab led to significant decrease in clinical disease activity in all evaluated patients. Nine out of 16 patients presented with no evidence of disease activity (NEDA)-3 up to 84 months (“complete-responder”), while 7 patients demonstrated clinical or/and subclinical MRI disease activity and received alemutzumab retreatment (“partial-responder”). In both response categories, all T- and B-cell subsets were markedly depleted after alemtuzumab therapy. In particular, absolute numbers of Th1 and Th17 cells were markedly decreased and remained stable below baseline levels—this effect was particularly pronounced in complete-responders. While mean cell numbers did not differ significantly between groups, analysis of event-driven immunoprofiling demonstrated that absolute numbers of Th1 and Th17 cells showed a reproducible increase starting 6 months before relapse activity. This change appears to predict emergent disease activity when compared with stable disease.Conclusion: Studies with larger patient populations are needed to confirm that frequent immunoprofiling may assist in evaluating clinical decision-making of alemtuzumab retreatment.

Improved Clinical and MRI Disease Activity Outcomes, Including Slowing of Brain Volume Loss, in Alemtuzumab-Treated RRMS Patients: 8-Year Follow-up of CARE-MS II (TOPAZ Study) (P3.2-058)

Improved Clinical and MRI Disease Activity Outcomes, Including Slowing of Brain Volume Loss, in Alemtuzumab-Treated RRMS Patients: 8-Year Follow-up of CARE-MS II (TOPAZ Study) (P3.2-058)

Improved Clinical and MRI Disease Activity Outcomes, Including Slowing of Brain Volume Loss, in Alemtuzumab-Treated RRMS Patients: 8-Year Follow-up of CARE-MS I (TOPAZ Study) (P3.2-037)

Improved Clinical and MRI Disease Activity Outcomes, Including Slowing of Brain Volume Loss, in Alemtuzumab-Treated RRMS Patients: 8-Year Follow-up of CARE-MS I (TOPAZ Study) (P3.2-037)

Profiling individual clinical responses by high-frequency serum neurofilament assessment in MS.

ObjectiveTo evaluate individual neurofilament light chain (NfL) variation over the time of disease course and the potential of NfL measurement to predict treatment response in patients with MS.MethodsWe investigated 15 patients with MS after immune reconstitution treatment with alemtuzumab (ATZ). Monthly serum NfL (sNFL) measurements were correlated with Expanded Disability Status Scale (EDSS), MRI, and relapse activity over an observational period of up to 102 months.ResultsBefore ATZ, sNfL was significantly increased in correlation with previous relapse/MRI activity. After ATZ, sNfL decreased quickly within the first 6 months. In patients classified as NEDA-3, sNfL declined and persisted at an individual low steady-state level of <8 pg/mL. During follow-up, 34 sNfL peaks with a >20 fold increase could be detected, which were associated with clinical or MRI disease activity. Even patient-reported relapse-suspicious symptoms, which have not been confirmed because relapses were accompanied by sNfL, increase, proposing sNfL assessment as a marker for relapse activity. sNfL started to increase earliest 5 months before, peaked at clinical onset, and recovered within 4–5 months. sNfL presented at higher levels in active patients requiring ATZ retreatment compared with responder patients. During 2 documented pregnancies, sNfL was at a low level, whereas a postpartum transient sNfL increase was seen without any signs of activity.ConclusionsThis study applied a long-term high-frequency sNfL assessment in an ATZ-treated cohort, allowing a holistic profiling on the individual level and highlighted that sNfL can eminently complement the individual clinical and MRI monitoring in clinical practice.

ACTRIMS 2019 – Posters

Background: In the 2-year (y) CARE-MS II phase 3 trial (NCT00548405), alemtuzumab (12 mg/day; baseline: 5 consecutive days; 12 months later: 3 consecutive days) significantly improved clinical and MRI outcomes versus SC IFNB-1a in RRMS patients with inadequate response to prior therapy. In a 4-y extension (NCT00930553), patients could receive additional courses of alemtuzumab (12 mg/day on 3 consecutive days; ⩾12 months apart) as needed for disease activity or receive other disease-modifying therapy (DMT) per investigator’s discretion. Efficacy on clinical/MRI outcomes was maintained through Y6, with 50% receiving no additional alemtuzumab or other DMTs in the extension. Following the initial 4-y extension, patients could continue in TOPAZ (NCT02255656), an additional 5-y extension study, for further evaluation. Objectives: To evaluate 8-y efficacy and safety outcomes in alemtuzumab-treated CARE-MS II patients. Methods: At the investigator’s discretion, patients in TOPAZ can receive additional as-needed alemtuzumab (⩾12 months apart; no criteria) or receive other DMT (at any time). Results: Of 435 alemtuzumab-treated CARE-MS II patients, 300 (69%) completed 8-y total follow-up; 44% received neither additional courses of alemtuzumab nor another DMT. Of 393 patients who entered the extension, 200 (51%) received ⩾3 courses of alemtuzumab (3 courses, 29%; 4 courses, 16%; 5 courses, 3%, >5 courses, 3%). Course 3 was given in Y3 (20%), Y4 (11%), Y5 (9%), Y6 (5%), Y7 (2%), and Y8 (3%). In Y8, the annualized relapse rate was 0.18, with 85% of patients relapse-free. Compared with core study baseline, 70% of patients had stable/improved EDSS scores at Y8, and mean change in EDSS score was 0.17. Over 8 y, 64% of patients were free of 6-month confirmed disability worsening, and 47% had 6-month confirmed disability improvement. In Y8, 58% of patients achieved no evidence of disease activity, and 70% were free of MRI disease activity. Median percent cumulative brain volume loss (BVL) from baseline through Y8 was −1.06%; median annual BVL from Y3 to Y8 was ⩽−0.19%. The safety profile in Y8 was consistent with the previous years; incidence of AEs, infections, and thyroid AEs continued to decline. No new cases of immune thrombocytopenia or nephropathy were seen. Conclusion: Alemtuzumab efficacy on clinical, MRI, and BVL outcomes was maintained over 8 y, with 44% of CARE-MS II patients receiving no additional treatment. Safety was consistent and manageable through Y8.

PACTRIMS 2018

Background: In CARE-MS II (NCT00548405), 2 alemtuzumab courses (12 mg/day; baseline: 5 days; 12 months [M] later: 3 days) significantly improved clinical/MRI outcomes versus SC IFNB-1a over 2 years (y) in RRMS patients with inadequate response to prior therapy. Efficacy was maintained in a 4-y extension (NCT00930553), wherein patients could receive additional alemtuzumab (12 mg/day; 3 days; ⩾12M apart) as needed for disease activity or other disease-modifying therapy (DMT). Patients could continue in an additional 5-y extension (TOPAZ; NCT02255656). Aims: To evaluate 8-y efficacy/safety of alemtuzumab in CARE-MS II patients. Methods: At investigator’s discretion, patients in TOPAZ can receive as-needed additional alemtuzumab (⩾12M apart; no criteria) or other DMT (any time). Results: 300/435 (69%) patients completed TOPAZ Y2 (Y8 after initiating alemtuzumab); 44% received neither additional alemtuzumab nor another DMT. At Y8, annualised relapse rate was 0.18, 85% were relapse-free, 70% had stable/improved EDSS versus baseline, and mean EDSS change was 0.17. Through Y8, 64% were free of 6-month confirmed disability worsening, and 47% achieved 6-month confirmed disability improvement. In Y8, 58% achieved no evidence of disease activity, and 70% were free of MRI disease activity. Median percent brain volume loss (BVL) from baseline through Y8 was –1.06%; BVL was –0.19% or less annually in Y3–8. Safety remained consistent through Y8, with no new immune thrombocytopenia or nephropathy cases. Conclusion: Efficacy of alemtuzumab on clinical, MRI, and BVL outcomes was maintained through Y8 in absence of continuous treatment in CARE-MS II patients, with a consistent and manageable safety profile.

Long-term Reduction in Brain MRI Disease Activity and Atrophy after 5 years of Ocrelizumab Treatment in Patients with Relapsing Multiple Sclerosis

Long-term Reduction in Brain MRI Disease Activity and Atrophy after 5 years of Ocrelizumab Treatment in Patients with Relapsing Multiple Sclerosis

Alemtuzumab Improves Clinical and MRI Disease Activity Outcomes, Including Slowing of Brain Volume Loss, in Relapsing-remitting Multiple Sclerosis Patients Over 8 Years: Care-MS Ii Follow-up (topaz Study)

Alemtuzumab Improves Clinical and MRI Disease Activity Outcomes, Including Slowing of Brain Volume Loss, in Relapsing-remitting Multiple Sclerosis Patients Over 8 Years: Care-MS Ii Follow-up (topaz Study)

PND10 - GENIUS RWE STUDY (FINGOLIMOD REAL WORLD EVIDENCE ITALIAN MULTICENTER OBSERVATIONAL STUDY IN MULTIPLE SCLEROSIS)PRELIMINARY RESULTS

To describe the Annualized Relapse Rate (ARR) (primary objective) and the proportion of patients with No Evidence of Disease Activity (relapses, disability progression and MRI activity, NEDA-3) (secondary objective) in a cohort of MS Italian patients after 1 and 2 years of fingolimod treatment. GENIUS is an observational, retrospective cohort study on MS patients who started fingolimod in the years 2013-2014. ARR and the proportion of NEDA-3 patients after 1 and 2 years of treatment were calculated. Data of 391 patients were analysed: 270 (69%) were females; mean (SD) age was 38.7 (9.8) years; mean (SD) duration of fingolimod treatment was 22.8 (4.2) months. Mean (SD) number of relapses in the year before treatment start was 1.0 (0.8). The one- and two-year ARR (95% CI) were 0.19 (0.15-0.23) and 0.18 (0.14-0.22), respectively. Relapsing patients were 53 (13.6%) in the first year of treatment, 47 (12.0%) in the second year and 85 (21.7%) after two years of treatment. At 1 and 2 years after fingolimod start, 81 (20.7%) and 60 (15.3%) patients had MRI disease activity, respectively; 114 (29.2%) patients had MRI disease activity during the 2 years after treatment start. At fingolimod start, 77 (19.7%) patients showed NEDA-3, whereas after 1 and 2 years of treatment there were 278 (71.1%) and 299 (76.5%) NEDA-3 patients respectively; 229 (58.6%) patients showed NEDA-3 after two years of treatment. GENIUS study results confirmed the effectiveness of fingolimod in the Italian RW setting; 391 patients were analyzed 1-year ARR was 0.19 (0.35 in NTZ+, 0.13 in NTZ-); 2-year ARR was 0.18 (0.30 in NTZ+, 0.16 in NTZ-); 71% of patients was NEDA-3 at 1 year and 77% at 2 years; RWD is becoming more and more important for assessing drug effectiveness

Shortening the washout to 4 weeks when switching from natalizumab to fingolimod and risk of disease reactivation in multiple sclerosis

BACKGROUNDThere is limited evidence about the optimal length of washout when switching from natalizumab to fingolimod. OBJECTIVETo study if a washout period of 4 weeks is associated with less disease activity compared to 8 weeks. METHODS25 patients with Relapsing Remitting Multiple Sclerosis were included in an open label, prospective study with a follow-up of 108 weeks. The primary endpoint (PE) was defined as “time to first relapse or MRI disease activity up to week 56”. In addition, a recurrent event analysis (REA) was performed up to week 108. RESULTSThe PE was not met (HR 0.67, 95% CI [0.22,1.97], p = 0.462). Number of relapses before stopping natalizumab was positively associated with the hazard of relapse (HR 3.91, p = 0.0117, 95% CI [1.36, 11.28]). The REA showed a reduction of the hazard to develop a relapse by 77% (HR 0.23, 95% CI [0.08, 0.69], p = 0.00854) in favor of the cohort with 4 weeks washout. CONCLUSIONSOur study suggests that switching from natalizumab to fingolimod with a shorter washout of 4 weeks might reduce the risk of disease reactivation after switching.

A.03 Durable clinical and MRI efficacy of alemtuzumab over 6 years in CARE-MS II patients with RRMS who relapsed between Courses 1 and 2

Background: In RRMS patients with inadequate response to prior therapy, 2 alemtuzumab courses (12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved outcomes over 2 years (y) versus SC IFNB-1a (CARE-MS II [NCT00548405]), with durable efficacy over a 4-y extension (NCT00930553). We present 6-y efficacy (2-y core study plus 4-y extension) in patients with relapse (relapsers) between Courses (C) 1 and 2. Methods: Annualized relapse rate (ARR); 6-month confirmed disability worsening (CDW); MRI disease activity (Gd-enhancing lesions; new/enlarging T2 hyperintense lesions); brain volume loss (BVL; derived by relative change in brain parenchymal fraction). Results: 105/435 (24%) patients relapsed between C1 and C2; 33% (relapsers) versus 55% without relapse (non-relapsers) received neither alemtuzumab retreatment nor another disease-modifying therapy through Y6. ARR (Y1: 1.2) declined post-C2 (0.5), remaining low through Y6 (0.2 [0.1, non-relapsers]; 10/105 [10%] relapsed). Through Y6, patients remained CDW-free (60% [relapsers]; 75% [non-relapsers]), Gd-enhancing lesion-free (94% [relapsers]; 90% [non-relapsers]), new/enlarging T2 hyperintense lesion-free (68% [relapsers]; 69% [non-relapsers]), and MRI disease activity-free (68% [relapsers]; 69% [non-relapsers]). Alemtuzumab slowed median percent yearly BVL (Y6: -0.13% [relapsers]; -0.10% [non-relapsers]). Conclusions: Patients relapsing between C1 and C2 improved post-C2 through Y6. These findings support administering 2 alemtuzumab courses to achieve optimal and durable benefit.

Active RRMS Patients Treated with Alemtuzumab Experience Durable Reductions in MRI Disease Activity and Slowing of Brain Volume Loss: 7-Year Follow-up of CARE-MS II Patients (TOPAZ Study) (P6.367)

Active RRMS Patients Treated with Alemtuzumab Experience Durable Reductions in MRI Disease Activity and Slowing of Brain Volume Loss: 7-Year Follow-up of CARE-MS II Patients (TOPAZ Study) (P6.367)

Durable Reduction in MRI Disease Activity and Slowing of Brain Volume Loss in Alemtuzumab-Treated Patients With Active RRMS: 7-Year Follow-up of CARE-MS I Patients (TOPAZ Study) (P6.375)

Durable Reduction in MRI Disease Activity and Slowing of Brain Volume Loss in Alemtuzumab-Treated Patients With Active RRMS: 7-Year Follow-up of CARE-MS I Patients (TOPAZ Study) (P6.375)

Alemtuzumab-Treated Patients Experienced Decreased MRI Disease Activity and Slowing of Brain Volume Loss Over 5 Years After Switching From SC IFNB-1a: Follow-up of Patients From CARE-MS I (TOPAZ Study) (S36.003)

Alemtuzumab-Treated Patients Experienced Decreased MRI Disease Activity and Slowing of Brain Volume Loss Over 5 Years After Switching From SC IFNB-1a: Follow-up of Patients From CARE-MS I (TOPAZ Study) (S36.003)

Predictors of retinal atrophy in multiple sclerosis: A longitudinal study using spectral domain optical coherence tomography with segmentation analysis

BackgroundMultiple sclerosis is an inflammatory demyelinating disease characterized by progressive axonal loss affecting mainly the inner retinal layers. Optical coherence tomography (OCT) provides in-vivo quantification of the retinal layers and allows measuring progressive retinal changes. Our objective was to assess the longitudinal changes in the retina using spectral domain OCT (SDOCT) and to identify independent predictors affecting retinal thinning in MS patients. MethodsA prospective study in a tertiary care MS center was conducted to study the longitudinal retinal changes in MS patients. All subjects underwent baseline and follow up OCT assessment with segmentation analysis. Regression analysis was performed to assess clinical factors (age, sex, disease duration, history of optic neuritis before baseline, non-ocular clinical relapses) and MRI disease activity during the follow-up period. ResultsThe study included 102 MS patients with a mean follow-up duration of 3.9 ± SD years. At the last follow-up assessments, there were significant thinning of the average macular thickness (AMT) (p < .001), macular nerve fiber layer (MRNFL) (p < .001), ganglion cell-inner plexiform layer (GCIPL) (p < .001), and the peripapillary nerve fiber layer (PRNFL) (p < .001), compared to baseline. Early disease duration up to 10 years was associated with thinning of AMT, PRNFL, and GCIPL, while longer disease duration (> 15 years) was associated with only GCIPL thinning. Prior optic neuritis was predictive of more thinning of PRNFL (p = < .01), while MRI activity and female gender were significantly associated with more MRNFL thinning (p = < .01). ConclusionMS is associated with longitudinal thinning affecting AMT inner retinal layers (MRNFL, GCIPL, PRNFL). Early disease duration, female gender, MRI activity, and prior optic neuritis were predictive of faster rate of neuro-axonal loss. This may have implications in the design of future therapeutic trials.

Neurofilament light chain predicts disease activity in relapsing-remitting MS.

Objective:To investigate whether serum neurofilament light chain (NF-L) and chitinase 3-like 1 (CHI3L1) predict disease activity in relapsing-remitting MS (RRMS).Methods:A cohort of 85 patients with RRMS were followed for 2 years (6 months without disease-modifying treatment and 18 months with interferon-beta 1a [IFNB-1a]). Expanded Disability Status Scale was scored at baseline and every 6 months thereafter. MRI was performed at baseline and monthly for 9 months and then at months 12 and 24. Serum samples were collected at baseline and months 3, 6, 12, and 24. We analyzed the serum levels of NF-L using a single-molecule array assay and CHI3L1 by ELISA and estimated the association with clinical and MRI disease activity using mixed-effects models.Results:NF-L levels were significantly higher in patients with new T1 gadolinium-enhancing lesions (37.3 pg/mL, interquartile range [IQR] 25.9–52.4) and new T2 lesions (37.3 pg/mL, IQR 25.1–48.5) compared with those without (28.0 pg/mL, IQR 21.9–36.4, β = 1.258, p < 0.001 and 27.7 pg/mL, IQR 21.8–35.1, β = 1.251, p < 0.001, respectively). NF-L levels were associated with the presence of T1 gadolinium-enhanced lesions up to 2 months before (p < 0.001) and 1 month after (p = 0.009) the time of biomarker measurement. NF-L levels fell after initiation of IFNB-1a treatment (p < 0.001). Changes in CHI3L1 were not associated with clinical or MRI disease activity or interferon-beta 1a treatment.Conclusion:Serum NF-L could be a promising biomarker for subclinical MRI activity and treatment response in RRMS. In clinically stable patients, serum NF-L may offer an alternative to MRI monitoring for subclinical disease activity.ClinicalTrials.gov identifier:NCT00360906.

A comparison of multiple sclerosis disease activity after discontinuation of fingolimod and placebo.

BackgroundCases of higher-than-expected disease activity have been reported following fingolimod discontinuation.ObjectiveThe objective of this paper is to assess the risk of substantially higher-than-expected disease activity post-study drug discontinuation (SDD) at the individual patient level using data from the Phase III, placebo-controlled FREEDOMS and FREEDOMS II trials.MethodsBaseline gadolinium-enhancing T1-lesion volumes were used to statistically model the expected level of MRI disease activity post-SDD. Patients exceeding this level were classed as “MRI outliers.” Patients with an unusually high increase in Expanded Disability Status Scale score, hospitalization for relapse, severe relapse, or relapse with incomplete recovery post-SDD were classed as “clinical outliers.”ResultsIn FREEDOMS, the number of MRI outliers post-SDD was 2/69 (2.9%), 1/65 (1.5%) and 7/83 (8.4%) for the placebo, fingolimod 0.5 mg, and fingolimod 1.25 mg groups, respectively. In FREEDOMS II, the corresponding numbers were 4/72 (5.6%), 6/79 (7.6%) and 3/73 (4.1%). The number of clinical outliers across both trials was low. No consistent evidence of placebo vs fingolimod, dose-related or inter-trial patterns was discernable.ConclusionThe low number of clinical and MRI outliers and lack of any discernible pattern within and between trials, including between placebo and fingolimod, argues against a systematic risk of higher-than-expected recurrence of disease activity following discontinuation of fingolimod.

Durable Reduction in MRI Disease Activity With Alemtuzumab in the Absence of Continuous Treatment in Patients With Active Relapsing-Remitting Multiple Sclerosis Who Were Treatment-Naive: 6-Year Follow-up of the CARE-MS I Study (S10.002)

Durable Reduction in MRI Disease Activity With Alemtuzumab in the Absence of Continuous Treatment in Patients With Active Relapsing-Remitting Multiple Sclerosis Who Were Treatment-Naive: 6-Year Follow-up of the CARE-MS I Study (S10.002)