Contributions
Abstract: 186
Type: Oral
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: Chronic lesion activity associated with smouldering inflammation and activated microglia/macrophages (chronic active plaques) may contribute to disability accumulation, especially in progressive multiple sclerosis (MS). Chronic lesion pathology is poorly characterised on conventional brain MRI.
Objectives: To develop a method for automatic detection of slowly evolving lesions (SELs; as a potential read-out of smouldering plaques) on conventional brain MRI, and characterise the relationship of SELs to T1 gadolinium (Gd) enhancement, the evolution of T1 intensity signal over time in SELs and the relative occurrence of SELs in primary progressive MS (PPMS) and relapsing MS (RMS) populations.
Methods: SEL candidates were identified by considering contiguous regions of existing areas of T2 lesions that show a positive determinant of the Jacobian of the non-linear deformation field between reference and follow-up scans. SEL candidates were assigned a heuristic score based on concentricity and constancy of change over time. SELs were identified in Phase III MS clinical trial data comprised of pooled treatment arms including 1,656 RMS (OPERA I [NCT01247324] and OPERA II [NCT01412333]) and 732 PPMS (ORATORIO [NCT01194570]) patients. Results are presented for candidate lesions with a SEL score ≥0.
Results: The percentage of voxels showing T1 Gd enhancement was higher in areas of persistent T2 lesion not classified as SEL [non-SEL] (1.5%) and in new T2 lesions (8.9%), compared with regions identified as SEL (0.3%, p< 0.001 for both). Compared with non-SEL, SELs had a lower normalised T1 intensity at baseline (0.262 vs 0.069, p< 0.001) and a larger decrease in T1 intensity from baseline to week 24 (p< 0.001) and week 48 (p< 0.001). Similar qualitative differences between SELs and non-SEL were observed in RMS and PPMS populations assessed separately. Compared with RMS patients, PPMS patients had a higher mean number of SELs (6.3 vs 4.6, p=0.002) and higher mean baseline T2 volume of SELs (1,838 mm3 vs 1,223 mm3, p< 0.001).
Conclusions: SELs were shown to evolve independently of T1 Gd enhancement and demonstrated a lower T1 intensity at baseline, and a decrease in T1 intensity over time, compared with non-SEL. Although more frequently detected in PPMS patients, SELs were also identified in those with RMS. This algorithm for automatic detection of SELs on conventional brain MRI may provide a marker for chronically evolving MS lesion pathology.
Disclosure: Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Health Interactions, USA, and Articulate Science, UK.
C. Elliott is an employee of NeuroRx Research and has served on an advisory board for F. Hoffmann-La Roche Ltd.
J.S. Wolinsky has served on advisory boards, data monitoring or steering committees, has consulting agreements, or received speaker honoraria from the following entities: AbbVie, Academic CME, ACTRIMS, Alkermes, Bayer HealthCare, Biogen, Bionest, Celgene, Clene Nanomedicine, CMSC, ECTRIMS, Forward Pharma A/S, MedDay Pharmaceuticals, Novartis Pharmaceuticals, PRIME, Roche Genentech, Sanofi Genzyme, Strategic Consultants International, Takeda, Teva Pharmaceuticals and WebMD; royalties are received for outlicensed monoclonal antibodies through UTHealth from Millipore Corporation.
S.L. Hauser serves on the board of trustees for Neurona and on scientific advisory boards for Annexon, Symbiotix and Bionure; he has also received travel reimbursement and writing assistance from
F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations.
L. Kappos's institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof Kappos's activities as principal investigator and member or chair of planning and steering committees or advisory boards in trials sponsored by Actelion, Addex, Almirall, Bayer HealthCare Pharmaceuticals, CLC Behring, Genentech, Inc., GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Ono Pharma, Pfizer, Receptos,
F. Hoffmann-La Roche Ltd, Sanofi, Santhera, Siemens, Teva, UCB and XenoPort; license fees for Neurostatus products; and research grants from the Swiss MS Society, the Swiss National Research Foundation, the European Union, the Gianni Rubatto Foundation, the Novartis Research Foundation and the Roche Research Foundation.
F. Barkhof is a board member of the following publications: Brain, European Radiology, Neurology, Multiple Sclerosis Journal and Radiology; he has received consultancy fees from Bayer Schering, Biogen Idec, Teva, Merck Serono, Novartis, Roche, Synthon, Janssen Research and Genzyme; he has received grants from the Dutch MS Society (EU-FP7/H2020); he has received payments for developing educational presentations, including service on speakers' bureaus, for Biogen Idec and IXICO.
C. Bernasconi is a contractor of F. Hoffmann-La Roche Ltd.
S. Belachew is an employee and shareholder of F. Hoffmann-La Roche Ltd.
D.L. Arnold reports personal fees for consulting from Acorda, Biogen, F. Hoffmann-La Roche Ltd, MedImmune, Mitsubishi, Novartis, Receptos and Sanofi Aventis; grants from Biogen and Novartis; and an equity interest in NeuroRx Research.
Abstract: 186
Type: Oral
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: Chronic lesion activity associated with smouldering inflammation and activated microglia/macrophages (chronic active plaques) may contribute to disability accumulation, especially in progressive multiple sclerosis (MS). Chronic lesion pathology is poorly characterised on conventional brain MRI.
Objectives: To develop a method for automatic detection of slowly evolving lesions (SELs; as a potential read-out of smouldering plaques) on conventional brain MRI, and characterise the relationship of SELs to T1 gadolinium (Gd) enhancement, the evolution of T1 intensity signal over time in SELs and the relative occurrence of SELs in primary progressive MS (PPMS) and relapsing MS (RMS) populations.
Methods: SEL candidates were identified by considering contiguous regions of existing areas of T2 lesions that show a positive determinant of the Jacobian of the non-linear deformation field between reference and follow-up scans. SEL candidates were assigned a heuristic score based on concentricity and constancy of change over time. SELs were identified in Phase III MS clinical trial data comprised of pooled treatment arms including 1,656 RMS (OPERA I [NCT01247324] and OPERA II [NCT01412333]) and 732 PPMS (ORATORIO [NCT01194570]) patients. Results are presented for candidate lesions with a SEL score ≥0.
Results: The percentage of voxels showing T1 Gd enhancement was higher in areas of persistent T2 lesion not classified as SEL [non-SEL] (1.5%) and in new T2 lesions (8.9%), compared with regions identified as SEL (0.3%, p< 0.001 for both). Compared with non-SEL, SELs had a lower normalised T1 intensity at baseline (0.262 vs 0.069, p< 0.001) and a larger decrease in T1 intensity from baseline to week 24 (p< 0.001) and week 48 (p< 0.001). Similar qualitative differences between SELs and non-SEL were observed in RMS and PPMS populations assessed separately. Compared with RMS patients, PPMS patients had a higher mean number of SELs (6.3 vs 4.6, p=0.002) and higher mean baseline T2 volume of SELs (1,838 mm3 vs 1,223 mm3, p< 0.001).
Conclusions: SELs were shown to evolve independently of T1 Gd enhancement and demonstrated a lower T1 intensity at baseline, and a decrease in T1 intensity over time, compared with non-SEL. Although more frequently detected in PPMS patients, SELs were also identified in those with RMS. This algorithm for automatic detection of SELs on conventional brain MRI may provide a marker for chronically evolving MS lesion pathology.
Disclosure: Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Health Interactions, USA, and Articulate Science, UK.
C. Elliott is an employee of NeuroRx Research and has served on an advisory board for F. Hoffmann-La Roche Ltd.
J.S. Wolinsky has served on advisory boards, data monitoring or steering committees, has consulting agreements, or received speaker honoraria from the following entities: AbbVie, Academic CME, ACTRIMS, Alkermes, Bayer HealthCare, Biogen, Bionest, Celgene, Clene Nanomedicine, CMSC, ECTRIMS, Forward Pharma A/S, MedDay Pharmaceuticals, Novartis Pharmaceuticals, PRIME, Roche Genentech, Sanofi Genzyme, Strategic Consultants International, Takeda, Teva Pharmaceuticals and WebMD; royalties are received for outlicensed monoclonal antibodies through UTHealth from Millipore Corporation.
S.L. Hauser serves on the board of trustees for Neurona and on scientific advisory boards for Annexon, Symbiotix and Bionure; he has also received travel reimbursement and writing assistance from
F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations.
L. Kappos's institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof Kappos's activities as principal investigator and member or chair of planning and steering committees or advisory boards in trials sponsored by Actelion, Addex, Almirall, Bayer HealthCare Pharmaceuticals, CLC Behring, Genentech, Inc., GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Ono Pharma, Pfizer, Receptos,
F. Hoffmann-La Roche Ltd, Sanofi, Santhera, Siemens, Teva, UCB and XenoPort; license fees for Neurostatus products; and research grants from the Swiss MS Society, the Swiss National Research Foundation, the European Union, the Gianni Rubatto Foundation, the Novartis Research Foundation and the Roche Research Foundation.
F. Barkhof is a board member of the following publications: Brain, European Radiology, Neurology, Multiple Sclerosis Journal and Radiology; he has received consultancy fees from Bayer Schering, Biogen Idec, Teva, Merck Serono, Novartis, Roche, Synthon, Janssen Research and Genzyme; he has received grants from the Dutch MS Society (EU-FP7/H2020); he has received payments for developing educational presentations, including service on speakers' bureaus, for Biogen Idec and IXICO.
C. Bernasconi is a contractor of F. Hoffmann-La Roche Ltd.
S. Belachew is an employee and shareholder of F. Hoffmann-La Roche Ltd.
D.L. Arnold reports personal fees for consulting from Acorda, Biogen, F. Hoffmann-La Roche Ltd, MedImmune, Mitsubishi, Novartis, Receptos and Sanofi Aventis; grants from Biogen and Novartis; and an equity interest in NeuroRx Research.