Neuromyelitis Optica
Celia Oreja-Guevara, Hospital Clinico San Carlos, Spain
Andrew Chan, Ruhr-University Bochum, Germany
Patrick Vermersch, University of Lille, France
www.paradigms.foundation
NeuroMyelitis Optica
Devic, 1894:
• 45-year-old patient with paraplegia and simultaneous amaurosis
• Demyelination and necrosis: optic nerves, spinal cord
Lennon 2004:
• Characterization of NMO-IgG, antigen: aquaporin IV (AQP4), pathogenetically relevant
Miyazawa I, et al. J Neurol. 2002;249:351-352. Lennon VA, et al. Lancet. 2004;364:2106-2112. 2
Aquaporin IV
3 6/26/2020
A serum autoantibody marker of neuromyelitis optica
Lennon
2004 4 6/26/2020
et al.,
Papadopoulos, M. C. et al. (2014)
Increase of glutamate release
BBB disruption
Down regulation of GLT1
Impaired astrocytic uptake of glutamate, oligodendrocyte injury and demyelination
Reduced Kir 4.1 expression: Impair efflux of K at the astrocytic end feet, impairment of coupling synaptic activity and cerebral blood flow
AQP4 co-localization
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Benarroch 2007, Nagelhus et al., 1999, Zeng et al., 2006, Marignier et al., 2010
.
F:M 10:1 (AQP4-positive NMO)
• Older presentation (34-43 years) than MS
• Very late onset possible
•
30% with other autoimmune diseases
•
3% NMO patients with NMO-relatives
• East Asian/African population
• Severe relapses
• Rare: chronic progressive cases
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Epidemiology
•
“Classical” phenotype
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AQP4-Ab: monophasic or recurrent isolated ON (RION), brainstem encephalitis
Brainstem manifestations: intractable hiccups or vomiting, symptomatic narcolepsy, and neuroendocrine dysfunctions
Posterior reversible encephalopathy syndrome
In children (and sometimes in adults): broader spectrum of encephalitic manifestations (seizures)
Spectrum
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NMO
Disorder
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•
•
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NMO-Spectrum Disorders (NMOSD)
1. NMO
2. Limited forms of NMO: - LETM: Longitudinal extensive transverse myelitis
- rON: relapsing bilateral optic neuritis
3. Opticospinal MS (Asia)
4. rON or LETM with systemic autoimmunity
5. „Cerebral“ NMO with lesions at typical topography, with/without rON/LETM
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Optic chiasm
-
Hypothalamus
-
3./4. Ventricle
-
Brainstem / Area postrema
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•
• Area postrema,
• Brainstem lesions
Dorsal medulla,
Wingerchuk, Neurology 2015 . 11 6/26/2020
Brainstem manifestations of NMO
Kremer et al., Mult Scler 2013
Intractable hiccups
✓ 8/47 (17 %) patients NMO (0/130 MS)
✓ Duration > 48 h (66 %) and/or nausea (80 %)
✓ Before a relapse in 54 %, during a relapse in 29 %
✓ Sometimes isolated and first symptom
✓ Medulla oblongata lesions (47%) +/- extensive myelitis (80 %)
Misu et al., Neurology 2005; Takahashi et al., J Neurol Neurosurg Psychiatry 2008
Area postrema
Intractable vomiting
✓ 12 patients AQP4-Ab+ with intractable vomiting (median 4 weeks)
✓ Followed by ON or acute transverse myelitis (NMO diagnosis in 7 cases)
✓ Area postrema lesions in MRI or at autopsy
al., Ann
2010
Apiwattanakul et
Neurol
Neuropathic pruritus
✓ 12/44 patients (27 %)
✓ Lesions frequently in the superior part of the cervical SC
✓ SC / brainstem
Elsone et al., Mult Scler J 2012
Corticospinal
ADEM/PRES
16
Corpus callosum
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Pencil sign Hodel and Vermersch, in press 2016.
Diencephalic lesions
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Hypothalamus lesion
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Linear involvement of corpus callosum
2016. 20 6/26/2020
Cloud-like enhancement
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Atypical cerebral white matter lesions
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NMO: visual parameters and outcomes
Microcystic macular oedema
MRI lesions
comparing with MS: More extended bilateral Chiasma
Comparing with MS: bilateral, VA lower, OCT lesions more severe (RNFL, GCL)
MSJ
Wingerchuck et al., Neurology 2015 Kim et al., Neurology 2015; ²Kremer et al., JAMA Neurol 2015; 3Bennett et al., Mult Scler 2015 23 6/26/2020
Hadhoum et al.,
2015,
Oertel. 2018 . 24 6/26/2020
NMO: French cohort
Collongues et al., Neurology 2010 25 6/26/2020
NMO cohorts
Papais-Alvarenga et al., J Neurol Neurosurg Psychiatry 2002; Wingerchuk et al., Neurology 2003; Ghezzi et al., J Neurol 2004; Cabre et al., J Neurol Neurosurg Psychiatry. 2009; Collongues et al., Neurology 2010 . 26 6/26/2020 Papais-Alvarenga et al., 2002 Wingerchuk et al., 2003 Ghezzi et al., 2004 Cabre et al., 2009 Collongues et al., 2010 Diagnostic criteria Kira 1999 1999 Various 2006 N= 24 80 46 96 125 Follow-up (mean) 7.7 7.6 8,8 10.2 10 Age of onset 32 38 35 29.5 34 Sexe Ratio F/M 5/1 2.5/1 4/1 11/1 3/1 First location (%) Spinal cord ON Both 37.5 33.3 29.212.5 39.1 56.6 4.3 31.2 50 18.8 46.9 37.5 15.6 NMO-IgG (%) - - - 32 55 Interval R1-R2 (mean/median) -/- -/- 1.4/- 2.3/1 2.4/1 Delay optico- spinal (mean/median) 3.9/1.3 - - 2.9/2 2.9/1.2
NMO cohorts
Papais-Alvarenga et al., J Neurol Neurosurg Psychiatry 2002; Wingerchuk et al., Neurology 2003; Ghezzi et al., J Neurol 2004; Cabre et al., J Neurol Neurosurg Psychiatry. 2009; Collongues et al., Neurology 2010 . 27 6/26/2020 PapaisAlvarenga et al., 2002 Wingerchuk et al., 2003 Ghezzi et al., 2004 Cabre et al., 2009 Collongues et al., 2010 EDSS 3 (median) EDSS 6 EDSS 8--0.5 71 8 229Number of deaths (%) 6 (25) 18 (22.5) 6 (13) 24 (25) 3 (2.3) Annualized relapse rate 1.19 - 1.3 0.95 0.94
Bourre et al., Neurology 2012
NMO and pregnancy
Pediatric NMO
Collongues et al., Neurology 2010 29 6/26/2020
Pediatric NMO
58 patients < 18 years old, AQP4-Ab + Brain lesions > 30 %
Pseudo-ADEM
Peri-aqueduccal
Cortico-spinal tracts
McKeon et al., Neurology 2008 . 30 6/26/2020
Revised diagnostic criteria 2015
Wingerchuk et al., Neurology 2015 . 31 6/26/2020
Wingerchuk et al., Neurology 2015 32 6/26/2020
NMOSD according to 2015 criteria
NMO associted with other systemic inflammatory disorders
Classical NMO AQP-4 + Spectrum NMO AQP-4 + (others) NMO AQP-4 –(20 - 40 %) Monophasic NMO
Differential diagnosis
• Bilateral severe optic neuritis, altitudinal defects
− MRI: longer lesions, optic chiasm; OCT: more widespread atrophy
• Brain lesions: up to 60%
−
Cave: Barkhof criteria 10-42%, no cortical lesions
CSF − >50/ml WBC, neutrophils/eosinophils >5/ml, 10-25% OCB (fluctuating), (GFAP, IL6)
• Severe Myelitis, subacute (not peracute/chronic)
−
Cave: 2-3% of MS LETM, 7-14% of NMO initially short lesions
Wingerchuk et al., Neurology 2015 34 6/26/2020
NMO vs. MS
•
Juryncik et al., JNNP 2015 . 35 6/26/2020
Differential diagnosis NMO vs. MS
differences NMO vs. MS 36 6/26/2020
Immunopathological
NMOSD without anti-AQP-4 ab
NMO without anti-AQP-4 ab: 20 - 40 % of NMO patients
Among theses 20-40%: Anti-MOG ab is detected in 20%
MOG
unknown
80%: no antibodies detected
NMO with anti-MOG+
Compared with NMO anti-AQP4+, NMO anti-MOG :
▪Are younger
▪First relapse more often multifocal
▪Better outcomes after relapses
Kitley et al., JAMA Neurol 2014
NMO with anti-MOG+
Sato et al., Neurology 2014
NMO with anti-MOG+
Comparing with NMO anti-AQP-4+, NMO anti-MOG :
▪ Fewer relapses
▪ First relapse more frequently monofocal
▪ Better outcomes
Sato et al.,
2014
Neurology
RED FLAGS
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TREATMENT
Relapses
Drugs to avoid
Relapses prevention: off-label treatments
New treatments
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•
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Treatment of NMO relapses
High doses IV steroids
➢ Methylprednisolone : 3-10 g/d 3-5 days
➢ Steroid oral tapering : 1 mg/kg/day 10 days-1 month (??)
Plasma exchange (Plex)
➢Severe, worsening or corticosteroid-refractory acute attack
➢5-7 times in alternative days
IVIg
Other options: cetirizine, bevacizumab
1Weishenker et al., Ann Neurol 1999; ²Elsone et al. Mult Scler 2013, Kleiter et al, Ann Neurol 2016
TREATMENT: Drugs to avoid
- Standard MS therapies are ineffective for NMO
- NMO worsening was reported with :
natalizumab
fingolimod
alemtuzumab
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•
•
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aggravate NMO
Interferon beta may
Kleiter for NEMOS, Arch Neurol 2012
Natalizumab
Natalizumab exacerbates NMO
Jacob et al., Neurology 2012
Min et al., Mult Scler 2012
2 Weeks Fingolimod
Gelffand et al., Neurol Neuroimmunol Neuroinflamm 2014
NMO: off-label used treatments
DMDs: Immunosuppressants versus immunomodulators
Immunosuppressants better than immunomodulators in NMO
Papeix et al., Mult Scler 2007
Traitements de fond Immunosuppressants
Escalate strategy? When ?
Induction strategy
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•
Which ?
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Azathioprine
Costanzi et al., Neurology 2011
Costanzi et al., Neurology 2011
Azathioprine
Mycophenolate
Jacob et al., Arch Neurol 2009
Mofetil
Cabre et al., J Neurol Neurosurg Psychiatry. 2013
Mitoxantrone
Jacob et al., Arch Neurol 2008
Rituximab
➢ Rituximab is effective
Rituximab (II)
➢ Used in first line : 84.3 % of patients realpse-free, used in second line: 52.3 % relapse-free
Zéphir et al., J Neurol 2015; Collongues et al., Multi Scler 2015
➢ Rituximab is effective
Rituximab (III)
➢ Frequent dose: 1 gr iv x 2 , 2 weeks apart
➢ Duration of effect: 6-10 months
➢ Re-treatment timed: ➢ Scheduled: 1 infusion every 6 months
➢ Retreat when CD19> 1% of total lymphocytes
➢ Retreat if CD27>0.05%
➢ Increased infections associated with IgG decrease
Zéphir et al., J Neurol 2015; Collongues et al., Multi Scler 2015
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NEW TREATMENTS
Approved: Eculizumab
Not yet approved (clinical trials are finished) :
Satralizumab
Inebilizumab
Other treatments:
Tocilizumab
>Bortezomib
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NMO CLINICAL TRIALS PHASE III
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It is an anti-C5 monoclonal antibody
Prevents MAC Inhibits C5a generation
Eculizumab Pittock et al., The Lancet 2013
Eculizumab Pittock et al., The Lancet 2013
Eculizumab: phase 3, randomized, double-blind, time-toevent trial
Pittock et al., NEJM 2019
Median time to first adjudicated relapse: not reached (eculizumab) vs. 103 weeks (placebo)
Note: data were censored at end of patient’s time in trial (after a “negatively adjudicated” physician-determined relapse and after discontinuation from trial)
This figure has been adapted for the purposes of this presentation. Copyright is held by The New England Journal of Medicine. CI, confidence interval.
67 Time since randomization (weeks) Patients free from relapse (%) 100 80 60 40 20 0 90 70 50 30 10 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 211 97.9% 96.4% 96.4% 63.2% 51.9% 45.4% 96 (2:1) 92 (2:1) 83 (3:1) 78 (3:1) 68 (3:1) 60 (4:1) 58 (4:1) 52 (5:1) 46 (5:1) 41 (7:1) 32 (6:1) 24 (5:1) 22 (5:1) 18 (6:1) 14 (5:1) 8 (2:1) 2 1 47 38 30 24 21 16 13 10 9 6 5 5 4 3 3 3 3 1 Number at risk (eculizumab:placebo ratio) Placebo Eculizumab
Primary endpoint: significantly reduced risk of adjudicated relapses for eculizumab vs. placebo
Hazard ratio for relapse, 0.06 (95% CI, 0.02 to 0.20); p < 0.001 Eculizumab Placebo Censored data
PREVENT core trial published in Pittock et al. N Engl J Med 2019; doi:10.1056/NEJMoa1900866. Pittock et al., NEJM 2019
Eculizumab Pittock et al., NEJM 2019
Eculizumab Pittock et al., NEJM 2019
Inebilizumab: anti-cd19 Therapy
Pittock et al., NEJM 2019
Inebilizumab: anti-cd19 Therapy
Cree, 2019
Is IL-6R Blockade an Option for NMO?
• IL-6 is elevated during NMO relapses in serum and CSF
• T cells and monocytes from NMO patients produce IL-6
• IL-6 activates plasmablasts to produce anti-AQP4 antibodies
• Anti-CD20 Abs do not target PBs/cells
• Inhibition of the IL-6R in vitro reduces survival of PBs
Chihara. PNAS. 2011, Varrin-Doyer M, et al. Ann Neurol. 2012;72:53-64., Linhares UC, et al. J Clin Immunol. 2013;33:179-189., Icöz S, et al. Int J Neurosci. 2010;120:71-75., Uzawa A, et al. Mult Scler. 2010;16:1443-1452. . 73
SA237 - Anti-IL-6R monoclonal antibody
➢SA237 is designed to improve pharmacokinetics (PK) by applying “Antibody Recycling technology”
Conventional antibody recycling antibody
Recycling technology
74
Nature Biotechnology, 28, 1203-1207
Tocilizumab
(2010)
IL-6R lysosome cell Bind (pH7.4) Dissociate (pH5.5~6.0)
SA237
SA237 Vs TCZ – Plasma half-life (Phase I single dose study in HV)
Minimum effective concentration = 1mg/mL
(n=12 each)
75
76
77
78
Tocilizumab
JAMA Neurol in press
in NMO Ringelstein,...Chan..., et al.
(Also Araki et al., Neurology 2014)
Treatment algorithm: ?? No guidelines, no consensus…
Tocilizumab
Eculizumab
Therapeutic trials
Mitoxantrone
Cyclophosphamide
Rituximab + steroids
Mild: Aza, MMF (± low dose prednisone)
Severe: Rituximab
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Summary
•Rapidly evolving field, clinically/scientifically
•Complex but reliable diagnostic criteria
•Studies difficult (logistics, ethics, methodology): high likelihood to fail
•High unmet need
•Very close to “translation”
•Major implications for understanding of more common disease multiple sclerosis
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