Transcript Document

‫חידושים במעקב וטיפול בחולים עם‬
‫ניוירומיליטיס אופטיקה‬
‫כנס עידכון בנוירולוגיה‬
‫‪ 17‬ביוני ‪2014‬‬
‫ד"ר עדי וקנין דמבינסקי‬
‫המרכז לטרשת נפוצה‪ ,‬המחלקה לנוירולוגיה‬
‫במרכז הרפואי הדסה עין‪-‬כרם‪ ,‬ירושלים‬
‫‪May 19, 2010‬‬
Eugene Devic, 1858-1930
Devic described a monophasic illness of bilateral ON and
myelitis in quick succession (1873-1936), published in 1894.
Patient description:
Caucasian female
Age 29: Severe visual
loss with normal
brain and c-spine
MRIs
Age 30: Para paresis
and recurrent ON
Exam: no light
perception, sheetwhite optic atrophy
in one eye, No motor
disability
Anti AQP4 Abs: positive
Neuromyelitis optica
Idiopathic, severe, autoimmune demyelinating disease of the
CNS that preferentially affects the optic nerve and spinal cord.
• Devic’s disease
•Common in Africa, east Asia and Latin America
More common in women than men
a female to male ratio ranging from 3:1 in France to 10:1
in Japan
•Median age: 39
•Has been long considered as a variant of Multiple sclerosis.
Misdiagnosed patients treated as “severe” MS
Neuromyelitis opticaEpidemyology
-There are very few epidemiological studies in NMO.
-NMO prevalence is estimated between 1 to 4.4/100.000 in the
Western world.
- There are differences in the regional distribution of NMO
worldwide.
E.g. – among the cohort of idiopathic demyelinating diseases of the
CNS in Thailand, there is a high proportion of AQP4-antibody-positive
patients (39%) if compared with European and American cohorts (less
than 10%).
2006 Diagnostic Criteria for
Neuromyelitis Optica
Absolute Criteria (All Required)
1. Optic neuritis
2. Acute myelitis
supportive criteria (At least 2-3 )
1. Negative brain MRI at onset
2. Spinal cord MRI with contiguous T2-weighted
signal abnormality extending over 3 or more
vertebral segments
3. NMO IgG seropositivity
Wingerchuk, D. M. et al. Neurology 2006;66:1485-1489
Neuromyelitis optica – clinical
course
• NMO is clinically characterized by acute, severe episodes
of ON and TM.
• The majority of patients have a relapsing disease course.
• NMO-IgG seropositivity, in particular, is predictive of a
relapsing course
• NMO has usually a worse course than that of MS
• 50% of untreated will be:
• blind in one or both eyes
• ambulatory disabled (requiring a wheelchair) within 5
years of disease onset
• Morbidity in NMO patients is more directly linked to attacks
In NMO, a secondary progressive phase, as seen in MS
patients, is uncommon
Neuromyelitis optica and other
autoimmune diseases
Coexisting autoimmune diseases and autoantibodies
are frequent in patients with NMO
Non organ specific - SLE, Sjogren syndrome
Organ specific - thyroid disease, type 1 diabetes, celiac
disease and myasthenia gravis.
Antinuclear antibodies
Autoantibody markers of Sjogren’s syndrome or SLE are
found in ~47% of patients with NMOSD.
NMO-IgG was not found in patients with Sjogren’s
syndrome, or SLE, in the absence of clinical features of
NMO
Neuromyelitis optica -Imaging
Although Negative brain MRI at onset is one of the
supporting NMO criteria ,
About 60%-90 % of the patients will have brain lesions:
10% have “MS-like” brain abnormalities fulfilling
Barkof criteria for MS Five (8%).
Unique brain involvement:
• thalamic or hypothalamic lesions
• Medullery lesions
Pittock et al, Arch Neurol 2006
Neuromyelitis optica -Imaging
NMO LETM lesions often ‘fragment’ into multiple
shorter lesions
Tackley G et al. Mult Scler 2014;1352458514531087
T1-weighted MRI hypointensities within a
LETM in NMO patient.
Tackley G et al. Mult Scler 2014;
Neuromyelitis optica -Imaging
•Currently, MRI monitoring during clinical remission does not
appear to be as useful as it is in MS
•LETM remains the archetypal MRI lesion of NMO – it is the
most specific non-clinical marker for NMO
•There is no brain MRI abnormality of comparable specificity
for NMO however the absence of Dawson’s fingers and
cortical lesions are more typical to MS.
•Single longitudinal lesion sometime evolve into multiple
shorter spinal lesions. Brain stem lesion sometime resolve
•Some patients fulfil MS imaging criteria
Pathological and immunopathological findings in
neuromyelitis optica (NMO).
Jacob A et al. J Neurol Neurosurg Psychiatry
Current concept of NMO spectrum
disorders (NMOSD)
The spectrum of NMO is wider than patients with both ON and
TM.
The term, NMO spectrum disorders (NMOSD), corresponds to
restricted and typical forms of the disorder including :
•recurrent optic neuritis
•relapsing transverse myelitis
•encephalitic presentations, which are common in children.
•brainstem disorders (including intractable hiccup and nausea,
or vomiting,and hypothalamic disorders (SIADH))
Current concept of NMO spectrum
disorders (NMOSD)
In NMOSD, especially in patients with brainstem or
hypothalamic presentations (in the absence of the
opticospinal phenotype)
NMO-IgG seropositivity is crucial
Characteristics of seronegative
NMO
SERONEGATIVE SEROPOSITIVE
Gender M:F
1:1
1:9
Simultaneous
ON&Myelitis
~36%
~3%
Other AIs
+
+++
severity
+
+++
Mostly
monophasic
Mostly
relapsing
Incomplete definitions – over diagnosis of NMO
Optic neuritis and partial, short spinal lesions,
are usually not NMO even with normal brain
MRI !
Criteria should therefore include:
• LETM, Sever ON
• Unique clinical syndrome – intractable hiccups
and nausea.
• hypothalamic dysfunction - symptomatic
hypersomnia, narcolepsy, and endocrinopathies.
• blood pressure fluctuations, vasogenic edema and
posterior reversible encephalopathy syndrome.
NMO – Hadassah clinical experience
Since 1.2013 we tested 489 samples
37 were ANTI AQP4 Abs seropositive
30 CDNMO
3 were with recurrent ON
2 with LETM only
2 were pediatric NMO
Out of 280 patients (with available clinical data)
6 CDNMO were Seronegative to AQP4
Treatments of NMO-spectrum
disorders
• Due to the low disease incidence, so far no clinical
study provided evidence for the efficacy of
therapeutic regimes.
• Therapeutic outcomes of some immunological
treatments are different between NMO and MS,
making early differential diagnosis of these two
disorders crucial
• IFNs, Natalizumab and M/P Fingolimod exacerbate
NMO
Treatments of NMOSD
treating the acute relapse
Treating ASAP is crucial !
• IV high dose Steroids
• Plasmapheresis
• IVIG
Treatments of NMO/NMOSDpreventive therapy
Steroids (monthly courses or oral)
Immunosuppressants (Azathioprine mainly; also
MTX, Celcept, and cyclophosphamide)
Rituximab
Monthly Plasmapheresis ?
Treatments of NMO/NMOSDpreventive therapy
Targeting B-cells B-cell targeting therapies:
Rituximab
Ocrelizumab
Ofatumumab
Rituximab: Anti-CD20
Target
CD-20 receptor
Other names
Mabthera Rituxan, and Zytux
Rationale
B cells involvement in autoimmune diseases –
antibody mediated , B cells role as APCs and
cytokine production
Mode of action
The antibody binds to CD20 expressed on B cells, from early pre-B
cells to later in differentiation, but absent on terminally differentiated
plasma cells. eliminates nearly all CD20-expressing B cells by
complement-dependent cytotoxicity (CDC) and ADCC as
well as induction of apoptosis
Safety and
tolerability
28
Severe infusion reaction, cardiac arrest, Infections – PML.
resistance development, most likely due to less efficient antibodydependent cytotoxicity or to generation of human antichimeric
antibodies (HACA). In the last years, newer generations of
“humanized” anti-CD20 antibodies have been generated in order to
reduce infusion-related side effects and the risk of HACA
development
humanized anti-CD20 antibodies
Ocrelizumab
Ocrelizumab (Roche) is a second-generation humanized anti-CD20
antibody that binds to a different but overlapping epitope compared to
rituximab. As it depletes B cells predo- minantly via ADCC, it is considered
to exhibit an improved efficacy profile combined with reduced infusionrelated reactions .
Ofatumumab
Ofatumumab (HuMax-CD20, Arzerra! [Genmab A/S and GlaxoSmithKline])
is a fully humanized anti-CD20 antibody binding to a completely distinct
epitope, which results in pro- nounced complement-mediated cytotoxicity
Therapy that targets complement
Complement mediated damage has been
demonstrated both in the brain and spinal cord of
NMO patients. Complement bind to the NMOantibody complex inducing membrane-attackcomplex damage and reducing the numbers of aqp4
channels.
Therapy that targets complement
• A study in 14 NMO patients performed at the Mayo Clinic.
A total of 40 attacks in all patients in the last year before study.
During treatment, only two patients had slight relapses, 12 patients
were completely relapse-free.
• The median EDSS score declined from 4.3 to 3.5.
• Despite immunization of all participants with tetravalent
meningococcal vaccine, one patient developed meningococcal
sepsis, from which he completely recovered and resumed treatment
with eculizumab.
• Eculizumab might be a very effective therapy for patients
with highly active NMO.
• Currently, there is an ongoing 12 months Phase I/II study
in NMO-Ig-positive patients (NCT00904826).
The role of B-cell activating factor
(BAFF) in myasthenia gravis
•B-cell activating factor (BAFF) is important in the
differentiation and maturation of B cells and plasma cells.
•BAFF may play a significant role in the immune process
involved in NMO.
•CSF BAFF levels were found to be significantly higher in
NMO patients
Vaknin-Dembinsky MSJ 2010
Belimumab : Anti-BAFF
Target
BAFF
Other names
Anti-BAFF
Rationale
BAFF- is important in the differentiation and
maturation of B cells and plasma cells
Mode of action
inhibits BAFF action via binding circulating BAFF and
reducing the number of circulating B-cells but not to
the extent as rituximab
Safety and
tolerability
approved in the US, Canada and Europe for the treatment
of systemic lupus erythematosis
34
Monoclonal antibodies targeting
cytokines
Anti IL-6 antibodies
Anti IL-17 antibodies
Future directions: anti-IL-6 antibodies
• The rationale for employing an IL-6 targeting
strategy in NMO is based on the observations that
i) NMO patients exhibit significantly elevated IL-6
levels in serum and CSF
ii) IL-6 signaling promotes AQP4-autoantibody
production in NMO
• Recently, one group reported that three rituximabrefractory patients with NMO responded to a
therapy with tocilizumab (Actemra®), a mAb
against IL-6, which is FDA-approved for treatment
of refractory RA
Anti IL-17 antibodies
• The rationale for employing an IL-17 targeting
strategy in NMO is based on the observations that
i) T cells derived from NMO patients exhibit Th-17
phenotype (Vaknin-Dembinsky et al Neurology 2012)
ii) IL-17 is increased in animal models with NMO
pathology
• a mAb against IL-17, is currently tested for
treatment of refractory RA, psoriasis.
Anti IL-17 antibodies
Anti IL-17 antibodies
Secukinumab - a human antibody that neutralizes IL-17A. TH17
cells are highly involved in the pathogenesis of T-cell-mediated
autoimmunity,
This antibody already demonstrated promising results in a Phase II
trial of psoriasis patients but failed in RA patients.
Ixekizumab- humanized IL-17A-neutralizing antibody has recently
proven effective in a Phase II trial for treatment of psoriasis.
Currently being tested in RA and ankylosing spondylitis.
Future and NMO specific strategies
Recent experimental strategies, which showed some
beneficial effect in animal models in vitro and in vivo
•Aquaporumab – a competitive, non-pathogenic AQP4specific antibodies
•Sivelestat -Neutrophil elastase inhibitors
•Antihistamines with eosinophil-stabilizing actions
• Enzymatic AQP4-IgG deglycosylation or cleavage
Neuromyelitis optica (NMO)
Take home massages :
1. NMO is a devastating disease that cause
demyelination, necrosis of optic nerves and
spinal cord
2. Associated with systemic and organ specific
autoimmune disease (Lupus , Sjögren's
syndrome, MG, Celiac etc).
3. Significant residua common
4. Anti AQP4 Abs should be tested in all patients
presenting with NMO symptoms (optic neuritis
and/or myelitis) as well in malignant MS (With
or without other autoimmune diseases,with
neoplasia,with atypical ADEM, with unique
symptoms - intractable hiccups or vomiting,
symptomatic narcolepsy, olfactory dysfunction
and neuroendocrine dysfunctions)
Neuromyelitis optica (NMO)
Take home massages :
•
•
•
•
•
Treatment in the acute relapse should be stated
immediately!
Preventive therapy in the majority of patients is with
steroids and other immunosuppressant medications
(AZA,MTX)
There is sufficient data to include RITUXIMAB to
prevent disease relapse in NMO patients with moderate
or severe disease.
Other monoclonal antibodies that might have beneficial
effect: humanized anti CD20, anti complement, anti
BAFF, ant-IL-6,17
Newer approaches: Aquaporumab, enzymatic AQP4IgG deglycosylation or cleavage, Neutrophil elastase
inhibitors, Antihistamines with eosinophil-stabilizing
actions
Neuromyelitis optica (NMO)
Unanswered questions :
•
•
•
•
•
•
What is the pathogenesis of NMO seronegative?
What causing AQP-4 Abs to enter the brain?
When and if we can stop therapy with RITUXIMAB
Do AQP-4 Abs causing damage in peripheral organs?
What is the role of astrocytes in the pathogenesis of
NMO?
What is the role of AQP4 specific T cells in the
pathogenesis of NMO?
Thank you!