Journal club
26-11-2014
What is NMO ?
Neuromyelitis opitic
•
•
•
•
Inflammatory demyelinating disease
Central nervous system (CNS)
Distinct from multiple sclerosis (MS)
Character
Optic neuritis (ON)
Longitudinally extensive transverse myelitis (TM)
Neuromyelitis opitic
AQP4-IgG (NMO IgG)
Neuromyelitis optica
Neuromyelitis opitic
Neuromyelitis opitic
JAMA Neurology March 2014 Volume 71, Number 3
IMPORTANCE
• Neuromyelitis optica (NMO) can leads to
blindness and paralysis.
• Effective immunosuppression is the standard of
care for relapse prevention
OBJECTIVE
• To compare the relapse and treatment failure
rates among 3 most common forms of
immunosuppression (IS) for NMO :
1. Azathioprine
2. Mycophenolate mofetil
3. Rituximab
DESIGN, SETTING, AND PARTICIPANTS
• Retrospective, multicenter analysis
• N =90 pts (NMO and NMOSD)
• Treated with azathioprine, mycophenolate,
and/or rituximab
• Mayo Clinic & Johns Hopkins Hospital
• Time = past 10 yrs
MAIN OUTCOME AND MEASURE
• Annualized relapse rates.
Introduction
• Neuromyelitis optica (NMO) = inflammatory
demyelinating disease of the central nervous
system (CNS)
• distinct from multiple sclerosis (MS).
• It is characterized by
• optic neuritis (ON),
• longitudinally extensive transverse myelitis (TM),
• approximately 70% of cases, the presence in
serum of IgG antibodies that target aquaporin 4
(AQP4-IgG; also known as NMO-IgG).
Introduction
• Neuromyelitis optica spectrum disorder
–
–
–
–
Seropositive for AQP4-IgG and evidence of
TM, or
ON, or
Brainstem inflammation
• Some immunomodulatory therapies used for MS
appear to aggravate NMO.
Introduction
• No placebo-controlled or comparative
randomized controlled trials of IS
• No consensus on how to select initial therapy
• Evidence that azathioprine, mycophenolate
mofetil, and rituximab are effective in reducing
relapse rates
• Retrospective study was conducted.
Methods
• Inclusion criteria
1. who diagnosed as having NMO based on the 2006
revised NMO criteria
Methods
2. NMOSD = TM,ON,or brainstem inflammation +
serum AQP4-IgG
3. On azathioprine/mycophenolate x 6 mons or
rituximab x 1 mon
*** prior immunomodulatory : glatiramer acetate,β
interferons, prednisone,HCQ >>> OK
Methods
• Exclusion criteria
1. Exposure to another IS : cyclophosphamide,
methotrexate, mitoxantrone
2. Receiving > 1 medications
Methods
• Medication failure = new inflammatory CNS
event that occurred despite IS treatment
• Relapses = new CNS symptoms and signs > 24
hours (with/without a new lesion on gadolinium
enhancing MRI)
Methods
• Medication regimens
– Optimal
– Suboptimal
***based on dosing and duration of treatment***
• Divide treatment failures into those that occur
because of insufficient treatment and those that
occur despite optimal medication use.
Suboptimal treatment
Azathioprine
mycophenolate rituximab
•Duration < 6 mons
•Duration<6 mons
•Duration<1 or>5
•Dosage < 2mg/kg/d •Absolute lymphocyte mons
count >1500/μL
•Presence of CD19
cells in circulation
(>0.1% of total
lymphocytes)
Methods
• Annualized relapse rates (ARRs) >>> number of
relapses/year
• Relapses analized :
– 40 mons before therapy
– Duration of the time undergoing therapy
• Cox regression analysis : 1st relapse-free
survival & repeated relapse survival
• P < .05
• SAS statistical software, version 9.3 (SAS
Institute Inc).
Results
Results
•
•
•
•
•
N = 90 (NMO = NMOSD)
Azathioprine = 32
Mycophenolate = 28
Rituximab = 30
No difference pretreatment relapse risk btw 3
treatments
Results
• 18 pts primary therapy failed were switched to
another treatment
♥
♥
♥
♥
4 pts : azathioprine → mycophenolate
4 pts : azathioprine → rituximab
4 pts : rituximab → mycophenolate
6 pts : mycophenolate → rituximab
Azathioprine
•
•
•
•
N = 32
NMO 72% , NMOSD 28%
Initial dosage 2 to 3 mg/kg/d
+ prednisone 5-60 mg x median duration of 6 mons (0122 mons)
• 17 pts (53%) had at least 1 relapse(total of 43)
• Median duration 23.5 mons (7-148mons)
• The ARR (reduction of 72.1% ,P = .004)
– Before therapy 2.26
– After therapy 0.63
• 9/17 pts relapsed despite concurrent prednisone
Azathioprine
ARR
before
= 2.26
ARR
after =
0.63
Mycophenolate
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•
•
•
•
•
•
N = 28
NMO 64%, NMOSD 36%).
Initial Dose 1000-2000mg/d and titrated
10 pts (36%) had at least 1 relapse (total of 23)
18 pts (64%) relapse free
Median duration 26 mons (6-86mons)
The ARR (reduction of 87.4%)
– Before therapy 2.61
– After therapy 0.33
Mycophenolate
• 7/10 pts (25%) had at least 1 relapse despite
optimal dose
• The ARR for patients receiving optimal dose
– Decreased 2.55 >>> 0.25
– Reduction of 90.2%(P < .001)
• 13 pts cotreated with prednisone, starting at
initiation of therapy 15–40 mg
• 6 pts relapsed despite concurrent prednisone
Mycophenolate
Mycophenolate
ARR
before
= 2.61
ARR
after =
0.33
Rituximab
• N = 30
• NMO 63% , NMOSD 37%
• Rituximab 1000mg IV + premedication
Methylprednisolone 100 mg
• Repeat 2 wks later
• CD19 cell counts monthly
Rituximab
•
•
•
•
10 pts (33%)had at least 1 relapse (total 13)
20 pts (67%) relapse free
Median duration 20 mons (5-83mons)
The ARR (reduction 88.6% p=0.04)
– Before therapy 2.89
– After therapy 0.33
Rituximab
• 5 pts (17%) had 1 relapse despite optimal dose
• The ARR for patients receiving optimal dose
– Decreased 3.25 >>> 0.20
– Reduction of 93.9 %(P =.02)
• Rituximab VS Azathioprine therapy in NMO
increases the risk of relapse > 2-fold
• Efficacy with Mycophenolate ≈ Rituximab
Rituximab
ARR
before
= 2.89
ARR
after =
0.33
Switched Treatments
• N = 18 pts treatment failure
• NMO 78% NMOSD 22%
♥ 1 pt azathioprine → mycophenolate (concerns of rare
cancer risk)
♥ 4/18 pts (22%) 2 therapies failed
 Mycophenolate and rituximab = 3 pts
 Azathioprine and rituximab = 1 pt
• The ARR reduction 86.4% but did not meet statistical
significance (p=0.54)
– 40 mons before switching = 1.03
– After median duration therapy 20months (6-97mons)
= 0.14
Interpretation
• Since 1998 there are treatment studies in NMO
have been published
–
–
–
–
–
–
Azathioprine
Mycophenolate
Rituximab
Methotrexate
Corticosteroids
Mitoxantrone
• All IS shown some benefit in reducing relapse
rates in NMO
Interpretation
• Comparative analysis 3 most widely used NMO
treatments in the United States (azathioprine,
mycophenolate, and rituximab)
– Reduction in relapse
– Treatment failure rates
– Beneficial effects of optimal dosing
• Similar to previous studies →reduction in
relapse rates in NMO patients with all 3 IS.
Interpretation
• Azathioprine
♥
♥
♥
♥
Reduct relapse rate of 72.1%
Mycophenolate 90.2% and rituximab 97.9%
Azathioprine tx carries a higher risk of relapse
Failure rate 53%, significantly higher compared with
mycophenolate (failure rate of 25%) and rituximab
(failure rate of 17)
Interpretation
• Azathioprine
• Costanzi et al
♥
♥
♥
♥
Relapses rate 66%
22% of patients discontinued use of the medication
3% developed lymphomas
Azathioprine has additional safety risks and
tolerability concerns
• Concurrent prednisone → adverse effects :
– Hypertension, hyperglycemia, mood disturbances,
glaucoma, and bone density loss
Interpretation
• Rituximab
♥ Effective treatment option
♥ Greatest reduction in relapse rate and lowest failure
rate
♥ Close monitoring of CD19 and CD20 cell counts
♥ Failure rate only 17%
♥ Infusion-related reactions are routinely managed with
methylprednisolone
♥ Other adverse effects rare
♥ Risk of progressive multifocal leukoencephalopathy is
1:25 000
♥ No pt has yet developed progressive multifocal
leukoencephalopathy.
Interpretation
• Mycophenolate
♥ Effective treatment option
♥ Close monitoring of lymphocyte counts to achieve
suppression of <15 000/μL
♥ Failure rate 25%
♥ Mycophenolate tx fails tend to relapse often → if
mycophenolate fails should be switched to another
medication as soon as possible
♥ Concurrent prednisone is recommended x first 6
mons → Adding risks of prolonged corticosteroid
therapy
Conclusions
• Switch IS : generally responded well to second
therapy
• 2 txs failed in only 4 pts (3 pts mycophenolate +
rituximab)
• Additional options : cyclophosphamide
methotrexate, eculizumab, aC5a
complementinhibitor.
• Phase 3 trial of eculizumab for whom standard
therapy fails.
Conclusions
• This study is limited
– Biases inherent to retrospective study design
– Between mycophenolate and rituximab, there were
other biases
Published: 15 March 2014
Background
• Neuromyelitis Optica (NMO) = severe demyelinating
inflammatory dz of the CNS
• Recurrent of myelitis and optic neuritis
• Requires long-term tx with IS
Background
• Pathogenesis
• Evidence suggests aquaporin 4-antibodies (AQP4-ab)
are primarily disease pathogenesis
• AQP4-IgG (NMO IgG)
–
–
–
–
Predominantly IgG1
Activating complement
Blood brain barrier disruption
Destruction astrocytic memb
• Recently interleukin 6 (IL-6) plays a critical role in the
pathogenesis
Background
• Jacob A. et al. 2008
– Rituximab
– Retrospective studies, 14/25 (56%) relapse free
– Median follow up of 19 mons
• Costanzi C. et al. 2011
– Azathioprine
– 37/99 (37%) relapse free
– Median follow up of 24 mons
• Jacob A. et al. 2009
– Mycophenolate mofetile
– 14/24 (58%) relapse free
– Median follow up of 28 mons
Background
• Pittock et al. 2013
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–
–
–
–
Eculizumab
Humanized monoclonal IgG
neutralizes complement protein C5
relapse free state in 12/14
period of 12 months
• Kieseier BC et al. 2013
– Tocilizumab
– Humanized monoclonal antibody directed against the
IL-6 receptor
– Improvement EDSS scores
Background
• Minimal data exists on methotrexate as a long-term
treatment for NMO and NMOSD
• Mechanisms of action of methotrexate
– Inhibition of purine metabolism,
– Interference with interleukin-1 beta binding to interleukin-1
receptors and
– Interference with T-cell adhesion
• NMO/NMOSD pts will likely need many years of IS
• Long-term safety record of methotrexate
• Overview 9 pts NMO/NMOSD tx with methotrexate
Methods
• Retrospective analysis
• Allegheny General Hospital
• All patients
– NMO : 2006 diagnostic criteria
– NMOSD : one or more attacks of optic neuritis only, or
transverse myelitis only + NMO-IgG seropositive
• Tx with methotrexate 2000 – 2012
Methods
• Record
– 1) demographics
– 2) baseline clinical information
– 3) treatment details (use of MTX during remission and
relapse, timing of MTX initiation, concomitant
corticosteroids, CBC, LFT, adverse effects, timing and
reasons for discontinuation)
– 4) clinical course to last follow-up
• Paired sample 2 tailed t test : annualized relapse
rate during 18 mons pre tx Vs 18 mons post tx
Results
• Median follow 62 mons (Ẋ= 82.89, SD = 43.779)
• Duration Tx with MTX median 29 mons (Ẋ = 40
mons, SD = 20.005)
• 2 pts (22%) presented with optic neuritis
• 7 pts (78%) presented with myelitis
• 4 pts (57%) of the myelitis = NMOSD throughout
follow up (no optic neuritis)
Result
• Initial attacks or relapses
– High-dose corticosteroids intravenously and/or
– Plasmapheresis
• Cont low-dose corticosteroids (5–10 mg per day)
throughout tx period
• Initial MTX dosage 7.5 mg/wk titration up to max
17.5 mg/wk
Result
• Pulse methylprednisolone 500 mg IV twice daily
for relapses
• Weaning protocol
– oral prednisolone 30- 60 mg/d x 4–6 wks
– 20–30 mg/d x 4–6 wks
– 10–20 mg/d x 4–6 wks
• then maintained on low dose prednisone 5–10
mg/d long term (at least 6 months)
Result
• Relapses = clinical deterioration of baseline
symptoms or appearance of new symptoms with
change in EDSS
• 5 pts started on methotrexate
• 3 pts started on pulse cyclophosphamide (700
mg/m2/mon) x 6 mons
• 1 pt started on azathioprine
Result
• Pt continued on MTX for their entire follow up =
6/9 (67%)
• Responded to treatment = 5 (stable or improve)
– Stable EDSS = 3
– Improve EDSS = 2
• 1 elderly pt worsening
Result
• 5/9 pt : TM+ON
• 2 pts had visual FSS (functional system scores)
= 5 pre & post MTX
• 2 pts had visual FSS of 0
• 1 pt had visual FSS of 1
• no change in visual subscores post MTX
Result
• 2 pts relapses free
• 3 pts had 2 relapses each (relapses being easily
managed with full recovery)
• 3 pts (33.33%) tx failures (multiple relapses ≥ 3)
– methotrexate → rituximab resulting in stabilization
Result
• No any signs or symptoms of toxicity (CBC
&LFT q 8–12 wks)
• Average annualized relapse rate
– 18 mons prior Tx =3.11
– 18 mons after Tx = 1.11
• p = .009
MTX
MTX
cyclophos
MTX
AZA
cyclophos
MTX
MTX
cyclophos
Discussion
• Scientifically weak
• Significant selection bias
• Limitations of EDSS as an assessment tool in
NMO
• Individual cases in series can give clinicians
insight into patterns of relapse and progression
seen in NMO.
Discussion
• pts with severe onset → IS which reported
success in reducing relapses
• pts with mild onset → initial MTX (excellent
safety profile)
• “step down” therapy
• Elderly patients
Discussion
• MTX has an excellent safety profile.
• Safety data for long-term use of mycophenolate
mofetile, azathioprine, and rituximab : inferior or
less robust
Discussion
• Other cohort studies : rituximab may be a
particularly effective 1st-or 2nd-line agent for
NMO/NMOSD
• Use of rituximab for treatment failure →
stabilization
• Head to head trials of rituximab versus other IS
are deemed to be difficult
• However, controlled trials are needed
Conclusion
• Methotrexate is a safe single IS therapy along
with low dose corticosteroids
• Possibly be used efficaciously for long-term
management