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 criteria1. 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•Dosage < 2mg/kg/d

•Duration<6 mons•Absolute lymphocyte count >1500/μL

•Duration<1 or>5 mons•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 (0-

122 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

• 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

MycophenolateARR

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

RituximabARR

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 ptsAzathioprine 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– 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

MTX

MTX

MTX

cyclophos

cyclophos

cyclophos

AZA

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