1. Journal club

3. What is NMO ?

4. Neuromyelitis opitic Inflammatory demyelinating disease
Central nervous system (CNS)
Distinct from multiple sclerosis (MS)
Character
Optic neuritis (ON)
Longitudinally extensive transverse myelitis (TM)

5. Neuromyelitis opitic
AQP4-IgG (NMO IgG)

6. Neuromyelitis optica

7. Neuromyelitis opitic

8. Neuromyelitis opitic

9. Neuromyelitis opitic

10. Neuromyelitis opitic

11. Neuromyelitis opitic

12. JAMA Neurology March 2014 Volume 71, Number 3

13. IMPORTANCE
Neuromyelitis optica (NMO) can leads to blindness and paralysis.
Effective immunosuppression is the standard of care for relapse prevention

14. OBJECTIVE
To compare the relapse and treatment failure rates among 3 most common forms of immunosuppression (IS) for NMO :
Azathioprine
Mycophenolate mofetil
Rituximab

15. 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

16. MAIN OUTCOME AND MEASURE
Annualized relapse rates.

17. RESULTS Rituximab Mycophenolate Azathioprine
Reduced the relapse rate 88.2%
2/3 = complete remission
Mycophenolate
Reduced the relapse rate 87.4%
36% failure rate
Azathioprine
Reduced the relapse rate by 72.1%
53%failure rate despite concurrent use of prednisone

18. CONCLUSIONS AND RELEVANCE
Initial treatment with rituximab,mycophenolate, and,azathioprine significantly reduces relapse rates.
If initial treatment fails often achieve remission when treatment is switched from one to another of these drugs.

19. 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).

20. 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.

21. 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.

22. Methods Inclusion criteria
who diagnosed as having NMO based on the 2006 revised NMO criteria

23. Methods NMOSD = TM,ON,or brainstem inflammation + serum AQP4-IgG
On azathioprine/mycophenolate x 6 mons or rituximab x 1 mon
*** prior immunomodulatory : glatiramer acetate,β interferons, prednisone,HCQ >>> OK

24. Methods Exclusion criteria
Exposure to another IS : cyclophosphamide, methotrexate, mitoxantrone
Receiving > 1 medications

25. 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)

26. 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.

27. 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)

28. 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).

29. Results

31. Results N = 90 (NMO = NMOSD) Azathioprine = 32 Mycophenolate = 28
Rituximab = 30
No difference pretreatment relapse risk btw 3 treatments

32. 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

33. 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

34. Azathioprine

35. ARR before = 2.26
ARR after = 0.63

36. Mycophenolate N = 28 NMO 64%, NMOSD 36%).
Initial Dose mg/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

37. 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

38. Mycophenolate

39. Mycophenolate
ARR before = 2.61
ARR after = 0.33

40. Rituximab N = 30 NMO 63% , NMOSD 37%
Rituximab 1000mg IV + premedication Methylprednisolone 100 mg
Repeat 2 wks later
CD19 cell counts monthly

41. 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

42. 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

44. Rituximab
ARR before = 2.89
ARR after = 0.33

45. 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

49. 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

50. 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.

51. 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)

52. 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

53. 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.

54. 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

55. 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.

56. Conclusions This study is limited
Biases inherent to retrospective study design
Between mycophenolate and rituximab, there were other biases

57. Published: 15 March 2014

58. Background
Review experience using methotrexate as a single long-term immunosuppressant (IS) therapy in neuromyelitis optica/neuromyelitis optica spectrum disorders (NMO/NMOSD).

59. Methods Retrospective chart review
NMO/NMOSD : positive NMO-IgG testing
Tx with MTX
A paired sample 2 tailed t test
annualized relapse rate 18 months pre treatment And post treatment with MTX

60. Results N = 9 median of 62 mons All patients were
Stabilized during attacks with high-dose steroids and/or plasmapheresis.
5 pts (55.55%) started on MTX
3 pts (33.33%) pulse cyclophosphamide followed by methotrexate
One patient started on azathioprine prior to methotrexate.

61. Results No patient had side effects 5 pts (55.55%) had stabilization
1 pt had a small increase in EDSS due to concomitant illness.
3 pts (33.33%) had MTX tx failure
Average annualized relapse rate reduced 64%
3.11 vs 1.11
A paired t-test highly significant (p = .009)

62. Conclusion
MTX is safe and possibly efficacious as a single long-term IS therapy along + low dose corticosteroids that can reasonably be offered to patients with NMO/NMOSD.

63. Background
Neuromyelitis Optica (NMO) = severe demyelinating inflammatory dz of the CNS
Recurrent of myelitis and optic neuritis
Requires long-term tx with IS

64. 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

65. Background Jacob A. et al. 2008 Costanzi C. et al. 2011
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

66. Background Pittock et al. 2013 Kieseier BC 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

67. 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

68. 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

69. 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

70. Results Median follow 62 mons (Ẋ= 82.89, SD = 43.779)
Duration Tx with MTX median 29 mons (Ẋ = 40 mons, SD = )
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)

72. 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

73. Result Pulse methylprednisolone 500 mg IV twice daily for relapses
Weaning protocol
oral prednisolone 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)

74. 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

75. 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

76. 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

78. 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

79. 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

81. MTX
MTX
cyclophos
MTX
AZA
cyclophos
MTX
MTX
cyclophos

82. 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.

83. 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

84. Discussion MTX has an excellent safety profile.
Safety data for long-term use of mycophenolate mofetile, azathioprine, and rituximab : inferior or less robust

85. 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

86. Conclusion
Methotrexate is a safe single IS therapy along with low dose corticosteroids
Possibly be used efficaciously for long-term management