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Multiple Sclerosis Treatment 05 November 2004 Aims 1.
Treatment to prevent ongoing destruction 2.
Symptomatic treatment 3.
Treatment designed to repair damaged myelin. Clinical Categories Relapsing-remitting: episodes of acute worsening with recovery and a stable course between relapses. (50% become secondary progressive) Secondary progressive: gradual neurologic deterioration with or without superimposed acute relapses in a patient who previously had relapsing-remitting MS. Primary progressive: gradual, nearly continuous neurologic deterioration from the onset of symptoms. (10% of all patients, tend to be older, myelopathy). Progressive relapsing: gradual neurologic deterioration from the onset of symptoms but with subsequent superimposed relapses. Prognostic Markers for more severe MS Progressive disease from the onset of symptoms Motor and cerebellar signs at presentation Short interval between the first two relapses Poor recovery from relapse Multiple cranial lesions on T2 MRI on presentation. Difficulties with Treatment Trials Highly unpredictable & variable course of disease. Measuring neurologic disability (EDSS) Utility of MRI Relapsing MS Corticosteroids 1 gm methylprednisolone for 3 days followed by 1mg/kg prednisolone for 11 days. For first episode of optic neuritis Definite MS developed in first two years 7.5% patients with methylpred Definite MS developed in first two years 14.7% patients with prednisolone (1mg/kg/d for 14 days). Definite MS developed in first two years 16.7% patients with placebo Patients with acute optic neuritis At 6 mths, methylpred recovered visual function faster (better fields, contrast sensitivity, color vision but not better acuity; all improved parameters P<0.05) RR of new episode of optic neuritis for prednisolone vs placebo 1.79 (95% CI 1.08 – 2.95) At 3 years, no difference between 3 groups. Plasmapharesis in acute fulminant CNS demyelination who failed methylpred can show dramatic improvement in patients. Beck et al A randomized trial of corticosteroids in the treatment of acute optic neuritis. NEJM 1992;326: 581-88. Beck
et al The effect of corticosteroids for acute optic neuritis on the subsequent
development of MS NEJM 1993;329: 1764-9. Beck
RW The Optic Neuritis Treatment Trial: three year follow-up results. Arch
Ophthal 1995;133: 136-7. Beta Interferon 1B Nonglycosylated bacterial cell product. 8 MU sc alternate days up to 5 years in ambulatory patients with mild-mod disability in relapsing remitting MS. Relapse rate reduced by 31% (1.12 placebo vs 0.78 IFN for annual exacerbation rate) Increased number of patients who were relapse free (27% vs 17%) 50% reduction in severe exacerbations. 6 fold reduction in rate of active MRI lesions. SE: 38% neutralizing antibodies by third year with loss of clinical efficacy, flu like symptoms relieved by NSAIDS, injection site tenderness/redness/swelling, LFT abnormalities (usually minor), depression, contraindicated in pregnancy & nursing, worsening of spasticity. IFNB Multiple Sclerosis Study Group Interferon beta-1b in the treatment of multiple sclerosis: Final outcome of the randomized controlled trial. Neurology 1995;45:1277-85. Beta Interferon 1A Glycosylated recombinant mammalian cell product 6 MU im weekly up to 3 years in patients with mild-mod disability in relapsing remitting MS. Reduced the probability of progression of disability and of severe disability (p=0.02). 32% reduction in annual rate of relapse(p=0.03) Reduced MRI number and volume of lesions (p=0.05) SE: 22% neutralizing antibodies by second year with loss of clinical efficacy, flu like symptoms relieved by NSAIDS, injection site tenderness/redness/swelling, LFT abnormalities (usually minor), depression, contraindicated in pregnancy. Jacobs et al Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996;39: 258-94. Unresolved questions for interferon therapy in relapsing remitting MS. When to start? Duration of therapy? Individualization of doses? Long term benefit? Which beta IFN is better? Alpha vs beta interferon? What to do when neutralizing antibodies develop? Cross reactivity of antibodies for B-IFN1B & B-IFN1A? Khan et al Neutralizing antibodies to interferon beta 1a and interferon beta 1b are cross reactive. Neurology 1998;51: 1699-1702. Rudick
et al Incidence and significance of neutralizing
antibodies to interferon beta 1a in multiple sclerosis. Neurology 1998;50:
1267-71. IFNB Multiple Sclerosis Study Group Neutralizing antibodies during treatment of multiple sclerosis with interferon beta 1b: Experience during the first three years. Neurology 1996; 47: 889-95. Lublin
et al Management of patients receiving interferon beta 1b or multiple sclerosis:
Report of a consensus conference. Neurology 1996;46: 12-18. Glatiramer acetate/ Copolymer1/ Copaxone Mixture of 4 synthetic polypeptides (L-alanine, L-glutamic acid, L-lysine, L-tyrosine) first found to be of efficacy in EAE. 20 mg sc daily for 2 years in patients with mild to moderate disability. 29% lower annualized relapse rate. 34% treated patients did not have a relapse to 27% in placebo. 25% improvement of >1 on EDSS score vs 15% in placebo. 21% had worsening of disability compared to 29% in placebo. Effects on MRI burden unknown. SE: 90% mild injection site reaction, 15% flushing/PIC/SOB /palpitations/anxiety, development of antibodies though no reduction in clinical efficacy. Johnson et al Copolymer1 reduces relapse rate and improves disability in relapsing remitting multiple sclerosis: Results of a phase III multicentre, double blind, placebo controlled trial. Neurology 1995;45: 1268-75. Johnson
et al Extended use of glatiramer acetate (Copaxone) is well tolerated and
maintains its clinical effect on multiple sclerosis relapse rate and degree of
disability. Neurology 1998;50: 701-7. Azathioprine Purine analogue affecting cell & humoral mediated immunity. 2-3 mg/kg/d reduces rate of relapse but no effect on progression of disability based on meta analysis of 5 RCT. Maybe useful in Devic’s disease (based on case series of 8) SE: potentially teratogenic, nonHodgkin’s lymphoma, skin cancer. Best reserved for patients who do not respond to beta interferon or glatiramer. Yudkin et al Overview of azathioprine treatment in multiple sclerosis. Lancet1991;338: 1051-5. Mandler et al Devic’s neuromyelitis optica: a clinicopathological study of 8 patients. Ann Neurol 1993;34:162-8. Intravenous
Immunoglobulin Relapsing
remitting MS treated with 0.2gm/kg/mth for 2 yrs showed a trend to less
worsening EDSS compared to placebo, reduction in acute relapses and MRI burden. Consensus
statement that routine use of this treatment cannot be recommended especially
not as first line treatment. Lisak et al AAN Consensus Statement: Intravenous Immunoglobulin in Multiple Sclerosis Neurology 1998;51 (Supp5): S25-9. Sorensen et al Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis. Neurology 1998;50: 1273-81. Progressive
Multiple Sclerosis Cyclophosphamide Induction
phase of im ACTH (40U bd for 7d, 40U daily for 4, 20U daily for 3d) with iv 125
mg cyclophosphamide qid till WCC<4000; thereafter, 7000 mg/m2
every 2 mths for 2 yrs. Without
boosters, majority of patients continued to progress. Time
to treatment failure after 1 year significantly prolonged. Statistically
significant benefit at 24 & 30 mths based on EDSS. SE:
alopecia, leukopenia, hemorrhagic cystitis, nausea, vomiting, infertility,
pulmonary fibrosis. Best
reserved for rapidly progressive disease. Weiner et al Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: Final report of the Northeast Cooperative Multiple Sclerosis Treatment Group. Neurology 1993;43: 910-8. Methotrexate Dihydrofolate
reductase inhibitor 7.5
mg weekly for 2 yrs. Based
on composite score of EDSS, Ambulation Index, & 2 tests of upper arm
function reduced clinical deterioration compared to placebo. Findings also
reflected on MRI. Major
SE is cumulative dose hepatotoxicity when > 1.5 gm. Goodkin et al Low dose oral methotrexate in chronic progressive multiple sclerosis: Analyses of serial MRIs. Neurology 1996;47: 1153-7. Goodkin et al Low dose (7.5 mg) oral methotrexate in reducing the rate of progression of neurological impairment in patients with chronic progressive multiple sclerosis. Ann Neurol 1995;37: 30-40. Cyclosporine 7
mg/kg/d for 2 yrs. Prolonged
the time period before patient became wheelchair dependent. 84%
developed nephrotoxicity outweighing any clinical benefits. The Multiple Sclerosis Study Group Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double blind, placebo controlled trial. Ann Neurol 1990;27: 591-605. B
IFN-1b 8
MU in secondary progressive patients for 3 yrs. Delayed
progression of disability for 10 mths over a study period of 3 yrs. SE: 38% neutralizing antibodies by third year with loss of clinical efficacy, flu like symptoms relieved by NSAIDS, injection site tenderness/redness/swelling, LFT abnormalities (usually minor), depression, contraindicated in pregnancy & nursing, worsening of spasticity. European Study Group on Interferon 1b in Secondary Progressive MS Placebo controlled multicentre randomized trial of B IFN 1b in treatment of secondary progressive MS. Lancet 1998;352: 1491-7. Bone
Marrow Transplant 6
patients with MS underwent autologous stem cell transplant with
improvement/stabilization of disease followed over 11 months. Burt et al Treatment of autoimmune disease by intense immunosuppressive conditioning and autologous hematopoietic stem cell transplantation. Blood 1998;92(10): 3505-14 Mitoxantrone Mitoxantrone
is an anthracenedione antineoplastic agent that intercalates with DNA and acts
as an immunomodulatory agent by reducing T cell numbers.
It is already marketed as a component of combination therapy of acute
nonlymphocytic leukemia in adults for the treatment of advanced
hormone-refractory prostate cancer in combination with corticosteroids.
Mitoxantrone
has also been shown in several randomised studies to be efficacious in the
treatment of multiple sclerosis Edan et al. (1) evaluated 42 patients with
secondary progressive disease. Mitoxantrone was given intravenously in a dose of
20mg/month for 6 months in combination with monthly methylprednisolone and
compared with methylprednisolone administered alone.
The average extended disability status scale (EDSS) score was 4.4 at
entry in the Mitoxantrone/methylprednisolone group and 4.7 in the
methylprednisolone only group. The
primary end-point was the percentage of patients without new enhancing lesions
on magnetic resonance imaging and by the completion of the study the percentage
was 90.5% with Mitoxantrone and 31.3% in the control group.
Unblinded clinical assessment revealed that the mean EDSS reduced in the
Mitoxantrone group to 3.4, whereas there was a mean increase of 0.3 in the
control group although analysis was complicated by the drop-out of 5 patients in
the latter group due to severe deterioration.
There was also a significant reduction in the number of relapses in the
Mitoxantrone treated group (7 versus 31, p<0.01).
Some of these results (reduced percentage of patients deteriorating and
reduction in relapse rate) were confirmed in a double-blind placebo-controlled
trial for 51 relapsing-remitting patients from Italy (2). The
results of another phase II study were presented at the American Academy of
Neurology annual scientific meeting in 1999.
The study assessed 194 patients with secondary progressive multiple
sclerosis treated with placebo or either 5mg/m2 or 12mg/m2 of Mitoxantrone
administered every 3 months, and patients were followed-up for an additional
year. It was shown that 17% of
patients in the 12mg/m2 arm, 24% in the 5mg/m2 arm and 44% in the placebo group
worsened by 1 point or more on the EDSS. Relapse
rate was also reduced, with 66% in the 12mg/m2 group relapse-free in comparison
with 51% in the placebo group. In
an unpublished follow-up two year phase III placebo controlled trial, which
formed the basis for an application to the FDA for approval of Mitoxantrone in
multiple sclerosis, it was shown that patients treated with Mitoxantrone
experienced a 65% reduction in the number of patients experiencing a 1 point
reduction in the EDSS. The
FDA recommended approval of Mitoxantrone for the treatment of multiple sclerosis
in January 2000. The
potential side-effect profile of Mitoxantrone is similar to that expected for
any chemotherapeutic agent. In
addition, functional cardiac changes, including irreversible decreases in the
left ventricular ejection fraction can occur with Mitoxantrone.
This propensity for the drug to cause cardiotoxicity at cumulative doses
exceeding 100mg/m2, indicates the need for regular cardiac monitoring, and
limits the administration of the drug to pulse therapy administered between
every 1 to 3 months over a 6 to 24 month period, respectively.
The need to use such a regimen indicates that further maintenance therapy
with alternative chemotherapeutic agents is likely to eventually be required,
given that the biological efficacy of the Mitoxantrone is likely to diminish
with time. 1.
Edan et al JNNP 1997;62:112-118 2.
Millefiorini et al J Neurol 1997;244:153-159 3.
Hartung et al. Neurology 52 (Suppl 2) S45.005 A290 Immunotherapy
Planning 1.
First line nontoxic therapy 2. Intravenous steroids for relapses. 3. Plasmapharesis for refractory fulminant CNS demyelination. 4. Second line immunosuppression to halt refractory or progressive disease. 5. Reinstitution of first line therapy. 6. Combination and pulse therapy. 7. Disease monitoring: EDSS, MRI, other immune measures. |
