High dose copaxone

Randomized, double blind dose comparison study of glatiramer acetate in relapsing-remitting MS . Cohen JA et al. Neurology 2007; 68:939-944. The study screened treatment naive patients EDSS 1-5, one relapse in prior year, about 45 patients in each group. Compared 20 v 40 mg. Trend towards less relapses in higher dose group. More injection reactions in higher dose group. MRI scores showed a trend favoring the higher dose group.

predictors of disability in MS

Langer-Gould A, Popat RA, Huang SM, Cobb K, et al. Clinical and demographic predictors of long-term disability inpatients with relapsing remitting multiple sclerosis. A systematic review. Arch Neurol 63: 1686-91 2006

Study based on meta-analysis, including studies in the literature since 1966 that met preselected criteria, including differentiation of RRMS, enrollment of greater than 40 patients, observation > 5 years, and followup collection exceeding 80 percent.

The most important predictors were sphincter symptoms at onset and early disease course outcomes. Age at onset, sex, were weak factors.

High dose cytoxan for multiple sclerosis

Gladstone DE et al. High dose cyclophosphamide for moderate to severe refractory multiple sclerosis. Arch Neurol 2006; 63:1388-1393.

The authors studied refractory MS, defined as EDSS scores of 3.5 or higher after 2 or more FDA approved DMD's. 12 patients received 200 mg/kg over four days. No patients increased EDSS by more than one point. Five decreased by one or more points. Patients reported improvement in ll QOL measures.

Goal of therapy is to stop disease progression.
Procedure was 200 mg/kg based on IBW over f days. Hemorrhagic cystitis prevention was done with mesna and forced diruresis. Antibacterial, antiviral and antifungal prophylaxis was given. Evaluation included EDSS, neuro-opthalmologic evaluation and MRI and QOL eval using short form 36.

Patients suffered absolute neutropenia for nine days, received a median of i unit prbc's

Alternatives: mitoxantrone, stem cell mobilization (filgastrim)

Tysabri risk and possible interventions

Stuve O et al. Potential risk of PML with natalizumab therapy. Arch Neurol 2007; 64:169-176. Neurological Review. The authors point out that neurologists must be aware of possible therapies because the n of patients studied is likely to be low. Possible treatments include antivirals, immunomodulatory treatments, hematopoietic growth factors, plasma exchange, IVIG, leukopheresis and autotransfusion of leukocytes. Points of note: 1) the risk of developing PML among 3116 patients treated in studies was 0.1 % and the risk of PML among patients treated longer is not known. 2) JC virus is ubiquitous in all people in kidney, peripheral blood cells and normal brain at autopsy. The prevalence of antibodies is around 90 %. 3) The biological half life of natalizumab is around six months , far exceeding its pharmacological half life. Goals of a possible therapy: 1)eliminate JCV; 2) generate new competent WBC's with unbound VLA-4; 3)neutralize free natalizumab, and 4)eliminate free natalizumab. 1)Antivirals help PML in HIV patients. Reconstitution of CD4 and CD* lymphocytes maybe required to ensure a positive outcome in the patients. 2) Natlizumab is present in blood for 3-8 weeks after dosing. Elimination depends upon the interaction with VLA 4 which is reversible bond and follows normal thermodynamic rules. The idea is to change the binding strength and the in vivo binding equilibrium between natalizumab and VLA4. Existing interventions: cytarabine iv and it did not help HIV patients with PML. Cidofovir showed no benefit in one study. Drugs can cause renal failure and myelosuppression. Interferon alpha and beta and IL2 have case reports of improvement. No data exist of their efficacy. Serotonin 2 alpha blockers may prevent JC viral infection of oligodendrocytes. These drugs include olanzepine, ziprasidone, and risperidone. Hematopoeitic growth factors: pros: Theoretically IL7, G CSF, GM-CSF is well tolerated and might produce unbound lymphocytes. In theory it could be used with IVIG or plasma exchange. Cons: see article

Mitoxantrone for Devic's disease

Weinstock-Guttman B et al. Study of mitoxantrone for the treatment of recurrent neuromyelitis optica. Arch Neurol 2006;63:957-963 The authors studied five patients over two years and felt they improved on MRI, edss.

Familial effects of the clinical course of MS

Hensieck AE et al. Neurology 2007; 68:376-383. There is concordance among family members for age at onset, NOT for severity. There are no apparent transmission patterns nor evidence for genetic loading. However, familial factors do affect the probability of an eventual progressive course (either PPMS or after RRMS, SPMS).

Normal appearing white matter (NAWM)& disability

Vrenken H. Altered diffusion tensor in multiple sclerosis normal-appearing brain tissue: cortical diffusion changes seem related to clinical deterioration. Journal of Magnetic Resonance Imaging 2006; 23:628-636.

Prospective controlled study of normal looking white and gray matter. 64 MS patients and 20 healthy controls. The 64 MS patients had 38 RRMS, 14 SPMS, and 12 with PPMS. Whole brain diffusion coefficient (ADC maps) and fractional anisotropy (FA) were obtained. In NAWM, global FA was decreased and global ADC increased in MS patients v. controls. The changes in ADC in NAWM correlated with disability more strongly than T2 lesion load. In gray matter regional analysis, changes in both ADC and FA were significant.
Note the correlation with disability was still "modest at best"

Copaxone and neuroprotection

Kahn O. Axonal metabolic recovery and potential neuroprotective effect of glatiramer acetate in relapsing-remitting multiple sclerosis. Multiple Sclerosis 2005; 11:646-651.

Two year study partly blinded with MR spectroscopy in treatment naive MS patients and controls. GA (Copaxone) reduced NAA, a surrogate of axonal injury. 18 patients who started GA were assessed, and four controls (subjects who elected not to begin therapy). The NAA/Cr increased in both groups. In the VOI (volume of interest) over two years, and the NAWM (normal appearing white matterO it increased by 10.7 and 7.1 in the treated group, and DECREASED by 8.9 and 8.2 % in the respective control groups.

Fred Lublin comments that while the number of patients is small, the study is ongoing (four more years) but warns that the attempts to correlate surrogate MRI markers for clinical disability have been "continually disappointing." Lublin wants to see proof that the marker NAA in MRS correlates with clinical measures, and also with other MRI measures such as balck holes and atrophy.

extension trials in MS-- Noseworthy

Extension trials-- limited benefit Noseworthy JH How much can we learn from long-term extension trials in multiple sclerosis? Neurology 2006; 67: 930-931 editorialcomments on Kappos et al. Long term interferon beta 1a therapy in patients with relapsing MSNeurology 67: 944-953 200632 % patients randomized in PRISMS did not participate in the extension. Blinding was eliminated. Visits were in some cases conducted every two years or retrospecive evaluations were substituted. About 25 % patients entering extension did not remain on treatment. Brain atrophy was not reduced. The NTT (number to treat) early v 24 months later to prevent one point progression on EDSS was 27. Conclusion of safety is warranted, not that of efficacy.Kappos et al-- 382 patients followed 8 years. 19 % progressed to spms. NABS generally disappeared with treatment. The authors claim 44 dose worked better than 22. 396/560 patients had EDSS < 3 at baseline; of those, 27 % went to EDSS of 4, 20 % went to an EDSS of six, 12 % to 6.5, and 6 % to edss of 7. Relapse rate was about .61 per patient per year in treated patients.

Antimeylin Antibodies and progression to MS

462 patients with CIS and at least 2 clinically silent lesions had anti MOG and anti MBP IgG and IgM antibodies measured with Western blot, and were followed for 24 months. There was no association found between the antibodies being present and the development of CDMS

CHAMPS CHAMPIONS AND ETOMS

CHAMPS 383 patients with very recent (27 days) CIS involving the optic nerve. Patients had to have 2 or more clinically silent lesions at least 3 mm in diameter, one ovoid or periventricular. Conversion to CDMS was a new event lasting at least 48 hours or deterioration of at least 1.5 points on the EDSS. All patients got three day Solumedrol pulse with taper at onset of study. Study was terminated after a positive interim analysis. Mean followup was 31 months. With interferon B1a (Avonex) the likelihood of developing MS was reduced 44 % (p<0.002). Posthoc analysis looked at high and low risk groups. The probability of CDMS in patients getting placebo was 50 %, 64 % in a high risk group (n=40) and 46 % in non high risk group (n=150). High risk was defined as nine or more lesions on T2 or one or more Gadolinium enhancing lesions. Only 20 % of Avonex group had CDMS at two years. Avonex reduced CDMS by 63 % at year 2, and 66 % by year 3. NTT=6.7 to prevent one patient from developing CDMS. Critiques: questionable blinding by treating physicians who followed side effects of patients. Disability and relapse rate were not applicable as points of study. No information is given on brain atrophy. AE's-- flu like reaction was 54 %, depression 20 % (v. 26, and 13 % respectively). Patients withdrawn from study did not get f/u scans. Chance of getting CDMS or dropping out was 64 % in placebo group, 51 % in active group. Class I study, category A.

The extension trial open label CHAMPIONS the original patients were all given Avonex (early and delayed treatment groups). N of the groups was 100, 103 , respectively. Thus slightly more than half the patients entered CHAMPIONS and they were treated UP TO five years (ie. not all made it that long). In the 2 groups, the respective rate of CDMS was 36 and 48 %. The rate of CDMS was decreased by 35 % in the immediate treatment group (looking at numbers could be 25 %). The NTT was 8 to treat early to prevent CDMS at five years. The mean number of relapses over five years was .9 and 1.7, respectively. The median number of T2 lesions was 3.5 and 6.0 respectively.

ETOMS studied Rebif in patients with unifocal or multifocal neurologic syndromes. Patients had at least 4 lesions on T2, or 3 if one was incfratentorial or enhancing. The primary measure was conversion to CDMS. Initial steroids were not given uniformly. Entry was allowed up to three months post event, and polysymptomatic patients were included. 39 % were in fact multifocal. The primary endpoint was conversion to CDMS. Like CHAMPS, effect of treating physician blinidng was criticized. There were 309 patients, 154 in each group and one patient thrown out). In the Rebif group, 34 % converted to CDMS and in the placebo group, 45 % converted at two years. The benefit was about 25 %, with NTT at 9.1 to prevent one CDMS at 2 years. The relapse rates were .33 and .43, respectively. The median number of active T2 lesions was 2 and 3, respectively.Actual data, percent, for placebo and rebif group, respectively: proportion converting to CDMS 45, 34; mean annual relapse rate: .43, .33 {Note: this is much lower than in pivotal betaseron trial}; median EDSS change to year 2: 0,0; median SNRS baseline to year 2: 0,0; median active T2 lesions per scan: 3,2; median enhancing lesions per scan: 0, 0.5; median change in T2 lesion volume from baseline to year 2: 8.8; -13.0. Class I study, Category A.

Meta-analysis favors glatiramer

Carra A. P635 ECTRIMS 2004. Odds ratio for relapse, disability progression favors glatiramer over interferon groups.

Based on pooled data of four open nonrandomized trials. Patients n= 695 with 135 patients on GA having less relapses and accumulated disability.

"Inflammation is Good"

On the horizon: possible neuroprotective role for glatiramer acetate. Kreitman RR and Blanchette F. Multiple sclerosis 2004. 10: S81-S89.

This non peer reviewed Teva sponsored article reviews evidence that disability in MS is caused by axonal damage, not inflammation, and that autoimmune T cells may protect against neuronal damage.

Paper has a nice discussion with lots of experts but no new data presented

PRISMS-4

PRISMS-4: Long-term efficacy of interferon B1a in relapsing MS. The PRISMS Study Group Neurology 2001:56:1628-1636

Have 2 years double blind and another 2 years of dose blind assessment.Placeo patients at end of frist two years were rerandmoized to rebif 22 or rebif 44

90% of patients continued to PRISMS 4 . Relapse rate, time to first relapse, time to progression of disability all favored high dose rebif and initial treatment wih high dose rebif. High dose was associated with 29% fewer 1 point edss changes over 4 years compared to crossover. Time to EDSS progression was not significant in low dose rebif in ITT analysis.

Lab changes (liver, CBC) were also more common in high dose group .

Burden of disease increased in years 3 and 4 for high dose group.

multiple sclerosis compare interferons

Etemadifar M et al. Comparison of Betaferon, Avonex and Rebif in treatment of relapsing-remitting multiple sclerosis Acta Neurol Scand 2006 1113:283-287

Head to head trial single blind randomized trial of rrms patients with active disease (>2 relapses in 2 years) and EDSS < 5. 90 patients. Design was to see which agent is best to prevent progression of MS.

High dose agents were better than avonex on number of patients who were relapse free for two years (B 43 %, R 56% A 20%). EDSS declined more with high dose than with Avonex. However, looking at table 3, all three groups had mean EDSS under 2.

Conclusion in the paper that high dose is better is contradicted by the clinical effect size, as all three drugs had low EDSS at conclusion of the trial.

multiple sclerosis site on medscape

http://www.medscape.com/resource/ms

Lit review by Doug Goodin/Coyle

http://www.medscape.com/viewprogram/6005

this CME program goes over evidence based medicine, treatment of CIS, and disease nonresponders in slide based format with either audio or transcript of lecture

Trials of extension trials PRISMS

neurology practice guidelines: "Extension trials-- limited benefit
Noseworthy JH How much can we learn from long-term extension trials in multiple sclerosis? Neurology 2006; 67: 930-931 editorial

comments on Kappos et al. Long term interferon beta 1a therapy in patients with relapsing MSNeurology 67: 944-953 2006

32 % patients randomized in PRISMS did not participate in the extension. Blinding was eliminated. Visits were in some cases conducted every two years or retrospecive evaluations were substituted. About 25 % patients entering extension did not remain on treatment. Brain atrophy was not reduced. The NTT (number to treat) early v 24 months later to prevent one point progression on EDSS was 27. Conclusion of safety is warranted, not that of efficacy.

Kappos et al-- 382 patients followed 8 years. 19 % progressed to spms. NABS generally disappeared with treatment. The authors claim 44 dose worked better than 22. 396/560 patients had EDSS < 3 at baseline; of those, 27 % went to EDSS of 4, 20 % went to an EDSS of six, 12 % to 6.5, and 6 % to edss of 7.

Relapse rate was about .61 per patient per year in treated patients."

Cytoxan for refractory MS high dose

Gladstone et al. High dose cyclophosphamide for moderate to severe refractory multiple sclerosis.Arch Neurol 63:10: 1388-1397
Patient selection: EDSS > 3.5 after 2 or more DMD's tried
Methods: 200/mg/kg cyclophosphamide over four days
Outcome measures : MRI neuroopthy exams every six months, EDSS quarterly, QOL measure every two years
Results: 12 patients followed median 16 months none increased EDSS more than 1 point. 5 decreased. Improvements were seen in QOL measure and MRI

Fine points
Mesna, forced diuresis to prevent hemorhhagic cystitis. Antibacterial, antifungal, anti viral prophylaxis used. Patients had median age 41, had disease median 15 years, 7 had tried mitoxantrone. 7/13 had spms. risk of hem cystitis is 2 percent, of transient dilated cardiomyopathy is 1 percent.. Fever, sepsis, zoster were common.

Note medline "Gladstone " for cyclophosphamide in MS CIDP MG