Primary/Progressive Multiple Sclerosis 2

Plasma samples from 70 patients with Multiple Sclerosis (MS), 41 patients with Other Neurological Diseases (OND), and 38 healthy subjects were examined for AntiBodies against Gangliosides GM1, GM3, GD1a, GD1b, and GD3 using enzyme-linked Immunosorbent assays.

The percentages of subjects with increased anti-GM3 responses were significantly higher in the Progressive MS (56.3%) and Secondary/Progressive MS (42.9%) groups than in the Relapsing/Remitting MS (2.9%), healthy subject (2.6%), and OND (14.6%) groups.

Elevated AntiGanglioside AntiBodies may be secondary to Axonal damage or may be a cause of Axonal damage and accumulating Disability in Progressive MS. In either case, they may serve as a marker of Axonal damage in MS.

Spasticity is a disabling symptom of MS that is enhanced during Interferon-ß-lb (IFN-ß-1b) treatment.

Nineteen patients with Primary/Progressive MS were treated with IFN-ß-1b; an additional 19 patients did not receive this treatment.

Thirteen of the 19 patients treated with IFN-ß-1b had increased Spasticity requiring increased AntiSpasticity drug administration.

This observation suggests that further studies are needed before Interferons can be so widely used in Primary/Progressive MS patients.

Background
The beneficial effects of Interferon-ß have only been shown for patients in the Relapsing/Remitting phase of Multiple Sclerosis (MS).

The role of Interferon-ß in the treatment of patients who are in the Secondary/Progressive phase of the disease (SP-MS), and for whom no effective drug treatment is available, has not been assessed.

Methods
In this multicenter, double-masked, randomized, placebo-controlled trial, outpatients with SP-MS having scores of 3.0-6.5 on the Expanded Disability Status Scale (EDSS) received either 8 million IU Interferon-ß-1b every other day subcutaneously, or placebo, for up to 3 years.

The primary outcome was the time to confirmed progression in disability as measured by a 1.0 point increase on the EDSS, sustained for at least 3 months, or a 0.5 point increase if the baseline EDSS was 6.0 or 6.5.

A prospectively planned interim analysis of safety and efficacy of the intention-to-treat population was done after all patients had been in the study for at least 2 years.

Findings
358 patients with SP-MS were allocated placebo and 360 were allocated Interferon bß-1b; 57 patients (31 placebo, 26 Interferon beta-1b) were lost to follow-up.

There was a highly significant difference in time to confirmed progression of Disability in favor of Interferon-ß-1b (p=0.0008).

Interferon-ß-1b delayed progression for 9-12 months in a study period of 2-3 years. The odds ratio for confirmed progression was 0.65 (95% CI 0.52-0.83).

This beneficial effect was seen in patients with superimposed relapses and in patients who had only progressive deterioration without relapses.

Positive results were also obtained regarding time to becoming wheelchair-bound, relapse rate and severity, number of Steroid treatments and hospital admissions, as well as on Magnetic Resonance Imaging variables.

The drug was safe and side effects were in line with previous experience with Interferon-ß-1b. The study was stopped after the interim results gave clear evidence of efficacy.

Interpretation
Treatment with Interferon-ß-1b delays sustained Neurological deterioration in patients with SP-MS.

Interferon-ß-1b is the first treatment to show a therapeutic effect in patients with SP-MS.

Objective
To determine whether Sulfasalazine is better than placebo in slowing Disability progression in MS.

Methods
In this randomized, double-blind, placebo-controlled phase III trial, 199 patients with active Relapsing/Remitting (n = 151) or Progressive (n = 48) MS were evaluated at 3-month intervals for a minimum of 3 years (94% completed 3 years of follow-up; mean follow-up, 3.7 years).

MRI studies were performed at 6-month intervals on a subset of 89 patients.

Results
Sulfasalazine failed to slow or prevent disability progression as measured by the primary outcome (confirmed worsening of the Expanded Disability Status Scale [EDSS] score by at least 1.0 point on two consecutive 3-month visits).

Sulfasalazine influenced favorably a number of secondary outcomes during the first 18 months of the trial (e.g., annualized relapse rate, proportion of relapse-free patients; Progressive subgroup only: rate of EDSS progression at 1 and 2 years, median time to EDSS progression) but these positive findings were not sustained into the second half of the trial.

Conclusions
Sulfasalazine does not prevent EDSS score progression in the subset of MS patients studied by this protocol.

Treatments may improve relapse-related outcomes in MS, at least temporarily, without providing sustained slowing of EDSS progression. Phase III MS trials should be of sufficient length to determine a meaningful impact on disease course.

In a double-blind prospective randomized trial, we assessed the efficacy and safety of modified Total Lymphoid Irradiation (TLI) plus Low Dose Prednisone (TLI-LDP) as compared to sham TLI plus Identical Prednisone therapy (sham TLI-LDP) in 46 patients with Progressive forms of Multiple Sclerosis (MS).

No significant difference existed between groups at study entry in patient age, sex, duration of MS, or disability status.

However, following treatment, significantly fewer TLI patients showed a sustained one point decline in the Expanded Disability Status Scale, the primary study endpoint, as compared to the sham TLI group using the Kaplan-Meier Product-limit survival analysis, (P<0.005).

Risk for relapse requiring treatment with IntraVenous MethylPrednisolone was reduced by 54% in the TLI-treated group (P<0.05).

Significantly fewer TLI-LDP patients had Gadolinium enhancing plus new T₂-weighted lesions (P=0.018) when compared to the sham group post-treatment.

There was also a substantial and significant decrease in blood Lymphocytes in the TLI-LDP group when compared to either pretreatment values or to sham TLI-LDP through at least 12 months post-therapy.

Side effects secondary to TLI were generally mild and well-tolerated. These results further support the hypothesis that TLI and systemic ImmunoSuppression have a beneficial effect in Progressive forms of MS.

A putative association between the course and severity of MS and the MHC remains controversial.

Methods
DR and DQ Genotyping by either restriction fragment length PolyMorphism or sequence-specific PCR-based typing in 119 patients representing 73.4% of the population with MS evaluated in a cross-sectional Disability survey and 100 healthy controls from Olmsted County, Minnesota.

Results
We found a positive association between MS susceptibility and the DR15-DQ6 and DR13-DQ7 haplotypes, and we found a negative association with the DR1-DQ5 haplotype.

We found a trend to a positive association of Primary/Progressive MS with DR4-DQ8 and DR1-DQ5 and an association of "bout onset" MS with DR17-DQ2. We did not find an association with disease severity, as defined by EDSS/duration.

Conclusion
Lack of consistency between different studies may be due to regional variation in MS and limitations of power but likely indicate a minor effect of MHC Class II Genes on the course and severity of MS.

Background
Patients with Primary/Progressive MS have atypical clinical and MRI characteristics and have been excluded from most therapeutic trials. The authors report a randomized, controlled trial restricted to Primary/Progressive MS.

Methods
Fifty subjects were randomized to weekly IM Interferon-ß-1a 30 microg, 60 microg, or placebo for 2 years. The primary endpoint was time to sustained progression in disability.

Secondary outcomes included the Timed 10-Meter Walk, Nine-Hole Peg Test, and on MRI, T₂ and T₁ Brain lesion loads and Brain and Spinal Cord Atrophy.

Results
The 30- microg dose of Interferon-ß-1a was well tolerated, but the 60- microg dose caused severe Flulike reactions and raised Liver Enzymes. No treatment effect was seen on the primary endpoint.

Subjects on Interferon-ß-1a 30 microg had a lower rate of accumulation of T₂ lesion load than controls (p = 0.025); subjects on 60 microg had a greater rate of Ventricular enlargement than controls (p = 0.025).