Coastal Neurological
Medical Group, Inc.

Coastal Neurological Medical Group, Inc.

REVIEW OF MOST RECENT TOPICS ON MS AT ECTRIMS

Biomarkers of MS have been studied and MRI seems to be a very important marker. It appears that combined measures of one year changes in the MRI lesions plus taking in consideration relapses after interferon therapy is very effective at estimating the two-year Expanded Disability Status Scale (EDSS) worsening. The more active the lesions and the greater the number of relapses, the greater worsening of the EDSS at two years. Brain atrophy is also a significant prognostic predictor. Whole brain atrophy and central atrophy and T2 lesion volume on the MRI supports a greater degree of disability and EDSS progression.

Single biomarker expressions when testing biomarkers in serum is not a good predictor of therapeutic response and combinations of biomarkers may be better, especially the Caspase-2/IL and its variations.

The REFLEX study comparing interferon beta-1a subcutaneous 44 mg three times a week to 44 mg weekly indicated that the more frequent dose reduced a conversion to clinically definite MS (CDMS) and the main number of combined unique active MRI lesions was reduced with the more frequent dose.

The Coptimize study was an open-labeled study on patients with MS who failed other disease-modifying therapy (DMT), and when the patients were switched to glatiramer acetate there was a 60% reduction in annual relapse rate, but there was no significant change in EDSS scores when the patients were followed.

The STRATA study and followup with natalizumab (Tysabri) documented that the annual relapse rate (ARR) remained low (0.17) and the EDSS scores remained stable post five years. There were eight cases of PML in over 1,000 patients and they were all anti-JCV antibody positive. The risk of developing PML in patients negative for anti-JVC antibody was 0.11/1000. There were some neoplasms and other infections. The STRATA study data showed that the length of exposure to natalizumab was also key and the increasing PML cases was significantly higher after 18 to 24 months. Positive anti-JC virus titer was significant in determining a higher risk of developing PML. Also, the patients who had prior use of immunomodulators had a higher risk of developing PML. When analyzing the group from 1 to 24 months of treatment as compared to 25 to 48 months of treatment, there was a significant increased risk of PML in the group treated from 25 to 48 months. That data showed that with no prior use of immunomodulators, with natalizumab used for 1-24 months, the risk of developing PML was 0.35/1000, where used for 24-48 months, the risk was 2.5/1000 (7 times greater). In the group with prior immunomodulator treatment, the group using natalizumab for 1-24 months had an incidence of developing PML of 1.2/1000 compared to the 25-48 month group, which was 7.8/1000.

When natalizumab was studied in the RESTORE trial, it was determined that interruption of the treatment resulted in a higher rate of reoccurrence of MRI lesions and clinical MS disease activity. This change started at about 12 weeks. If the patients were discontinued from natalizumab and given interferon beta-1a, there may have been some suppression of MRI activity. Monthly methylprednisolone did not appear to be effective in changing the reoccurrence rate or the MRI.

IV versus oral methylprednisolone was compared with a 1000 mg per day of IV methylprednisolone for three days and a 1,250 mg per day of oral methylprednisolone and it was determined that there was no significant difference in the groups that were treated either in MRI changes or in EDSS scoring.

One study did seem to suggest that vitamin D supplements may have had a significant reduction in the risk of new gadolinium-enhancing lesions and new T2 lesions. There did seem to be a decreased median MRI T2 burden at one year, but relapses, EDSS scores and adverse side effects were not any different. There were a reduced number of gadolinium-enhanced lesions at 12 months, however.

Fampridine (Ampyra) improved timed walk at 25 feet. Most common side effects were dizziness, nausea, and insomnia and there were 82 concurrent seizures, which are considered to be a risk for the drug.

Duloxetine was used at 60 mg per day to reduce central neuropathic pain in MS patients.

Teriflunomide was studied in a five-year followup and there was a significant reduction in T2 total lesion volume. There was no difference in total gadolinium-enhancing T1 lesions or brain atrophy. Most common side effects were nasal pharyngitis, headaches, elevated liver function test, and diffuse pain, but also back pain and diarrhea.

Laquinimod was studied in the ALLEGRO trial and it did show reduction in EDSS progression after two years, reduction in the use of steroids for annual relapse rate, and reduced EDSS score progression at three and six months. There was a reduction in new hypointense T1 lesions and reduction in brain atrophy, and in the BRAVO trial the annual relapse rate was reduced by 21% from placebo but equal to the interferon 1a IM once a week. Laquinimod did not have as robust of an effect on reducing gadolinium-enhancing T1 lesions and new T2 lesions compared to placebo as did interferon type 1a once a week. In measuring EDSS progression laquinimod was significantly better than placebo, but not better than interferon 1a IM once a week. It did seem to be better, however, than interferon 1a IM once a week in reducing brain atrophy. It is thought that laquinimod is effective in reducing the parameters of neurodegeneration, mainly progression of disability and brain volume loss, and it seems to be independent from anti-inflammatory activities.

BG-12 (dimethyl fumarate) showed a significant robust benefit as compared to placebo in delaying the time to first relapse and there is a robust reduction in annual relapse rate using BG-12 b.i.d. or BG-12 t.i.d. There is definitely a reduction in concurrent disability progression. Also, with BG-12 using it t.i.d., there was a very significant reduction in gadolinium-enhancing lesions or newly enlarged T2 lesions. Adverse side effects were flushing, which was significant, diarrhea, nausea, and upper abdominal pain.

Alemtuzumab, when compared to interferon beta-1a subcutaneous, showed a significant reduction in annual relapse rate and significant reduction in gadolinium enhancing lesions at one year, at 1-2 years and over 2 years, and showed improvement in other MRI parameters. There is also some evidence of reduction in the brain parenchymal fraction. Adverse side effects with alemtuzumab were significant and thyroid disorders were common in 18% of the cases as compared to 6.4% of the cases in the interferon with hypothyroidism being the most common. Alemtuzumab was given IV 12mg daily for 5 days then in 1 year given IV 12mg daily for 3 days.

In the SELECT study the drug daclizumab was studied and reduced the annual relapse rate, increased relapse-free patients, and reduced T2 lesions and gadolinium-enhancing lesions.

Another drug, ocrelizumab, was also studied.

BAF 312 was studied and annual relapse rate was reduced at higher doses.

In a study on pregnancy and relapse rate and disability progression, it was noted in almost 900 pregnancies that pregnancy had a protective effect on relapse rate. Relapse rates doubled from the pre-pregnancy rate during the first three months of the postpartum period. However, EDSS scores were stable. With interferon beta and glatiramer acetate treatments, there is probably no increased rate of spontaneous abortion or birth defects. Breastfeeding delays return of relapses during the first six months after giving birth, and this does not support that women should avoid breastfeeding in order to resume immunomodulators.

Dee E. Silver, M.D.

Refer a Friend

Coastal Neurological Medical Group
9850 Genesee Avenue
Suite 860
La Jolla, CA 92037
Tel: 858.453.3842
Fax: 858.535.9390

map

[ HOME ]