Objective: To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis. Methods: A total of 943 patients with primary progressive multiple sclerosis were randomized to GA or placebo (PBO) in this 3-year, double-blind trial. The primary end point was an intention-to-treat analysis of time to 1-(entry expanded disability status scale, 3.0 -5.0) or 0.5-point expanded disability status scale change (entry expanded disability status scale, 5.5-6.5) sustained for 3 months. The trial was stopped after an interim analysis by an independent data safety monitoring board indicated no discernible treatment effect on the primary outcome. Intention-to-treat analyses of disability and magnetic resonance imaging end points were performed. Results: There was a nonsignificant delay in time to sustained accumulated disability in GA-versus PBO-treated patients (hazard ratio, 0.87 [95% confidence interval, 0.71-1.07]; p ϭ 0.1753), with significant decreases in enhancing lesions in year 1 and smaller increases in T2 lesion volumes in years 2 and 3 versus PBO. Post hoc analysis showed that survival curves for GA-treated male patients diverged early from PBO-treated male subjects (hazard ratio, 0.71 [95% confidence interval, 0.53-0.95]; p ϭ 0.0193). Interpretation:The trial failed to demonstrate a treatment effect of GA on primary progressive multiple sclerosis. Both the unanticipated low event rate and premature discontinuation of study medication decreased the power to detect a treatment effect. Post hoc analysis suggests GA may have slowed clinical progression in male patients who showed more rapid progression when untreated.

We enrolled 116 patients in a multicenter, randomized, double-blind controlled trial of an 8-week course of 11 plasma exchange (PE) treatments in exacerbations of MS. The control group received sham PE, and both groups received identical treatment with IM ACTH and oral cyclophosphamide. Serum IgG decreased in the PE and sham treatment groups by 76% versus 22% by treatment 5, and by 64% versus 14% by treatment 11. PE also produced significant reductions in IgA, IgM, C3, and fibrinogen. PE patients had moderately enhanced improvement at 2 weeks relative to the sham group. PE patients with relapsing/remitting disease had significantly enhanced improvement at 4 weeks and there was also an increased improvement at 12 months, although this latter effect disappeared when we analyzed relapsing/remitting patients as a separate subgroup. Life table analysis showed the median time to recover preattack disability status was shorter in PE- than in sham-treated relapsing/remitting patients (4 vs. 13 weeks), a result confirmed by raw disability status scores in which there was recovery to their average preattack disability score by 3 months. PE given with ACTH plus cyclophosphamide enhances recovery from an exacerbation of disease in relapsing/remitting patients, although we observed no clear long-term benefits.

Previous studies reported that a 2- to 3-week course of IV cyclophosphamide plus adrenocorticotropic hormone (ACTH) induction can temporarily halt progressive MS for a period of 12 months in the majority of patients treated, after which reprogression occurs. The Northeast Cooperative Multiple Sclerosis Treatment Group was formed to determine whether outpatient pulse cyclophosphamide therapy could affect reprogression and whether there were differences between a modified induction regimen and the previously published regimen. Two hundred fifty-six progressive MS patients were randomized into four groups to receive IV cyclophosphamide/ACTH via the previously published versus a modified induction regimen, with or without outpatient IV cyclophosphamide boosters (700 mg/m2 every other month for 2 years). There were blinded evaluations performed every 6 months. Results demonstrate that (1) there were no differences between the modified and the published induction regimens either in terms of initial stabilization or subsequent progression; (2) without boosters, the majority of patients continued to progress; and (3) in patients receiving boosters, there was a statistically significant benefit at 24 months and 30 months (p = 0.04). Time to treatment failure after 1 year was also significantly prolonged in the booster versus the nonbooster group (p = 0.03). Age was the most important variable that correlated with response to therapy in that amelioration of disease progression occurred primarily in patients 40 years of age or younger. Boosters had a significant benefit on time to treatment failure in patients ages 18 to 40, p = 0.003, but not in patients ages 41 to 55, p = 0.97.(ABSTRACT TRUNCATED AT 250 WORDS)

Linkage studies in multiple sclerosis (MS) identified several susceptibility loci. One of these regions includes chromosome 17q11 where a meta-analysis of data from three genome scans suggested linkage. This region encodes a cluster of genes for b-chemokines or CC chemokine ligands (CCLs), which may be involved in the development of MS lesions. Here we aimed to test if CCL alleles and haplotypes are associated with MS. Using methods of linkage and association, we observed deviations from the expected 50% transmission of haplotypes from unaffected parents to their affected children at CCL2, CCL11 -CCL8-CCL13 and CCL3 within the investigated 1.85 MB chromosomal segment. Analyses of the linkage disequilibrium map support that variants with possible relevance to MS can be located within these subregions. Identification of MS associated CCL variants may have direct clinical significance, as it can lead to the design of small competitive antagonists of these molecules with beneficial effects in the treatment of patients with early and active disease. Keywords: multiple sclerosis; susceptibility; b-chemokines; SNP; haplotype IntroductionMultiple sclerosis (MS) is a complex trait disorder of unknown etiology. Its phenotypic presentations represent a spectrum with characteristics of autoimmunity and neurodegeneration. 1 -4 The involvement of autoimmunity is supported by epidemiological, clinical and pathological studies. 4 -6 A survey of genome-wide scans reveals that 65% of the positive non-HLA linkage data map into 18 overlapping clusters of MS and other autoimmune diseases. 3 The risk of this nonspecific autoimmunity is estimated to be l s ¼ 1.65, 7 -8 and involves a complex mechanism with chemokines playing an important role in it. 9 The main function of chemokines and their receptors is to attract immune cells to the site of inflammation. In addition, these small molecules are involved in T-cell differentiation, apoptosis, cell cycle regulation, angiogenesis, metastatic processes and in the generation of soluble inflammatory products such as free radicals, nitric oxide, cytokines and matrix metalloproteases. 9 In humans, approximately 50 chemokine genes have been described, which are divided into four subfamilies based on the characteristic patterns of cysteine residues close to the Nterminal end of molecules. In the CC chemokine ligand family (CCL) (also known as b-chemokines or small cytokine group A -(SCYA)), the two cysteines are adjacent to each other, while in the CXC and CX 3 C chemokine families the two cysteines are separated by one or three amino acids, respectively. In the XC family, only one cysteine is present. 10 Recently, two quantitative trait loci (QTL), eae6 and eae7, were investigated by classic marker-specific linkage and interval mapping in a murine experimental allergic encephalomyelitis (EAE) model. Eae 6 and eae7 mapped to a region of mouse chromosome 11 syntenic to human chromosome 17q11. Eae 6 and eae7 were implicated in the severity and duration of the clinical presentation of EAE. Howe...

Background: Current disease-modifying therapies (DMTs) are of benefit only in people with relapsing forms of multiple sclerosis (RMS). Thus, safely stopping DMTs in people with secondary progressive MS may be possible. Methods: Two groups of patients with MS were studied. Group A consisted of 77 patients with secondary progressive MS and no evidence of acute central nervous system inflammation for 2 to 20 years. These patients were advised to stop DMTs. Group B consisted of 17 individuals with RMS who stopped DMTs on their own. Both groups were evaluated at treatment cessation and for a minimum of 1 year thereafter. Multiple variables were assessed to determine those that predicted recurrent acute disease. Results: Nine patients in group A (11.7%) and ten patients in group B (58.8%) had recurrent acute disease, almost always within 1 to 2 years of stopping treatment. The only variable of significance in group A distinguishing stable and relapsing patients was age (P = .0003), with relapsing patients being younger. Group B patients were younger and had significantly lower Expanded Disability Status Scale scores than group A, with no significant differences in age between relapsed and stable patients. Conclusions: The DMTs can be stopped safely in older patients with MS (≥7 decades) with no evidence of acute disease for 2 years or longer, with an almost 90% probability of remaining free of acute recurrence. The high proportion of untreated patients with RMS experiencing recurrent acute disease is consistent with published data.