Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate.

The ongoing US Glatiramer Acetate (GA) Trial is the longest evaluation of continuous immunomodulatory therapy in relapsing-remitting multiple sclerosis (RRMS). The objective of this study was to evaluate up to 15 years of GA as a sole disease-modifying therapy. Two hundred and thirty-two patients received at least one GA dose since study initiation in 1991 (mITT cohort), and 100 (43%, Ongoing cohort) continued as of February 2008. Patients were evaluated every 6 months using the Expanded Disability Status Scale (EDSS). Mean GA exposures were 8.6 +/- 5.2, 4.81 +/- 3.69, and 13.6 +/- 1.3 years and mean disease durations were 17, 13, and 22 years for mITT, Withdrawn and Ongoing cohorts, respectively. For Ongoing patients, annual relapse rates (ARRs) maintained a decline from 1.12 +/- 0.82 at baseline to 0.25 +/- 0.34 per year; 57% had stable/improved EDSS scores (change < or = 0.5 points); 65% had not transitioned to secondary progressive multiple sclerosis (SPMS); 38%, 18%, and 3% reached EDSS 4, 6, and 8. For all patients on GA therapy (the mITT cohort), ARRs declined from 1.18 +/- 0.82 to 0.43 +/- 0.58 per year; 54% had stable/improved EDSS scores; 75% had not transitioned to SPMS; 39%, 23%, and 5% reached EDSS 4, 6, and 8. In conclusion, multiple sclerosis patients with mean disease duration of 22 years administering GA for up to 15 years had reduced relapse rates, and decreased disability progression and transition to SPMS. There were no long-term safety issues.

Failure to develop multiple sclerosis in patients with neurologic symptoms without objective evidence.

BACKGROUND: Many patients referred to multiple sclerosis (MS) centers with symptoms suggestive of MS are found to have normal neurologic examinations, normal or non-specific brain magnetic resonance imaging (MRI) scan findings, and normal cerebrospinal fluid (CSF). Persistent symptoms often lead to multiple consultations and repeated diagnostic investigations. We performed a study to evaluate the diagnostic utility of repeated evaluations in patients with normal initial assessments and persistent neurologic symptoms. METHODS: 143 patients were evaluated initially and 109 returned for a second evaluation after a mean interval of 4.4 years. RESULTS: All 143 patients had normal initial examinations, brain MRI scans, screening blood tests, and CSF studies. Spinal cord imaging was normal in all patients tested (cervical cord, n = 126; 88.1%; thoracic cord, n = 58; 40.6%). Evoked potential studies were abnormal in a small percentage of patients: visual evoked potentials, VEP (8.1%), somatosensory evoked potentials, SSEP (4.9%), and brainstem auditory evoked potentials, BAEP (2.8%). All follow-up patients (n = 109) had normal examinations and MRI scans. Repeat CSF studies (n = 35; 32.1%) and spinal cord imaging (cervical cord n = 57; 52.3%; thoracic cord n = 32; 29.4%) were normal in all follow-up patients tested. No patients at initial presentation or at follow-up fulfilled diagnostic criteria for MS. PATIENTS: and clinicians may be reassured that persistent neurologic symptoms in the absence of objective clinical evidence do not lead to the development of MS. Costly serial investigations should be carefully considered, particularly in the presence of normal neurologic examination at follow-up.

Oral prednisone taper following intravenous steroids fails to improve disability or recovery from relapses in multiple sclerosis.

BACKGROUND: A short course of intravenous methylprednisolone (IVMP) followed by oral prednisone taper (OPT) is often used for the treatment of relapses in multiple sclerosis (MS). We examined the effect of IVMP plus OPT compared with IVMP only on neurologic disability 1 year after treatment of a relapse in patients with relapsing-remitting multiple sclerosis. METHODS: Two hundred eighty-five consecutive relapses were analyzed in a retrospective fashion. One hundred fifty-two patients with a total of 171 relapses received IVMP plus an OPT at the time of relapse whilst 112 patients who experienced 114 relapses received IVMP without OPT. RESULTS: There was no difference between the two groups in the baseline characteristics as well as the mean or categorical EDSS at baseline, at the time of relapse confirmation, and at months 3, 6 and 12 after relapse confirmation. CONCLUSION: Our observations suggest that OPT following treatment with IVMP for an MS relapse does not lead to improved neurologic outcome after 12 months compared with treatment with IVMP only. Moreover, our findings raise concerns regarding the common practice of using OPT following IVMP. Further studies are indicated to validate our findings and minimize exposure to systemic corticosteroids, well known for systemic toxicity.

Predictors of well-being among significant others of persons with multiple sclerosis.

OBJECTIVE: To examine patient and significant other characteristics as predictors of significant other well-being. METHODS: A total of 74 persons with multiple sclerosis (MS) and their significant others participated. Executive functioning was measured using neuropsychological tests. Awareness of cognitive deficit was measured as the discrepancy between the patient's reports of their abilities and objective test results. Awareness of functional deficit was measured as the discrepancy between the patient's and significant other's reports of the patient's functional abilities. Patient neurobehavioral disturbance was measured using a significant-other rated questionnaire. Significant other perceived social support and well-being (ie, psychological distress, life satisfaction, and general health status) were assessed using questionnaires filled out by the significant other. RESULTS: Executive dysfunction, neurobehavioral disturbance, and lack of awareness of functional deficits in patients were associated with poor well-being outcomes; whereas, lack of awareness of cognitive deficits was only weakly related to well-being. Social support was associated with positive well-being outcomes. CONCLUSIONS: Diminished insight regarding functional limitations may increase significant others' supervisory burden as patients attempt activities independently, whereas lack of awareness of cognitive deficits may not be directly associated with behavior-relevant impairments that significant others find distressing. Social support appears to be a powerful aid in diffusing the distress among significant others of MS patients.

A prospective open-label study of glatiramer acetate: over a decade of continuous use in multiple sclerosis patients.

A decade of continuous glatiramer acetate (GA) use by relapsing remitting multiple sclerosis (RRMS) patients was evaluated in this ongoing, prospective study, and the neurological status of 'Withdrawn' patients was assessed at a 10-year long-term follow-up (LTFU) visit. Modified intention-to-treat (mITT, n=232) patients received > or =1 GA dose since 1991; 'Ongoing' patients (n = 108) continued in November 2003. Of 124 patients, 50 Withdrawn patients returned for LTFU. Patients were evaluated every six months (EDSS). Mean GA exposure was 6.99, 10.1 and 4.26 years for mITT, Ongoing, and Withdrawn/LTFU patients, respectively. While on GA, mITT relapse rates declined from 1.18/year prestudy to approximately 1 relapse/5 years; median time to > or = 1 EDSS point increase was 8.8 years; mean EDSS change was 0.73 +/- 1.66 points; 58% had stable/improved EDSS scores; and 24, 11 and 3% reached EDSS 4, 6 and 8, respectively. For Ongoing patients, EDSS increased 0.50 +/- 1.65; 62% were stable/improved; and 24,8 and 1% reached EDSS 4, 6 and 8, respectively. For Withdrawn patients at 10-year LTFU, EDSS increased 2.24 +/- 1.86; 28% were stable/improved; and 68, 50 and 10% reached EDSS 4, 6 and 8, respectively. While on GA nearly all patients (mean disease duration 15 years) remained ambulatory. At LTFU, Withdrawn patients had greater disability than Ongoing patients.

Clinical course after change of immunomodulating therapy in relapsing-remitting multiple sclerosis.

We examined the clinical course after switching disease-modifying therapy (DMT) in patients with relapsing-remitting multiple sclerosis (RRMS). Eighty-five consecutive RRMS patients who received weekly interferon beta-1a (IFN beta-1a) 6 MU i.m. for at least 18 months were enrolled. Baseline annualized relapse rate (ARR) for the 2 years prior to initiating therapy with IFN beta-1a was obtained from charts. All 85 patients received treatment with IFN beta-1a at 6 MU i.m. weekly for 18-24 months (mean 19.7 months). Treatment with IFN beta-1a reduced the mean ARR from 1.41 to 1.23 (P=0.005). All 85 patients were then switched to glatiramer acetate (GA) 20 mg s.c. daily and prospectively followed up for 36-42 months (mean 37.5 months). Patients were switched because of persistent clinical disease activity (n=62) or persistently unacceptable toxicity (n=23) as determined by the treating neurologist. Treatment with GA reduced the mean ARR from 1.23 to 0.53 (P=0.0001). Subgroup analysis showed that in patients who were switched because of lack of efficacy (n=62), the mean ARR was reduced from 1.32 on IFN beta-1a to 0.52 on GA (P=0.0001). In contrast, in patients who switched because of persistent toxicity (n=23), the mean ARR was reduced from 0.61 on IFN beta-1a to 0.47 on GA (P, non-significant). Our observations suggest that clinical observations such as relapse rate and tolerability may be used as criteria for switching DMT in clinical practice. More definitive consensus criteria incorporating magnetic resonance imaging and clinical observations for defining optimal response and tolerability need to be developed for the routine clinical management of RRMS patients receiving DMT.

Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for immune-related molecules by central nervous system mixed glial cell cultures.

Cytokines secreted within the central nervous system (CNS) are important in the development of multiple sclerosis (MS) lesions. The balance between Th1, monocyte/macrophage (M/M) and Th2 cytokines in the CNS may be pivotal in determining the outcome of lesion development. We examined the effects of mixtures of cytokines on gene expression by CNS glial cells, as mixtures of cytokines are present in MS lesions, which in turn contain mixtures of glial cells. In this initial analysis by gene array, we examined changes at 6 hours to identify early changes in gene expression that represent primary responses to the cytokines. Rat glial cells were incubated with mixtures of Th1, M/M and Th2 cytokines for 6 hours and examined for changes in early gene expression employing microarray gene chip technology. A minimum of 814 genes were differentially regulated by one or more of the cytokine mixtures in comparison to controls, including changes in expression in a large number of genes for immune system-related proteins. Expression of the proteins for these genes likely influences development and inhibition of MS lesions as well as protective and regenerative processes. Analysing gene expression for the effects of various combinations of exogenous cytokines on glial cells in the absence of the confounding effects of inflammatory cells themselves should increase our understanding of cytokine-induced pathways in the CNS.

Neurologic consequence of delaying glatiramer acetate therapy for multiple sclerosis: 8-year data.

OBJECTIVE: To assess the long-term effectiveness of continuous glatiramer acetate (GA) therapy in relapsing-remitting multiple sclerosis (RRMS). METHODS: This open-label extension followed a randomized, placebo-controlled, double-blind study of GA of approximately 30 months duration. Patients originally randomized to GA continued on it (group A) and those randomized to placebo switched to GA (group B). RESULTS: Of 251 original patients, 142 (56.6%) remained in the study after 8 years. Annual relapse rate for both groups declined to approximately 0.2 (approximately one relapse every 5 years). However, a significantly larger proportion of patients in group A had stable or improved Expanded Disability Status Scale scores compared with group B (65.3% vs 50.4%, respectively; P = 0.0263), possibly attributable to the delay of GA treatment for approximately 30 months in group B. GA was well tolerated and no drug-related laboratory changes were observed. CONCLUSIONS: These data support early initiation of GA therapy as an efficacious and well-tolerated long-term treatment for RRMS patients.

Glatiramer acetate (Copaxone): comparison of continuous versus delayed therapy in a six-year organized multiple sclerosis trial.

The aim of this study was to assess the long-term safety and efficacy of glatiramer acetate (GA) for patients with multiple sclerosis (MS) who received active treatment versus those on placebo for approximately 30 months (24-35 months) before receiving GA during a six-year organized, prospective open label study. Entry required two relapses in the previous two years and an Expanded Disability Status Scale (EDSS) score of 0-5. Patients (251) were equally randomized to daily subcutaneous GA, 20 mg, or to placebo. After approximately 30 months, 208 patients continued in an open label study: 101 continued on GA and 107 switched from placebo to active drug. Groups were well matched at randomization and entry to the open label study. Patients always on GA showed a steady decline in relapses: a mean of 1.5 per year at entry, a mean of 0.42 over the entire six years (95% CI = 0.34-0.51), a 72% reduction (P = 0.0001). They averaged a relapse every four + years (yearly rate 0.23 in year six) and 26/101 remain relapse free. Patients did less well if on placebo for 30 months, but relapses then declined, and by year six the rates were similar. Of patients always on GA, 69% showed neurological improvement of > or = 1 EDSS steps or remained stable compared with 57% if GA treatment was delayed. Of relapse-free patients always on GA over six years, only three of 26 (11%) were worse by > or = 1 EDSS steps, whereas nine of 21 (43%) in the placebo/active group were worse (P < 0.03). Disability, measured every six months, showed that the group of patients always on GA was relatively stable over the six years, while the group who received placebo for the first two-and-a-half years did significantly less well. Daily injections of GA were well tolerated. This longest ever organized MS treatment trial shows that delaying therapy with GA increases the risk of neurologic disability, reinforcing the rationale for using GA as a first-line treatment early in the course of relapsing-remitting MS.

Intercaudate nucleus ratio as a linear measure of brain atrophy in multiple sclerosis.

Intercaudate nucleus ratio (ICR) is a linear measure of brain atrophy that does not require software application and is independent of image acquisition techniques. The authors examined the relationship between ICR and disability in 190 patients with MS. The results show that ICR correlates with Expanded Disability Status Scale score (r = 0.67; p = 0.0001) and disease duration (r = 0.32; p < 0.01). Intercaudate ratio appears to be a reliable and reproducible linear measure of brain atrophy and correlates with disability and disease duration in MS.

Reporting clinical trials: full access to all the data.

Authors' right to access to all data obtained in their study

Interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta inhibit cyclic AMP-induced Schwann cell differentiation.

Schwann cells differentiate in vivo in response to contact with axons, and cAMP simulates some of these aspects of differentiation in vitro, particularly morphologic changes and expression of certain phenotypic molecules. Unfractionated inflammatory cytokines inhibit cAMP-induced Schwann cell expression of galactolipids (Gal). We sought to identify which cytokines were responsible for this inhibition and to determine whether other phenotypic indicators of Schwann cell differentiation were also affected. Neonatal rat Schwann cells were incubated in vitro with 1 mM 8 Bromo cAMP (8 Br cAMP) with or without the addition of interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-6, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), or transforming growth factor-beta (TGF-beta). Cells were then examined for morphologic changes and for expression of surface Gal and low-affinity nerve growth factor receptor (NGFRp75), employing indirect immunofluorescence. 8 Br cAMP induced Schwann cell upregulation of Gal, downregulation of NGFRp75, and the cells became enlarged and somewhat amorphous and irregular in appearance. Cells treated with IFN-gamma or TNF-alpha alone were more bipolar and more evenly distributed on coverslips than were control cells, whereas TGF-beta alone induced elongated cells often in a swirling pattern. None of the cytokines alone induced upregulation of Gal or downregulation of NGFRp75. TNF-alpha, IFN-gamma, and TGF-beta inhibited the 8 Br cAMP-induced morphologic changes, as well as the upregulation of Gal and downregulation of NGFRp75. The other cytokines had no effects on Gal or NGFRp75 expression. Thus, these three cytokines, which are present in inflammatory lesions in the peripheral nervous system, are capable of inhibiting Schwann cell differentiation.

Expression of urokinase plasminogen activator receptor on monocytes from patients with relapsing-remitting multiple sclerosis: effect of glatiramer acetate (copolymer 1).

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system in which peripheral blood monocytes play an important role. We have previously reported that patients with chronic progressive MS (CPMS) have significantly increased numbers of circulating monocytes which express the urokinase plasminogen activator receptor (uPAR). In the present study, we examined the expression of uPAR on monocytes in patients with relapsing-remitting multiple sclerosis (RRMS) not currently participating in a clinical trial and in patients with RRMS who were enrolled in a double-blind multicenter clinical trial designed to examine the effect of glatiramer acetate (copolymer 1; Copaxone) on relapsing disease. Patients with CPMS have sustained high levels of circulating uPAR-positive (uPAR(+)) monocytes. In comparison, patients with RRMS displayed variable levels of circulating uPAR(+) monocytes. Mean values for uPAR in patients with RRMS were above those seen for controls but were not as high as those observed for patients with secondary progressive MS. Patients with RRMS in the clinical trial also had variable levels of monocyte uPAR. However, patients in the treatment group displayed lower levels following 2 years of treatment. In both placebo-treated and glatiramer acetate-treated patients, the percentage of circulating uPAR(+) monocytes, as well as the density of uPAR expressed per cell (mean linear fluorescence intensity), increased just prior to the onset of a clinically documented exacerbation. Values fell dramatically with the development of clinical symptoms. uPAR levels in all groups correlated with both clinical activity and severity. Results indicate that monocyte activation is impatient in MS and that glatiramer acetate may have a significant effect on monocyte activation in patients with RRMS.

Use of intravenous gamma globulins in neuroimmunologic diseases.

Intravenous gamma globulin (IVIg) is used in the treatment of immunologic diseases that affect the entire neuroaxis, including the brain, spinal cord, peripheral nerves, muscles, and neuromuscular junction. The panel reviewed the available literature on the use of IVIg in order to evaluate the efficacy of this therapy in neuroimmunologic diseases. In prospective, rigorously controlled, double-blinded clinical trials, IVIg was found to have proven efficacy in the Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, dermatomyositis, and Lambert-Eaton myasthenic syndrome. It was found to be probably effective in myasthenia gravis and polymyositis, and possibly effective in several other neuroimmunologic diseases. Further studies are needed to evaluate the use of IVIg for neuroimmunologic diseases in which its efficacy is suspected but not proven and to elucidate its mechanisms of action.

Effect of monthly intravenous cyclophosphamide in rapidly deteriorating multiple sclerosis patients resistant to conventional therapy.

Fourteen consecutive clinically definite relapsing-remitting multiple sclerosis (MS) patients were treated with monthly intravenous cyclophosphomide (CTX) for 6 months. All had experienced severe dinical deterioration during the 12 months prior to treatment with CTX despite treatment with conventional immunomodulating agents and intravenous methylprednisolone. Treatment with CTX led to improvement and neurologic stability within 6 months which was sustained for at least 18 months after the onset of treatment with CTX. Therapy with CTX was well tolerated. CTX may be of benefit in MS patients who experience rapid clinical worsening and are resistant to conventional therapy.

The thymus and myasthenia gravis.

Self acetylcholine receptor (AchR) is targeted by a wayward immune response in myasthenia gravis (MG). The current understanding of the pathogenesis of the AChR-directed immune response is reviewed. Furthermore, the thymus is suspected of initiating and perpetuating the disease process in the majority of patients; its role as a central and peripheral lymphoid organ in MG is discussed. MG seems to result from a failure of (1) establishing tolerance to the AChR and (2) regulating the immune response.