Multiple sclerosis (MS), a T-cell-mediated chronic inflammatory disease of the CNS characterised by demyelination and axonal loss, is a common cause of neurological disability in young adults, affecting over a million people worldwide. Research in this disease area is ongoing, and the results of key recent studies are described here, along with one patient’s experience of current MS drugs.
Interferon beta-1b in secondary-progressive MS
Based on a prospectively planned interim analysis, the European study of interferon beta-1b (IFN beta-1b) provided evidence that treatment delays neurologic deterioration in patients with secondary-progressive MS (SPMS). The authors analysed all data collected until closure of the double-blind study to further scrutinise the consistency of the findings. The final analysis was published at the end of 2001.
The multicentre, double-blind, randomised, placebo- controlled trial treated patients for up to 36 months. The primary and all secondary endpoints were evaluated using the dataset at study termination. Alternative and more demanding definitions of disease progression were also explored. Confirmed progression was analysed in subgroups according to baseline demographics and baseline indicators of disease activity.
Researchers looked at the Expanded Disa-bility Status Scale (EDSS) progression for both groups and found that time to confirmed 1.0-point EDSS progression for patients receiving IFN beta-1b was delayed. The proportion of patients with a confirmed 2.0-point EDSS progression was approximately 27% lower for the group treated with IFN beta-1b, both including and excluding EDSS data collected during relapses. The proportion of patients with either progression or relapses decreased by nearly 30% in patients treated with IFN beta-1b compared with placebo.
Analysis of subgroups suggested that patients with higher prestudy disease activity (more than two relapses or EDSS progression by more than 1.0 point or both) seemed to have a more pronounced treatment effect.
Analysis of the dataset at study termination including additional posthoc outcome measures was consistent with original findings. The results of this study support the conclusion that treatment with IFN beta-1b is effective in patients with SPMS fulfiling the inclusion criteria of this study.
Kappos L, Polman C, Pozzilli C, et al. Final analysis of the European multicenter trial on IFN beta-1b in secondary-progressive MS. Neurology 2001;57(11):1969-75.
The CHAMPS study
The Controlled High Risk Avonex(®) Multiple Sclerosis Study (CHAMPS) was an American study that tested whether interferon beta-1a (Avonex(®)) treatment would benefit patients who had experienced a first acute demyelinating event involving the optic nerve, brainstem/cerebellum or spinal cord, and who displayed magnetic resonance imaging (MRI) brain signal abnormalities, which had been shown previously to predict a high likelihood of future MS-like events.
The study randomised 383 patients into an Avonex(®)- treated and a placebo-treated group; both groups received intravenous methylprednisolone 1g/day followed by prednisone 1mg/kg for 11 days.
The Avonex(®)-treated group showed a 44% reduction in the three-year cumulative probability of developing clinically definite MS. At 18 months, treatment with Avonex® was associated with a significant reduction of new T2 lesions, gadolinium-enhanced lesions and T2 lesion volume. At 18 months in the placebo group, 82% of patients had developed a new subclinical MRI signal abnormality. Treatment benefit was observed irrespective of the qualifying event.
The findings of this study support the efficacy of Avonex(®) therapy in significantly reducing the three-year likelihood of future neurologic events and worsening of the brain MRI in patients with a first acute CNS demyelinating event.
Galetta SL. The Controlled High Risk Avonex(®) Multiple Sclerosis Trial (CHAMPS STUDY). J Neuroophthalmol 2001;21(4):292-5.
Chemokine receptor expression on B-cells and effect of interferon beta in MS
A group from the MS Clinic in Glostrup Hospital, Denmark, investigated the B-cell expression of chemokine receptors CXCR3, CXCR5 and CCR5 in the blood and cerebrospinal fluid (CSF) from patients in relapse of MS and in neurological controls. Chemokine receptor expression was also studied in interferon beta-treated patients with relapsing-remitting or SPMS.
Results showed significantly higher expression of CXCR3 on B-cells in the CSF in active MS than in controls. Patients with active MS also had higher B-cell expression of CCR5 in blood. No major differences between RRMS and SPMS patients were detected, and chemokine receptor expression was not affected by interferon beta treatment.
Sorenson TL, Roed H, Sellebjerg F. Chemokine receptor expression on B cells and effect of interferon-beta in multiple sclerosis. J Neuroimmunol 2002;122:125-31.
Update on the therapeutic potential of PDE4 inhibitors
Phosphodiesterase (PDE) enzymes are responsible for the inactivation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Phosphodiesterase-4 (PDE4) is a cAMP-specific phosphodiesterase expressed in inflammatory cells such as eosinophils. Inhibition of PDE4 results in an elevation of cAMP in these cells, which in turn downregulates the inflammatory response. The anti-inflammatory effects of PDE4 inhibitors have been well documented both in vitro and in vivo in a range of animal models.
The potential use of PDE4 inhibitors as anti-inflammatory agents for the treatment of diseases such as asthma, chronic obstructive pulmonary disease (COPD) and MS has received considerable attention from the pharmaceutical industry, but to date there are no selective PDE4 inhibitors on the market.
Early PDE4 inhibitors, such as rolipram, suffered from
dose-limiting side-effects, including nausea and emesis, which severely restricted their therapeutic utility. Second-generation compounds, such as cilomilast, have been identified with reduced side-effect liability. Indeed, cilomilast is showing good therapeutic effects in clinical trials for asthma and COPD, and represents the most advanced selective PDE4 inhibitor for any indication.
The utility of this class of inhibitor in other inflammatory diseases is less well advanced. However, data in animal models of rheumatoid arthritis and MS suggest that there is also significant potential for PDE4 inhibitors as treatments for these diseases, and the results of clinical trials in these disease areas are eagerly awaited.
Dyke HJ, Montana JG. Update on the therapeutic potential of PDE4 inhibitors. Expert Opin Investig Drugs 2002;11(1):1-13.
Efficacy and safety of modafinil for the treatment of fatigue in MS
Rammohan et al. from the Department of Neurology, Ohio State University, undertook a study to assess the efficacy and safety of modafinil for the treatment of fatigue in MS. Patients aged 18–65 years with a diagnosis of MS, a stable disability level less than or equal to 6 on the Kurtzke EDSS, and a mean score >4 on the fatigue severity scale (FSS) were eligible for the nine-week, single-blind, phase 2, two-centre study. Exclusion criteria included a diagnosis of narcolepsy, sleep apnoea, or clinically significant major systemic disease and recent use of medications affecting fatigue.
All patients, who remained blinded for the treatment regimen, received placebo during weeks 1–2, 200mg/day modafinil during weeks 3–4, 400mg/day modafinil during weeks 5–6, and placebo during weeks 7–9. Safety was evaluated by unblinded investigators. Efficacy was evaluated by self-rating scales, using the FSS, the modified fatigue impact scale (MFIS), a visual analogue scale for fatigue (VAS-F), and the Epworth sleepiness scale (ESS).
Adverse events were recorded.
Seventy-two patients (74% relapsing-remitting MS; 7% primary progressive MS; 19% SPMS) received treatment. After treatment with 200mg/day modafinil for two weeks, a significant improvement in fatigue versus placebo run-in was demonstrated. Fatigue scores for 400mg/day modafinil were not significantly improved versus placebo run-in. Mean ESS scores were significantly improved with 200mg/day modafinil (7.2) and 400mg/day (7.0) versus the score at baseline (9.5). Serious adverse events were not found at either dose. The most common adverse events were headache, nausea and asthenia. Sixty-five patients (90%) completed the study.
The authors concluded from these data that 200mg/day modafinil significantly improves fatigue and is well tolerated in patients with MS.
Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety of modafinil (Provigil®) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study.
J Neurol Neurosurg Psychiatry 2002;72(2):179-83.
International Federation of MS Societies
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3–6 April 2002
3rd World Congress in Neurological Rehabilitation
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9–11 Sept 2002
5TH International Congress of the International Society for Neuro-immunomodulation
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