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60th Annual Meeting of the American Academy of Neurology

Chicago, Illinois / April 12-19, 2008

Clinical evidence strongly suggests that early treatment is necessary in patients with clinically-definite or McDonald-positive multiple sclerosis (MS). However, it is seen as less certain that patients experiencing a first event suggestive of this disease require similar treatment. Recently, data from the Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) trial has confirmed a rationale for early treatment. The 468-patient study found that initiation of interferon beta-1b (IFN beta-1b) treatment in patients with a first clinically demyelinating event and evidence on MRI was associated with a significant 40% reduced risk of confirmed Expanded Disability Status Scale (EDSS) progression over three years compared to delayed treatment. New evidence broadens the recommendation for use of early treatment to include patients presenting with clinically isolated syndrome (CIS).

Early Rather than Delayed Treatment of RRMS

Prompted by an absence of data on the impact of early vs. delayed IFN beta-1b treatment on long-term disability in relapsing-remitting (RRMS) patients, Dr. Maria Trojano, Department of Neurological and Psychiatric Sciences, University of Bari, Italy, used a Cox proportional hazards regression adjusted for propensity score to assess differences between patients assigned to early treatment and those assigned to delayed treatment in terms of time since their treatment assignment to reach EDSS levels 4 and 6. Different models were calculated according to early treatment cut-off ranging from one to five years from disease onset. A Recursive Partitioning and Amalgamation (RECPAM) algorithm examined interactions among several baseline covariates and allowed the researchers to identify distinct patient groups in terms of incidence of EDSS levels 4 and 6.

Results showed that early treatment significantly decreased the risk of EDSS 4 (hazard ratio [HR], 0.67; 95% CI, 0.49-0.93; P=0.017) and trended to a reduction in EDSS 6 (HR, 0.58; 95% CI, 0.31-1.08; P=0.087) compared with delayed treatment. The RECPAM algorithm showed that the highest rates of early treatment benefit occurred in two patient groups: the first group included patients with baseline EDSS between 2.5 and 3 and more than one attack (risk reduction for EDSS 4: HR, 0.19; 95% CI, 0.07-0.52; P=0.0012); the second group included patients with a baseline EDSS between 2 and 2.5 (risk reduction for EDSS 6: HR, 0.25; 95% CI, 0.06-1.06; P=0.059).

Dr. Trojano indicated that the results support early rather than delayed IFN beta treatment for staving off long-term disability in RRMS, with the greatest benefit anticipated in patients with mild disability and/or high disease activity.

Corroborative Evidence

A previous Cochrane meta-analysis had reported that the efficacy of IFN beta in reducing disease activity does not extend beyond the first year of treatment. However, as reported here at the AAN by Dr. Marinella Clerico, Department of Clinical and Biological Sciences, Division of Neurology, Ospedale Universitario, S. Luigi Gonzaga, Università di Torino, Italy, and associates, results from a new Cochrane meta-analysis of published trials support the use of early IFN beta treatment for reducing the risk of conversion from CIS to clinically definite MS (CDMS).

Dr. Clerico and co-investigators assessed the efficacy of early IFN beta treatment in reducing the risk of conversion using information obtained from seven published articles. All patients in whom treatment was initiated had a long disease history. The articles focused on three studies: Controlled High Risk Avonex Multiple Sclerosis Trial (CHAMPS) and Early Treatment of Multiple Sclerosis (ETOMS), both of which used once-weekly low-dose IFN beta 1a (30 mcg i.m.or 22 mcg s.c.); and BENEFIT, which used IFN beta 1b 250 mcg s.c. every other day. These studies had different primary outcome measures: the occurrence of a second clinical episode or of disease progression for CHAMPS, the occurrence of a second clinical episode for ETOMS, and time to CDMS for BENEFIT.

Per-protocol analyses indicated that IFN beta treatment significantly delayed conversion to CDMS in all studies. The meta-analysis at one year was significant in per-protocol analysis and in most sensitivity analyses. The meta-analysis at two years, which was possible only for ETOMS and BENEFIT, was significant both in per-protocol as well as all sensitivity analyses.

“While the results strongly demonstrate that the benefit of IFN beta given early on is sustained at two-year follow-up, we still need to determine whether different types of CIS presentation have a different sensitivity to immunomodulatory treatment,” Dr. Clerico remarked. “The identification of different responses to early therapy on the basis of different types of presentation would allow clinicians to better tailor treatments to the individual patient.”

Clinical Markers Correlate Well with Long-term Outcome

Baseline EDSS value can provide clinicians with a good evaluation of the patient’s likely long-term outcome when treated early with IFN beta-1b, according to results from the 16-year Long-Term Follow-Up (LTF) study. Dr. Douglas Goodin, Director, UCSF Multiple Sclerosis Center and Professor of Neurology, University of California, San Francisco, and colleagues evaluated long-term outcomes in RRMS patients who participated in the IFN beta-1b pivotal study from 1989 to 1993.

Results in 328 of the original 372 patients showed that baseline EDSS values of >2 predicted poorer outcome. MRI markers were not strongly correlated with outcome. IFN beta-1b treatment showed an excellent safety and tolerability profile, with side effects and neutralizing antibodies decreasing over time. “Current trends toward early treatment initiation, as supported by recent three-year data from BENEFIT, appear to be supported by these analyses,” commented Dr. Goodin.

EDSS and MRI Disease Burden Predict Cognitive Status at 16 Years

The LTF study has also yielded important information on predictors of long-term cognitive status. In short, some of the best predictors of cognition at 16 years appear to be baseline neurological variables. According to Dawn Langdon, PhD, Reader in Neuropsychology, Royal Holloway, University of London, UK, “Cognition is not routinely tested in detail in the clinic or within the context of clinical trials. In addition, the relation of EDSS to cognition is not clear from the literature. In fact, a significant relation between cognitive test results and EDSS has only been demonstrated in large-scale, single-centre studies.” Furthermore, the relation of MRI parameters to cognition has not been consistent, particularly in individual cognitive test scores.

Dr. Langdon’s team found that pre-morbid intellectual level, EDSS and burden of disease on MRI obtained at enrolment were the best predictors of cognition 16 years later. “What this says is that ‘the story’ of the disease is written very early and clinicians can know early on how the disease will develop over time,” she told delegates. “For example, a patient with a higher EDSS and T2 lesion load within a year or two of being diagnosed will likely have greater cognitive impairment.”

EDSS, Clinical Assessment Help Predict Course of Early MS

New data suggest that nadir EDSS can help predict which patients with CIS are at high risk of a second clinical event. The results come from a meta-analysis of placebo arms of two phase III trials in a total of 136 CIS patients at high risk for MS. Clinical variables examined in the analysis included baseline MRI parameters and nadir EDSS, defined as evidence of on-study EDSS score recovery before the second clinical event compared to baseline. “Since recent data suggest that early treatment of CIS has clinical benefit, it is crucial to identify, as early as possible, CIS patients at high risk for developing MS,” indicated Dr. Anneke Neuhaus, Sylvia Lawry Center for Multiple Sclerosis Research, Munich, Germany.

A conscientious neurological assessment of symptoms and signs is also important for defining the risk of conversion to CDMS, researchers reported. Using 468 patients enrolled in BENEFIT for their analysis, Dr. Jessica M. Nielson, Department of Neurology, VU University Medical Centre, Amsterdam, The Netherlands, and colleagues found no difference in time to CDMS between monofocal and multifocal patients. In monofocal patients, the risk for CDMS over two years was significantly higher when nine or more T2 lesions were present at the first event, or when at least one gadolinium-enhancing lesion was present at the first event or at the third or sixth month after the first event. In patients with a multifocal presentation, these MRI parameters had no significant predictive value for time to CDMS.

Summary

Since the CHAMPS, ETOMS and BENEFIT trials, there has been a paradigm shift in the treatment of MS as new corroborative evidence broadens the recommendation for use of early treatment to now include people with CIS. For these patients, IFN beta treatment may be used to prevent long-term disability in the presence of mild to high disease activity. Furthermore, EDSS and burden of disease on MRI appear to be independent predictors of cognition of 16 years post-diagnosis. These latest findings further reinforce the current trend towards early treatment initiation.