Reports

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PRIORITY PRESS - 22nd Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC)

Denver, Colorado / May 28-31, 2008

Multiple sclerosis (MS) is a chronic progressive disease process with subclinical degeneration and axonal loss. The current paradigm for treating MS is to intervene early at the first clinical episode, i.e. clinically isolated syndrome (CIS). While CIS is primarily caused by an acute inflammatory event, axonal deterioration has already begun, emphasized Dr. Peter Rieckmann, Research Chair, MS Society of Canada and Director of the MS Program, University of British Columbia and Vancouver Coastal Health. “We don’t want to wait for more relapses [before beginning treatment],” he continued. “MS never sleeps.” Early predictors of a more severe disease course include T2 lesion load by MRI, intrathecal IgG bands, and multifocal onset as detected by evoked potentials.

MRI has become a critical tool for establishing a diagnosis of MS at CIS. Dr. Anthony Traboulsee, Department of Medicine, Division of Neurology, Research Group MS/MRI, University of British Columbia, strongly recommended the use of the international, standardized clinical protocol for MRI in suspected MS (CMSC Consensus Guidelines, 2006). This approach, which uses both T2 and gadolinium-enhanced T1 images, can help identify which patients with CIS will likely progress to clinically definite MS (CDMS). Of those who have an abnormal MRI at first attack, 65% to 90% develop MS within five years of onset. Of those who have a normal MRI at first attack, only 3% to 20% go on to develop MS.

The early diagnosis of CIS is ultimately clinical, however; with no single, universally accepted laboratory work-up, a differential diagnosis must be excluded, explained Dr. Heather MacLean, Assistant Professor Neurology, University of Ottawa and Ottawa Hospital, Ontario. Her list of the top 10 differential diagnoses included stroke, migraine, systemic lupus erythematosus, Sjögren’s syndrome, sarcoidosis, central nervous system vasculitis, CNS lymphoma, acute disseminated encephalomyelitis, neuromyelitis optica, and Lyme disease. Major “red flags” include an atypical history (including age of presentation), normal MRI, or normal findings for cerebrospinal fluid evaluation.

Clinical Trials Support Early Treatment

“I think you can create a good rationale for early treatment in MS,” stated Dr. Patricia K. Coyle, Director, MS Comprehensive Care Center, Stony Brook University Medical Center, New York. Once MS is clinically apparent, she explained, the disease course is already underway, with potentially irreversible damage beginning very early. Furthermore, current disease-modifying treatments (DMTs) work much better if used early. “There truly is a window of opportunity for treatment,” Dr. Coyle continued, explaining that immediate treatment once CIS is identified appears to be changing the natural history of MS. She reviewed four phase III clinical trials that have documented benefits of early treatment.

Results from CHAMPS (Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study) and ETOMS (Early Treatment of MS) showed that the use of interferon (IFN) beta-1a (i.m. and s.c.) delayed conversion to CDMS in patients with CIS over the period of two years. MRI lesion burden was also decreased. In the BENEFIT (Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment) study, immediate treatment with IFN beta-1b at CIS reduced the risk of a second attack by 41% at three years (hazard ratio [HR], 0.59; 95% CI, 0.44-0.80; P=0.0011; absolute risk reduction 14%) and, using more sensitive McDonald MRI criteria, delayed conversion to MS by 46% at three years (HR, 0.54; P=0.000007). MRI results at two years also showed a reduction in the cumulative number of newly active lesions and the T2 lesion volume (disease burden). “The most remarkable finding of all was the decrease in the development of disability at three years in the patients who had received early DMT,” emphasized Dr. Coyle, citing a 40% cumulative relative risk reduction based on a 1.0 change in the Expanded Disability Status Scale (EDSS) (HR, 0.60; 95% CI, 0.39-0.92; P=0.022; absolute risk reduction 8%). Results from PreCISe (the Study to Evaluate the Effect of Early Glatiramer Acetate Treatment in Delaying the Conversion to CDMS in Subjects Presenting With a Clinically Isolated Syndrome) also confirmed that early treatment, in this case with glatiramer acetate (GA), delayed the time to CDMS (placebo, 336 days; GA, 722 days; P=0.0005).

Longer-term Data Important

Dr. Mark Freedman, Director, MS Research Unit, University of Ottawa, emphasized that additional, long-term studies are needed to ascertain whether initiating treatment at CIS will translate into better long-term outcomes. While MS is a disease of 30 to 40 years’ duration, most studies of MS therapies last only two to three years. Some longer-term results are beginning to be available, however. Data over three years (an extension of BENEFIT) and five years (an extension of CHAMPS called CHAMPIONS [Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance]) indicate the continued effect of these drugs beyond two years. The BENEFIT expansion was also the first CIS trial to show a statistically significant effect in slowing EDSS progression at three years: the risk of confirmed EDSS progression was reduced by 40% over three years (P=0.022) in the early treatment group. Relapse rates no longer differed by year 3, but the EDSS progression curves continued to diverge. The release of five-year results from BENEFIT is anticipated in the near future.

Improving Treatment Adherence

Despite known advantages of early intervention with DMTs, patients face barriers to initiating and continuing treatment. Ms. Amy Perrin Ross, APN, MSN, CNRN, MSCN, Neuroscience Program Coordinator, Loyola University School of Medicine, Maywood, Illinois, summarized the major reasons for treatment discontinuations, which include adverse events linked to DMTs (injection-site reactions, flu-like symptoms, depression, fatigue) and perceived lack of treatment efficacy. Ms. Ross recommended management of treatment-related adverse events to increase patient adherence using, for example, dose titration, analgesics, injection-site rotation, autoinjectors and local measures such as ice packs. She also emphasized that MS nurses and other MS team members can play important roles in promoting adherence to treatment.

Dr. Randall Schapiro, adult neurologist, The Schapiro Center for Multiple Sclerosis, Minneapolis Clinic of Neurology, Minnesota, reviewed results from a study “Barriers to Treatment Commitment.” Participants included 220 Canadian and US patients living with MS. For those who had used injectable medications (n=193), the most important barrier was “not being able to afford treatment (27% of respondents),” with 21% citing “not wanting to inject myself” as a barrier. At least one medication–related side effect was listed by 41% of patients as an extremely strong or very strong barrier. Motivating factors included the knowledge that medication could decrease the risk of disability in the long term (81%), and 69% would have started treatment earlier if they had known it would reduce the risk of disability. External support was an additional strong motivator. Dr. Patricia A. Farrell, clinical psychologist, Englewood Cliffs, New Jersey, discussed relaxation and positive self-talk to control anxiety related to self-injection. Nurses are particularly important in helping patients reduce this anxiety and change a patient’s firm belief that he is unable to self-inject.

Summary

Evidence from clinical trials supports treating MS early, at the first clinical episode (CIS). Doing so can delay conversion to CDMS, reduce the cumulative number of newly active lesions detected by MRI, reduce lesion volume (disease burden), and decrease the development of disability in the first three years. Patient support to improve adherence is essential for optimal early treatment.