Clinically Isolated Syndrome: BENEFIT of Early Treatment?

Early treatment of clinically isolated syndrome (CIS) with subcutaneous interferon beta 1b (IFN-b-1b; Betaseron) may reduce disability at 3 years, according to the latest news from the Betaferon/Betaseron in Newly Emerging MS For Initial Treatment (BENEFIT) study. The data were presented by Mark Freedman, MD, director of the Multiple Sclerosis Research Unit at the University of Ottawa, in Ontario, at the recent Annual Meeting of the American Academy of Neurology (AAN), held April 28 to May 5 in Boston.

Early treatment of clinically isolated syndrome (CIS) with subcutaneous interferon beta 1b (IFN-b-1b; Betaseron) may reduce disability at 3 years, according to the latest news1 from the Betaferon/Betaseron in Newly Emerging MS For Initial Treatment (BENEFIT) study. The data were presented by Mark Freedman, MD, director of the Multiple Sclerosis Research Unit at the University of Ottawa, in Ontario, at the recent Annual Meeting of the American Academy of Neurology (AAN), held April 28 to May 5 in Boston.

Subtypes of CIS, such as optic neuritis, brain stem symptoms, and partial myelitis, represent the first attack of multiple sclerosis (MS) in many patients.2 After experiencing CIS, most patients convert to clinical MS within 5 years.2 Clinical trials of intramuscular IFN-b-1a (Avonex),3 subcutaneous IFN-b-1a (Rebif),4 and subcutaneous IFN-b-1b5 have demonstrated that early treatment significantly slows the rate of conversion from CIS to clinically definite MS.

"This is the first study in patients with [CIS] to show a clinically relevant and statistically significant effect at delaying disability progression with IFN-b-1b or any other disease-modifying treatment," said Freedman.

MS is the most common inflammatory demyelinating disorder of the CNS,6 affecting 250,000 to 350,000 persons in the United States, many of them young adults in their most productive years.7 Women are affected twice as often as men, and symptoms may include bladder and bowel dysfunction, depression, fatigue, limb weakness, gait problems, and visual and sensory disturbances, leading to physical distress and disability.2,6

Clinical diagnosis relies on the occurrence of at least 2 typical episodes of CNS demyelination.2 The McDonald criteria, introduced in 2001 and revised in 2005, allow for the earlier diagnosis of MS by evaluating MRI lesions, cerebrospinal fluid (CSF) level, and evoked potential abnormalities.8 The cause of MS is unknown, although it has features of chronic autoimmune disease and may require an environmental trigger.6 In the United States, direct medical and nonmedical costs, production losses and informal care are estimated at $47,215 per patient per year.9

In the BENEFIT study, CIS was defined as a "first neurologic event suggestive of MS lasting for at least 24 hours and with symptoms and signs indicating either a single lesion [monofocal] or more than one lesion [multifocal] within the CNS." Participants had to be between the ages of 18 and 45 years and have at least 2 clinically silent T2-weighted lesions. The lesions had to be at least 3 mm in diameter and at least 1 had to be ovoid, periventricular, or infratentorial (as is typical in MS).5

Study participants with CIS were treated with IFN-b-1b (250 µg SC qod) (n = 292) or placebo (n = 176).5 At the 2-year evaluation, CIS progressed to clinically definite MS in 28% of the patients receiving IFN-b-1b and 45% of the patients receiving placebo (P < .0001).

According to Freedman in his presentation at the AAN meeting, at the end of the 2-year study, patients in the placebo group were invited to begin IFN-b-1b therapy. Of the 176 placebo-treated patients, 143 (81%) completed 12 months of treatment. At the end of a total 3 years since entry into the study, disease progressed in 24% of these patients compared with only 16% of patients treated with IFN-b-1b continuously (P = .0218).

In another follow-up study10 presented at the AAN meeting, Gilles Edan, MD, professor at the faculty of medicine, University of Rennes, France, reported that of the 12 (7.2%) placebo-treated patients in the BENEFIT study in whom further disease activity did not develop, 1 dropped out at 3 years and none of the remaining 11 showed signs of clinically definite MS, although MS, as defined by the McDonald criteria, developed in 2 patients.

Eight of these patients took IFN-b-1b for the third year of the study while 4 chose no treatment. Predictive factors influencing "inactivity" of disease were older age at onset (mean age, 36.8 vs 30 years; P = .0024), negative CSF findings (P = .0464), and the presence of 9 or fewer T2-weighted lesions at initial screening (P = .0455).

BUT IS EARLY TREATMENT RECOMMENDED?

Among the arguments for early treatment of disease activity that may be a sign of or that may progress to MS is the observation that although clinical relapses in MS may be followed by apparent complete recovery, permanent tissue injury may occur even in initial stages of inflammation.11 Although MRI activity may decrease over time, brain atrophy, disease burden, and clinical disability tend to progress.11 However, some physicians, such as Brian Weinshenker, MD, rarely treat patients with CIS. Weinshenker, professor of neurology at the Mayo Clinic in Rochester, Minnesota, told Applied Neurology that "a high percentage of patients with [CIS]-even those with MRI findings-will not convert to MS, so why subject them to lifelong treatment, which is only partially effective anyway?"

Weinshenker added, "I take into account the presentation and demographic characteristics of the patient. For example, a young woman with optic neuritis and low brain lesion burden has a relatively good prognosis, whereas a man over 40 presenting with ataxia and a high MRI lesion burden with several active lesions would likely have a worse prognosis. I might not suggest disease-modifying therapy for the first patient, but might do so for the second.

"Those are extreme examples," continued Weinshenker, "but my usual inclination is to follow the patient clinically and with routine MRI scans of the head-and possibly of the cervical spine in patients with a predilection to spinal lesions-roughly every 12 to 18 months and decide to initiate treatment based on the patient's course. Should definitive studies prove that long-term therapy has a major long-term benefit when started early, I may change my practice. For the moment, I regard this issue of a delay in treatment as being harmful as still open."

Luanne Metz, MD, professor of clinical neurosciences and director of the Calgary Multiple Sclerosis Clinic in Calgary, Alberta, is reluctant to embrace the new BENEFIT findings without reviewing all the data, which are not yet published.

Metz says that she never treats patients with CIS. "I follow patients who have CIS with MRI to detect those patients in whom MS develops and then I treat. Today's reality is that we can easily select patients with actual MS very early using the McDonald diagnostic criteria. MRI is so useful in sorting out active disease in patients."

Both IFN-b-1a and IFN-b-1b have demonstrated effectiveness in slowing the rate of conversion of CIS to MS. However, which patients-if any-with CIS should be treated appears to be a hot topic among MS specialists.

References:

REFERENCES


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