Early Immunosuppression Preserves Brain Function in MS

Internal Medicine World Report, November 2007, Volume 0, Issue 0

By Wayne Kuznar

BOSTON—Three months of immunosuppression with mitoxantrone HCl (Novantrone) before treatment with glatiramer acetate (Copaxone) results in fewer brain lesions and fewer relapses in patients with relapsing?remitting multiple sclerosis (MS).

The induction therapy strategy may represent the future of treatment for relapsing?remitting MS, which until now has consisted of immunomodulatory therapy alone, said investigators at the American Academy of Neurology annual meeting.

Timothy Vollmer, MD

"It is possible to take current therapies and use them in tandem in a rational way to get much bigger effects that will help prevent brain injury early on, so that patients have more cranial reserve later in life and will be more functional and less likely to be disabled," said Timothy Vollmer, MD. "Preserving brain function up front is key."

Glatiramer acetate induces a shift in the cytokine profile of central nervous system (CNS)-reactive T cells from T-helper (Th) cell 1 to Th2 cell, while downregulating autoaggressive Th1 cells. Th2 cells secrete high levels of antiinflammatory cytokines that cross the blood?brain barrier and accumulate in the CNS, increasing the expression of growth factors favorable to neuroprotection.

Early clinical results with mitoxantrone induction for 3 months before glatiramer acetate therapy produced an approximate 90% reduction in the mean total number of enhancing brain lesions at 15 months, which was significantly greater than the reduction with glatiramer acetate alone. In this randomized study of 40 patients, there was also a trend toward fewer relapses in the induction group.

This superiority of early use of mitoxantrone induction over glatiramer acetate alone extends to 24 months, reported Dr Vollmer, director, Neuroimmunology Program, Barrow Neurological Institute, St. Joseph's Hospital, Phoenix.

Of the 40 patients enrolled in the aforementioned study, 28 had follow-up at 24 months. At entry to the core study, they received either 3 monthly infusions of mitoxantrone, followed by 21.5 months of glatiramer acetate, 20 mg/day, or 24 months of glatiramer acetate, 20 mg/day, alone.

At 24 months, disease activity, as monitored by brain magnetic resonance imaging (MRI), was reduced by 90% in the mitoxantrone/glatiramer acetate group versus 59% in the glatiramer acetone-only group, compared with baseline. The mean relapse rate was similar for both groups at the 24-month visit.

Sequential mitoxantrone and glatiramer acetate is already being used in the United Kingdom, targeting patients who have markers for poor prognosis, said Jason Ramtahal, MD, of the University of Liverpool and the Walton Centre for Neurology and Neurosurgery, United Kingdom.

Markers for poor prognosis while taking beta interferon are a high lesion load on MRI, early motor or ataxic brain stem relapses, and incomplete recovery from a relapse. "It's difficult to justify keeping patients on beta interferon if they've had a relapse and lost use of their legs," he said. "We use mitoxantrone/glatiramer acetate both for interferon failure and in treatment-na?ve patients who have accrued disability or have frequent relapses or other poor prognostic factors."

The reductions in enhancing lesions with mitoxantrone/glatiramer acetate are paralleled by favorable effects on MRI markers of disease burden and tissue damage, according to Douglas L. Arnold, MD, of the Montreal Neurological Institute, Canada.

In assessing the MRI scans of patients treated with either mitoxantrone/glatiramer acetate or glatiramer acetate alone, a significant difference favoring the former group was observed not only in the volume of brain lesions but also in the proportion of lesions that evolved into chronic black holes, he said.

"Prevention of chronic black holes may slow disease progression by avoiding permanent tissue destruction," said Dr Arnold.