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Serial combination therapy: is immune modulation in multiple sclerosis enhanced by initial immune suppression?

Montreal Neurological Institute Montreal, Quebec, Canada amit.bar-or{at}mcgill.ca

J Oger

Division of Neurology, Department of Medicine, Multiple Sclerosis Clinic and Brain Research Centre, The University of British Columbia, Vancouver, British Columbia, Canada

E Gibbs

Division of Neurology, Department of Medicine, Multiple Sclerosis Clinic and Brain Research Centre, The University of British Columbia, Vancouver, British Columbia, Canada

M Niino

Montreal Neurological Institute Montreal, Quebec, Canada

T Aziz

Division of Neurology, Department of Medicine, Multiple Sclerosis Clinic and Brain Research Centre, The University of British Columbia, Vancouver, British Columbia, Canada

C Renoux

Montreal Neurological Institute Montreal, Quebec, Canada

S Alatab

Montreal Neurological Institute Montreal, Quebec, Canada

FD Shi

Barrow Neurology Institute of St Joseph’s Hospital and Medical Center, Phoenix, Arizona, USA

D Campagnolo

Barrow Neurology Institute of St Joseph’s Hospital and Medical Center, Phoenix, Arizona, USA

F Jalili

Montreal Neurological Institute Montreal, Quebec, Canada

S Rhodes

Barrow Neurology Institute of St Joseph’s Hospital and Medical Center, Phoenix, Arizona, USA

T Yamashita

Montreal Neurological Institute Montreal, Quebec, Canada

B Fan

Montreal Neurological Institute Montreal, Quebec, Canada

MS Freedman

Multiple Sclerosis Research Unit, The Ottawa Hospital General Campus, University of Ottawa, Ottawa, Canada

H Panitch

Department of Neurology, Multiple Sclerosis Center, University of Vermont, College of Medical, Burlington, Vermont, USA

DL Arnold

Montreal Neurological Institute Montreal, Quebec, Canada

T Vollmer

Department of Neurology, Rocky Mountain MS Center, Anschutz Medical Center, University of Colorado, Denver, Colorado, USA

Background

Although the concept that an initial course of immune-suppression facilitates subsequent immune-modulation (such as Th1 to Th2 deviation) is attractive for several autoimmune diseases, such a mechanism for serial-combination therapy has never been formally demonstrated. Recently, brief mitoxantrone induction-chemotherapy followed by immune-modulation with glatiramer acetate (GA) was significantly more effective at reducing multiple sclerosis disease activity than with GA alone.

Objective

To examine whether the benefit of initial immune suppression with mitoxantrone before GA treatment is associated with more efficient immune modulation.

Methods

IgG1/IgG4 GA-reactive antibody profiles, previously established as markers of GA-induced Th2 immune-deviation, were prospectively measured in vivo in patients treated with GA alone or with mitoxantrone induction therapy followed by GA.

Results

Significant and sustained increase in IgG4 antibodies (and the anticipated reversal of the IgG1/IgG4 ratio) was seen in patients treated with GA alone. Combination therapy resulted in lesser IgG4 induction (and no reversal of IgG1/IgG4 ratio). Thus, the enhanced efficacy of mitoxantrone–GA combination regimen was associated with decreased, rather than increased, efficiency of shifting the GA-reactive IgG1/IgG4 antibody profile.

Conclusion

These results provide important insights into mechanisms of combination therapy and therapeutic strategies for autoimmune diseases.

Key Words: B cells • combination therapy • GA-reactive antibodies • glatiramer acetate • IgG1-4 • mitoxantrone • multiple sclerosis • Th2 immune-deviation

Multiple Sclerosis, Vol. 15, No. 8, 959-964 (2009)
DOI: 10.1177/1352458509106230


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