B Cell Depletion for Systemic Lupus Erythematosus
David Isenberg
United Kingdom
B lymphocytes are an essential component of the adaptive immune response. The surface antigen CD20 is expressed throughout B cell differentiation except at the very earliest and plasma cell stages. It is thought to act as a cross membrane calcium ion channel and to play a key role in B cell activation. In consequence it has been hypothesised that targeting CD20 may prove therapeutic in the management of diseases like lupus that are largely B cell mediated. B cell depletion using rituximab, a chimeric human-mouse monoclonal antibody, was first utilized for the treatment of non-Hodgkin’s lymphoma in 1997. For the past six years my colleagues and I have been treating patients with severe SLE who have failed conventional immunosuppressive therapy (N=40) and although our studies remain open label the results have been extremely encouraging. Our preferred therapeutic regime is 1g rituximab IV, 750mg of cyclophosphamide IV and 250mg of Methylprednisolone IV - each infusion is given on two occasions two weeks
apart. Our results (1,2) have indicated that this combination of drugs will achieve B cell depletion in virtually every case and that mean period of B cell depletion is approximately six months. Well over 80% of our patients have responded very satisfactorily but there are some interesting differences between the timed return of the B cells and the return of the clinical features. In some cases patients flare within weeks of the return of the B cells, in other cases it is over a year. One patient B cell depleted on a single occasion remains B cell depleted after five years. Three of our patients have died, one a tragic suicide for reasons quite unrelated to B cell depletion and in the other two cases the B cells had returned before a combination of overwhelming disease and infection caused their deaths.
This approach has been very well tolerated principally we believe because we stop any additional
immunosuppression the patients were taking (e.g. mycophenolate, azathioprine) prior to B cell depletion until the B cells have returned. We have demonstrated that it is safe to repeat B cell depletion on at least two further occasions and our encouraging results have been confirmed by others (3,4). Using the BILAG disease activity index we have also shown that B cell depletion achieves improvement in each of the eight organs or systems in which BILAG defines disease activity.
In summary B cell depletion using a combination of cyclophosphamide, rituximab and intravenous steroids shows outstanding promise as a new more targeted therapy for patients with SLE.
(1) Leandro M et al. Arthritis Rheum 2002; 46: 2673-7.
(2) Leandro M et al. Rheumatology 2005; 44: 1542-5.
(3) Looney RJ et al. Arthritis Rheum 2004; 50: 2580-09.
(4) Sfikakis PP et al. Arthritis Rheum 2005; 52: 501-13.