B cell depleting therapy in systemic lupus erythematosus

Abstract

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune inflammatory disease characterized by multiple organ involvement, production of a wide range of autoantibodies and local formation or tissue deposition of immune complexes in the affected organs. Lupus nephritis (LN) is a common and serious organ involvement in patients with SLE. Despite better treatment and care of patients during the last decades there is still a great unmet need in the treatment with many patients being refractory to available therapies or suffering from serious adverse events. Advances have been made in the understanding on pathopysiology of the disease but many aspects are still unknown. B cells are known to be potent mediators in the regulation of normal and abnormal immune responses.

Rituximab (RTX) is a chimeric monoclonal antibody directed against CD20 found on all mature B cells but not on stem cells, pro-B cells or plasmacells. RTX depletes B cell from the circulation and studies support that B cells are also depleted from the bone marrow, primary and secondary lymphoid tissue as well as from target tissue. We constructed an open-labeled trial where we treated patients with severe SLE resistant to conventional therapy with RTX in combination with intravenous cyclophosphamide and glucocorticoids. The majority of patients achieved a good clinical response six months after treatment when studied in a lupus cohort with heterogeneous disease manifestations.

We found both a clinical and a histological improvement in patients with biopsy proven proliferative and membranous LN. A significant reduction was found in proteinuria, an improvement in urine sedimentation analysis and stabilization of serum creatinine and kidney function. A significant reduction in anti-double stranded DNA was found and normalization of complement C3, C4 and C1q in most patients. A reduction of immune deposits in the basal membrane was found in patients with membranous LN. In long-term follow-up of LN patients (mean 36 months) 22/25 achieved a complete (CR) or partial response (PR). Six nephritis flares were observed.

A trend toward a correlation between a shorter time to PR and lower levels of CD19+ B cells at baseline was observed. Patients achieving a CR within the first year had significantly longer B cell depletion time. A correlation was found between low IgM levels at baseline and shorter time to achieve CR. Immunoglobulin (Ig) G and A were kept stable while IgM was significantly reduced although with levels kept within the normal range. The treatment was generally well tolerated. Few mild/moderate infusion reactions and minor infections were noticed. Serious adverse events were noted in four patients, three with severe neutropenia and one patient with severe necrotizing faciitis and septicaemia.

In conclusion the results of this thesis support that rituximab in combination with cyclophosphamide may serve as a treatment option in patients with severe SLE, resistant to conventional therapy.