Two Drugs, Two Mechanisms of Action for SLE Patients

Patients with systemic lupus erythematosus (SLE) display a wide range of symptoms and disease activity. Accordingly, there are a variety of therapeutic regimens designed for them. Each has its own mechanism of action, but often times patients experience the same clinical relief of symptoms. This can confound the clear choice of treatment for patients with SLE, but a group of researchers at University Hospital Münster and Brandenburg Medical School in Germany is working to clarify the differences in SLE medications and has identified that the medications work on different cell populations.

“Treatment guidelines based on clinical trials have been published recently,” explained Dr. Till Fassbinder in an article published in Arthritis Research & Therapy. “However, due to the heterogeneity of the disease, employment of immunosuppressive drugs is largely based on clinical experience.” The group previously discovered that treating patients with azathioprine (AZA) or mycophenolate mofetil (MMF) altered different cell types. Whereas MMF blocked plasma cell differentiation, AZA was cytotoxic to naïve and transitional B cells.

To continue this work, the team recently looked at MMF versus cyclophophamide (CYC), which is another cytotoxic reagent, in the article, “Differential Effects of Cyclophosphamide and Mycophenolate Mofetil on Cellular and Serological Parameters in Patients with Systemic Lupus Erythematosus.”

The group evaluated 25 SLE patients receiving MMF immunosuppressive therapy, 20 SLE patients receiving CYC therapy, and 22 SLE patients receiving no immunosuppressive therapy. The choice of therapy was based on the presence of certain clinical features such as nephritis, mucocutaneous, arthritis, or myositis in the MMF group and nephritis, myositis, or alveolitis in the CYC group.

Throughout the study, researchers gathered data on cellular and serological parameters through flow cytometric analysis and diagnostic testing, respectively. Both MMF and CYC affected circulating cell numbers and reduced activity. MMF targeted circulating plasmablasts and plasma cells, affecting the level of circulating antibodies (mostly IgA) after three months of treatment. CYC boosted circulating CD8+ effector T cells and plasmacytoid dendritic cells within three months of beginning treatment.

“Our data suggest differences between MMF and CYC with regard to the mechanism of action,” wrote Dr. Fassbinder. “MMF but not CYC treatment leads to a fast and enduring reduction of surrogate markers for B cell activation, such as circulating plasmablasts, plasma cells, and free light chains. The data might help to pave the way for more customized therapies in SLE and the impact of MMF and CYC on cellular and serological parameters should be considered when biomarker panels for clinical trials are discussed and free light chains or plasmablasts and plasma cells are monitored.”

Now that the mechanisms of MMF and CYC action are more understood, treatments can be prescribed to patients with evidence of higher or lower cell types, rather than prescribed in a guess-and-check manner.