Rituximab: the Lupus Journey

Since the 1950s, lupus has changed from being a life-threatening condition to being treatable in most cases thanks to the introduction of steroids, immunosuppressive drugs, dialysis and renal transplantation. However, apart from the introduction of mycophenolate mofetil, successful new drugs for lupus have been hard to find in the past two decades. In an assessment of our lupus nephritis cohort over the past 30 years (Croca et al., Rheumatology. 11; 50:1424-1430), we reported that both morbidity and mortality have changed little during this period, suggesting that we have optimized the use of corticosteroids and conventional immunosuppressive drugs. If we want to seek further improvement in outcome, new approaches will be necessary. In this review, we will focus on the use of rituximab in the treatment of systemic lupus erythematosus (SLE). Although not fully understood, it has become clear that B cells play a key role in SLE pathogenesis. They are implicated in the production of autoantibodies, presentation of autoantigen to T cells, T cell activation and cytokine production. In theory, B cell-targeted therapies which eliminate pathogenic B cells and promote the expansion and function of protective B cells, or both, should be beneficial (Rahman and Isenberg, N Engl J Med. 2008; 358:929–39), (Yildirim-Toruner and Diamond, J Allergy Clin Immunol. 2011; 127:303-12). Many openlabel and registry studies do indeed report the successful use of rituximab in both renal and non-renal lupus. However, two major clinical trials using it failed to meet their end points. We review the road travelled by rituximab as a lupus treatment in the past 14 years and consider where the journey is heading.