Why targeted therapies are necessary for systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) continues to have important morbidity and accelerated mortality despite therapeutic advances. Targeted therapies offer the possibility of improved efficacy with fewer side effects. Current management strategies rely heavily on nonspecific immunosuppressive agents. Prednisone, in particular, is responsible for a considerable burden of later organ damage. There are a multitude of diverse mechanisms of disease activity, immunogenic abnormalities and clinical manifestations to take into consideration in SLE. Many targeted agents with robust mechanistic preclinical data and promising early phase studies have ultimately been disappointing in phase III, randomized, controlled studies. Recent efforts have focused on B-cell therapies, in particular given the success of belimumab in clinical trials, with limited success. We remain optimistic regarding other specific therapies being evaluated, including interferon-alpha blockade. It is likely that in SLE, given the heterogeneity of the population involved, precision medicine is needed, rather than expecting that any single biologic will be universally effective.

Keywords: SLE; current treatments; mechanisms of disease; targeted therapy; treatment.

Figure 1

Dysregulated immune responses in SLE. Interferon alpha, released by plasmacytoid dendritic cells in response to exogenous antigens, contributes to disease initiation by priming the adaptive immune system, thereby providing T-cell help for autoreactive B cells ( loop1). Alternatively, excessive B cell activating factor is sufficienct to initiate disease without T cell help by promoting activation and class-switching og autoreactive B cells ( loop 2). igG autoantibodies that recognize nucleic acids are internalized via Fc recepto or B cell antigen receptor into toll like receptor expressing cendritic cells or B cells respectively. Toll like receptor engagement in plasmacytoid dendritic cells amplifies the production of type I interferon, whereas toll like receptor engangement in C cells increases B cell receptor signalling and antibody production. Therefore, once long-loved plasa cells that secrete autoreactive IgG are present, perpetuation of the autoreactive response might continue in a Tcell dependent manner ( loop 2). Reproduced with permission(61) from Nat Rev Rheumatol. 2010;6(1):13–20.