Systemic Lupus Erythematosus: The Current State of Therapy
Systemic lupus erythematosus (SLE) is a chronic, systemic, autoimmune disease primarily affecting young females of reproductive age and causing a multitude of clinical manifestations that may be life- or organ-threatening. Besides the major histocompatibility II locus, many other genes have been recently implicated in SLE, and it is likely that different combinations of various, otherwise weak genes are active in any given patient. Many of these genes are implicated in the activation of both innate and adaptive immune mechanisms, especially in the setting of environmental triggers such as drugs, infections, and ultraviolet light. In SLE, recent data have shown a prominent role for such innate immunity signaling pathways as the Toll-like receptors (TLRs) and type I interferon (IFN). Lupus pathogenesis is thought to involve innate immunity pathways that are capable of activating adaptive immunity mechanisms, such as autoimmune T and B cells, with subsequent generation of autoantibodies and immune complexes. The latter may cause tissue inflammation and damage via activation of the complement and/or Fc-gamma receptor effector systems.
Conventional SLE therapies include antimalarial drugs, such as hydroxychloroquine and quinacrine, that are believed to inhibit TLR 7, 8, and 9 signaling, and many nonspecific immunosuppressive medications, such as glucocorticoids, azathioprine, methotrexate, mycophenolate mofetil, and cyclophosphamide. The goal has been the suppression and rebooting of an overactive immune system and thus disease amelioration. However, because of the nonspecific nature and broad immunologic impact of these therapies, the effects have not been optimal and not without a price with regard to infectious and other adverse events. In addition, many of these therapies have been empirically introduced in the clinic without the support of good-quality randomized controlled trials (RCTs). However, over the past few years, an explosion of sponsored clinical trials has taken place, fueled by the recent advances in our understanding of the disease pathogenesis and the advances in the technology of the development of targeted therapies.
Although outcome measures of lupus have been problematic -- with the exception of lupus nephritis -- significant progress has recently been made after careful analysis of recent trial data. This has allowed for the development of a new outcome measure, the SLE responder index (SRI), that is based on both the SELENA SLEDAI and BILAG (Safety of Estrogens in Lupus Erythematosus: National Assessment -- SLE Disease Activity Index and British Isles Lupus Assessment Group) instruments. As a result, the first successful trials in SLE soon followed. The new candidate therapies have tried to address several aspects of the disease pathogenesis, such as B cells, T cells, co-stimulatory molecules, growth/survival factors, and cytokines. The Table summarizes some of these therapies and their stage in development.
Table. Selected New Promising Therapies in SLE
| Target | Agent | Stage in Development |
| B-cell targets | ||
| CD20 | Rituximab | Failed phase 3 in both SLE and LN |
| CD20 | SBI-087 (anti-CD20 small modular immunopharmaceutical) | Phase 1 in SLE |
| CD22 | Epratuzumab | Phase 2/3 studies in SLE |
| BLyS | Belimumab | Under FDA review |
| BLyS and APRIL | Atacicept | Phase 2 in LN halted because of to infections Phase 3 in SLE ongoing |
| Proteasome | Bortezomib | Preclinical efficacy data in lupus |
| Costimulatory molecule/T-cell targets | ||
| CD80/CD86 | Abatacept (CTLA4-Ig) | Phase 2 trial in SLE failed Phase 2/3 in LN ongoing |
| B7RP-1 | AMG557 | Phase 1 in SLE |
| Cytokine targets | ||
| Type I interferon | Sifalimumab | Phase 2 in SLE |
| Rontalizumab | Phase 2 in SLE | |
| NNC 0152-0000-0001 | Phase 1 in SLE | |
| Interleukin-6R | Tocilizumab | Completed phase 1 in SLE |
| Other targets | ||
| Tolerogen* | Lupuzor (IPP 201101) | Phase 3 trial in SLE |
| Immunomodulatory* | Laquinimod | Phase 2 trial in lupus arthritis Phase 2 trial in LN |
| Glutathione (induction effect) |
N-acetylcysteine | Phase 2 trial in SLE |
| MCP1 (CCL2) | NOX-E36 spiegelmer | Phase 1 in SLE |
*Exact targets not known; complex mechanisms are probably involved.
FDA = Food and Drug Administration; LN = lupus nephritis; SLE = systemic lupus erythematosus