Patients with SLE are currently treated with non-specific immunosuppressive drugs. Although morbidity and mortality have been improved significantly over the last few decades, treatment-related morbidity remains a significant problem [131
]. Advances in our understanding of the autoimmune-mediated organ damage has led to the introduction of successful biologics in the treatment of rheumatoid arthritis, spondyloarthropathies, and Crohn's disease, but the development of a new disease specific therapeutic agent for SLE is elusive. The clinical heterogeneity of the disease, the multiplicity of the involved pathogenic mechanisms, the lack of reliable biomarkers and the failure to design proper clinical trials have been frequently blamed for the failure. In , we have listed clinical trials which have either being concluded or are still in progress.
Biologies in the treatment of SLE
BLyS is a cytokine that is involved in the survival of immature B cells especially at the transition stage, a major checkpoint for elimination of autoreactive B cells. Blockade of BLyS [133
] with an anti-BLyS antibody (belimumab) has gathered sufficient attention. In the largest clinical trial ever done in SLE patients (865 patients), high dose anti-BLyS was found superior to placebo (57.6% vs. 43.6% patients reached the primary endpoint at 52 weeks) [134
]. Although moderate, this effect is significant enough to make anti-BLyS a good therapeutic option for patients with mild to moderate SLE. IL-6 promotes antibody production in humans and mice with lupus [135
] and is present in the urine of patients with lupus nephritis [136
]. An anti-IL-6 receptor monoclonal antibody was tested in phase I clinical trials in patients with SLE; it led to a decrease in acute phase reactants but at the same time caused neutropenia in two patients. Given the role of IFN in the development of murine lupus and the established upregulation of IFN-α-inducible genes, the use of anti-IFN-α antibodies to treat SLE is currently under consideration. Phase I trials showed safety and a phase II trial is underway. Complement activation is profoundly increased in SLE patients and inhibition of C5 with an antibody, which proved efficacious in the treatment of patients with paroxysmal nocturnal hemoglobinemia, should be considered.
B cell depletion in the treatment of autoimmune and rheumatic diseases showed clinical efficacy. A chimeric anti-human CD20 antibody (rituximab) showed initially promise in small studies and case series in SLE [137
] but a trial of rituximab with mycophenolate mofetil in SLE nephritis failed to reach its primary endpoint of remission at 52 weeks of treatment. Another phase II/III trial of rituximab in moderate to severe non-renal SLE is currently underway. CD22 is a molecule that is expressed on the surface of mature B cells but not plasma cells or memory B cells. A humanized anti-CD22 antibody (epratuzumab) is currently undergoing a phase II trial in patients with moderately active SLE. Given the initial failure of anti-CD20 treatment in lupus nephritis, the exact role, if any, of B cell depletion in SLE is unclear. Successful B cell depletion treatment may not come to fruition in SLE until we understand which subset of B cells (autoreactive vs. non-autoreactive) repopulate the empty B cell space and whether the production of B cell-tropic cytokines is altered following depletion. For example, increased production of BLyS following B cell depletion may negate the expected clinical benefit.
Attempts to reestablish B tolerance in patients with SLE have sufficient rationale. LJP-394 (abetimus sodium) is an artificial compound made of four deoxynucleotide-like molecules bound together and thus resembles ds-DNA. It can theoretically bind to autoreactive B cell receptors that recognize dsDNA. In clinical trials of SLE patients, abetimus led to a decrease in dsDNA antibody levels. However clinical trials in humans have not been successful aside from improving quality of life measures [138
Considerations to block the cognate interaction between T and B cells have led to the use of a fusion molecule of CTLA4 with immunoglobulin (Abatacept). Abatacept with background treatment with mycophenolate mofetil or cyclophosphamide is in phase II/III clinical trial in SLE patients with nephritis. The inducible co-stimulator (ICOS) interaction with its ligand B7-related peptide-1 presents another costimulatory pair and blockade of this cognate interation with a human antibody is currently in a phase I clinical trial in SLE patients. Finally, the costimulatory pair CD40-CD40 ligand has been demonstrated important in the production of autoantibodies. Clinical trials have been conducted with two different types of anti-CD40L (BG9588 and IDEC-1) and although some clinical efficacy was noted (only by BG9588) they were both suspended because of unexpected thomboembolic events [139
Failure to develop new drugs has not quenched effort and enthusiasm. The gained experience elucidates the absolute need of biomarkers, the design of better trials and consideration of the heterogeneous nature of the disease and should meet success in the near future.