2 Proteasome inhibitors in experimental therapeutics of autoimmune diseases

Submitted 2 Proteasome inhibitors in experimental therapeutics of autoimmune diseases Submitted 28 Abstract Current treatment strategies for rheumatoid arthritis (RA) consisting of disease modifying antirheumatic drugs or biological agents are not always effective , hence driving the demand for new experimental therapeutics. The anti-proliferative capacity of proteasome inhibitors (PIs) has received considerable attention given the success of its first prototypical representative bortezomib (BTZ) in the treatment of B cell and plasma cell-related hematological malignan-cies. Therapeutic application of PIs in an autoimmune disease setting is much less explored, despite a clear rationale of (immuno) proteasomes involvement in (auto)antigen presentation, and PIs harboring the capacity to inhibit the activation of NF-κB and suppressing the release of pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα)) and interleukin 6 (IL-6). Here, we review the clinical positioning of (immuno) proteasomes in autoimmune diseases , in particular RA, systemic lupus erythematosus, Sjögren's Syndrome (SS) and sclerodema, and elaborate on (pre)clinical data related to the impact of BTZ and next generation PIs on immune effector cells (T cells, B cells, dendritic cells, macrophages, osteoclasts) implicated in their pathophysiology. Finally, factors influencing long term efficacy of PIs, their current (pre)clinical status and future perspectives as anti-inflammatory and anti-arthritic agents are discussed.