Abstract
Current treatment strategies for rheumatoid arthritis (RA) consisting of disease-modifying anti-rheumatic drugs or biological agents are not always effective, hence driving the demand for new experimental therapeutics. The antiproliferative capacity of proteasome inhibitors (PIs) has received considerable attention given the success of their first prototypical representative, bortezomib (BTZ), in the treatment of B cell and plasma cell-related hematological malignancies. Therapeutic application of PIs in an autoimmune disease setting is much less explored, despite a clear rationale of (immuno) proteasome involvement in (auto)antigen presentation, and PIs harboring the capacity to inhibit the activation of nuclear factor-κB and suppress the release of pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-6. Here, we review the clinical positioning of (immuno) proteasomes in autoimmune diseases, in particular RA, systemic lupus erythematosus, Sjögren’s syndrome 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.
Highlights
We review the clinical positioning of proteasomes in autoimmune diseases, in particular Rheumatoid arthritis (RA), systemic lupus erythematosus, Sjögren’s syndrome and sclerodema, and elaborate onclinical data related to the impact of BTZ and generation Proteasome inhibitor (PI) on immune effector cells (T cells, B cells, dendritic cells, macrophages, osteoclasts) implicated in their pathophysiology
Rheumatoid arthritis (RA) is a common autoimmune disease characterized by synovial inflammation and hyperplasia, autoantibody production, and cartilage and bone destruction, the underlying cause of which lies in immune regulatory factors such as the loss of tolerance [1]
We cover the diversity and relevance of constitutive and immunoproteasome subtypes in immune competent cells involved in autoimmune diseases, and provide an overview of several classes of reversible and irreversible PIs for therapeutic interventions
Summary
Rheumatoid arthritis (RA) is a common autoimmune disease characterized by synovial inflammation and hyperplasia, autoantibody production, and cartilage and bone destruction, the underlying cause of which lies in immune regulatory factors such as the loss of tolerance [1]. Proteasome inhibitors (PIs) may fall in the category of potentially attractive investigational drugs for their ability to (a) inhibit the activation of nuclear factor (NF)-κB and transcriptional regulation of pro-inflammatory cytokine release, and/or (b) induce apoptosis of activated immune cells.
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