title: Proteasome inhibitors as experimental therapeutics of autoimmune diseases.
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.
authors.affiliation: Department of Rheumatology, VU University Medical Center, 1081 HV, Amsterdam, The Netherlands. c.s.e.verbrugge@umcutrecht.nl.
authors.forename: Sue Ellen
authors.initials: SE
authors.lastname: Verbrugge
authors.affiliation: Department of Pathology, VU University Medical Center, 1081 HV, Amsterdam, The Netherlands. rj.scheper@vumc.nl.
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.affiliation: Department of Rheumatology, VU University Medical Center, 1081 HV, Amsterdam, The Netherlands. mf.lems@vumc.nl.
authors.forename: Willem F
authors.initials: WF
authors.lastname: Lems
authors.affiliation: Department of Medical Oncology, VU University Medical Center, 1081 HV, Amsterdam, The Netherlands. td.degruijl@vumc.nl.
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
authors.affiliation: Department of Rheumatology, VU University Medical Center, 1081 HV, Amsterdam, The Netherlands. g.jansen@vumc.nl.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Jansen
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001327:Autoimmune Diseases / Q000188:drug therapy*; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000009:adverse effects; D061988:Proteasome Inhibitors / Q000627:therapeutic use*
chemical_list: D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex