title: Pharmacodynamic monitoring of (immuno)proteasome inhibition during bortezomib treatment of a critically ill patient with lupus nephritis and myocarditis.
abstract: OBJECTIVE
  To describe the pharmacodynamic monitoring of (immuno)proteasome inhibition following treatment with bortezomib in a therapy-refractory systemic lupus erythematosus (SLE) patient with life-threatening myocarditis and lupus nephritis.
  
  
  METHODS
  Inhibition of catalytic activities of the proteasome subunits β5 (constitutive proteasome), β5i and β1i (immunoproteasome) were measured in peripheral blood mononuclear cells using subunit-specific fluorogenic peptide substrates in a patient who received three cycles of bortezomib (1.3 mg/m(2) subcutaneously, days 1, 4, 8 and 11; every three weeks) along with plasma exchange during the first two cycles.
  
  
  RESULTS
  Proteasome β5, β5i and β1i subunit activities were readily inhibited 1 h after bortezomib administration. Twenty-four hours post-bortezomib administration, β5 and β5i activities were largely restored, whereas inhibition of β1i activity was sustained. Clinically, after three cycles, cardiac function had improved, with concurrent improvement of haemodynamic stability during haemodialysis. Anti-ds-DNA dropped from >400 to 12 IU/mL along with normalisation of complement C3 and C4. Bortezomib therapy was well tolerated, and patient now has a sustained remission for >16 months.
  
  
  CONCLUSIONS
  This case illustrates the potential benefit of pharmacodynamic monitoring of (immune)proteasome subunit-specific activity after bortezomib dosing in patients with therapy refractory SLE. This tool may hold potential to guide personalised/precision dosing aiming to achieve maximal efficacy and minimal toxicity.
authors.affiliation: Department of Nephrology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Karina A
authors.initials: KA
authors.lastname: de Groot
authors.affiliation: Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Michel
authors.initials: M
authors.lastname: Tsang A Sjoe
authors.affiliation: Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Denise
authors.initials: D
authors.lastname: Niewerth
authors.affiliation: Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cloos
authors.affiliation: Takeda Oncology, Cambridge, MA 02139, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Blank
authors.affiliation: Department of Pathology and Cardiac Surgery, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Hans W M
authors.initials: HW
authors.lastname: Niessen
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Sonja
authors.initials: S
authors.lastname: Zweegman
authors.affiliation: Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Voskuyl
authors.affiliation: Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Jansen
authors.affiliation: Department of Nephrology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Joost W
authors.initials: JW
authors.lastname: van der Heijden
keywords: B cells; Lupus Nephritis; Pharmacokinetics; Systemic Lupus Erythematosus