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. 2015 Dec 18;2(1):e000121.
doi: 10.1136/lupus-2015-000121. eCollection 2015.

Pharmacodynamic monitoring of (immuno)proteasome inhibition during bortezomib treatment of a critically ill patient with lupus nephritis and myocarditis

Karina A de Groot  1 , Michel Tsang A Sjoe  2 , Denise Niewerth  3 , Jacqueline Cloos  3 , Jonathan L Blank  4 , Hans W M Niessen  5 , Sonja Zweegman  6 , Alexandre E Voskuyl  2 , Gerrit Jansen  2 , Joost W van der Heijden  1
Affiliations

Pharmacodynamic monitoring of (immuno)proteasome inhibition during bortezomib treatment of a critically ill patient with lupus nephritis and myocarditis

Karina A de Groot et al. Lupus Sci Med. .

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.

Patient and 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.

Keywords: B cells; Lupus Nephritis; Pharmacokinetics; Systemic Lupus Erythematosus.

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Figures

Figure 1
Figure 1
Immunohistochemical staining of myocardial tissue before start of bortezomib treatment. (A) Lymphocytes (CD45) and (B) macrophages (CD68). Magnification ×200.
Figure 2
Figure 2
Time course for laboratory parameters of a patient with systemic lupus erythematosus prior and during bortezomib therapy (arrow). (A) Anti-ds-DNA (normal range: <15 IU/mL), (B) erythrocyte sedimentation rate (ESR; normal: <10 mm/h), (C) complement C3 (normal range: 0.9–1.8 g/L) and (D) complement C4 (normal range: 0.15–0.4 g/L).
Figure 3
Figure 3
Bortezomib (BTZ)-induced inhibition of (immuno)proteasome activity in peripheral blood cells of a patient with systemic lupus erythematosus . Catalytic activity of β5, β5i and β1i is depicted at three time points during bortezomib treatment either prior to bortezomib dosing and 1 and 24 h post-bortezomib administration. NA, sample not available.
See this image and copyright information in PMC

References

    1. Cervera R, Khamashta MA, Hughes GR. The Euro-lupus project: epidemiology of systemic lupus erythematosus in Europe. Lupus 2009;18:869–74. doi:10.1177/0961203309106831 - DOI - PubMed
    1. Isenberg DA, Rahman A. Systemic lupus erythematosus in 2013. Taking a closer look at biologic therapy for SLE. Nat Rev Rheumatol 2014;10:71–2. doi:10.1038/nrrheum.2013.203 - DOI - PubMed
    1. Verbrugge SE, Scheper RJ, Lems WF et al. . Proteasome inhibitors as experimental therapeutics of autoimmune diseases. Arthritis Res Ther 2015;17:17 doi:10.1186/s13075-015-0529-1 - DOI - PMC - PubMed
    1. Neubert K, Meister S, Moser K et al. . The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med 2008;14:748–55. doi:10.1038/nm1763 - DOI - PubMed
    1. Ichikawa HT, Conley T, Muchamuel T et al. . Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells. Arthritis Rheum 2012;64:493–503. doi:10.1002/art.33333 - DOI - PMC - PubMed