Background and objectives (Immuno) proteasomes play a crucial role in processing of key proteins involved in the functioning of immune effector cells implicated in the pathology of autoimmune diseases. To this end, proteasome inhibitors, e.g. bortezomib, have received considerable attention as experimental therapeutics of autoimmune diseases. Here, we report the clinical case of a 44-old male SLE patient following treatment with bortezomib, along with pharmacodynamic monitoring of the inhibition of (immuno) proteasome catalytic activity. The patient was previously treated with - and unresponsive - to hydroxychloroquine, high dose oral and iv corticosteroids, azathioprine, mycofenolate mofetil, rituximab, IVIG, and cyclophosphamide (cumulative 5100 mg). His manifestations of SLE were arthritis, pericarditis, lymphadenopathy, class IV lupus nephritis (WHO classification), with the following antibody profile: ANA-, anti- Sm-, anti-U1RNP-, and anti-dsDNA antibodies. At the time of bortezomib administration, he was critically ill, suffering from renal and cardiac failure, most likely due to lupus myocarditis. Materials and methods Patient received 3 cycles of bortezomib (1.3 mg/m2) with 1 month interval. During the first two cycles plasma filtration was also initiated: three times weekly after the first cycle and twice weekly after the second. Two weeks after the start of bortezomib, hemodialysis was necessary due to renal failure. Pharmacodynamically, inhibition of catalytic activity (mean of 3 cycles) of constitutive proteasome subunit b5 and immunoproteasome subunits b5i and b1i was examined in cell extracts of peripheral blood mononuclear cells (collected prior to therapy, 1hr and 24 h after bortezomib administration) using subunit-specific fluorogenic peptide substrates. Results One hour after bortezomib administration, b5-associated catalytic activity was 45% inhibited compared to pretreatment control, and after 24 h, this activity was largely recovered (11% inhibition). Immunoproteasome b5i-catalytic activity was more potently inhibited after 1 h bortezomib (73%) and partially recovery after 24 h (25% inhibition). b1i-associated catalytic activity was also potently inhibited 1 h after bortezomib administration (74%), and remarkably sustained after 24 h (65%). Clinically, after three months, cardiac function improved (ejection fraction 16% to 43%), with concurrent improvement of haemodynamic stability during hemodialysis. Anti-dsDNA (ELISA) dropped from >=498 to 12 IU/ml. After two months the patient was dismissed from the hospital. Conclusions Bortezomib treatment in combination with plasma filtration proved useful in a complicated case of SLE. Pharmocodynamic monitoring of (immuno) proteasome catalytic activity with subunit-specific probes may be a potential tool to assess the potency and duration of bortezomib inhibition as parameter attributing to the therapeutic efficacy of bortezomib.
|Journal||Annals of the Rheumatic Diseases|
|Publication status||Published - 2015|