Background/Purpose:  Neuropsychiatric systemic lupus erythematosus (NPSLE) with psychosis is challenging to treat with refractory cases often requiring prolonged hospitalization due to significant functional impairment and co-morbidities. Although plasma cells are the major source of pathogenic autoantibodies in SLE, current B-cell directed therapies for SLE do not target these cells. Both neoplastic and normal plasma cells are very susceptible to the proteasome inhibitor bortezomib. Bortezomib is approved for the treatment of multiple myeloma, a plasmacytoma, and has been shown to prevent and reverse antibody-mediated rejection in solid organ transplantation and in prevention of disease progression in lupus mouse models. Therefore, bortezomib may provide benefit to patients with treatment refractory NPSLE as well.

Methods: We describe the first pediatric case series of 3 patients with refractory NPSLE and psychosis who were treated safely and effectively with subcutaneous and/or IV bortezomib. All patients had persistent psychosis despite aggressive immunosuppression with repeated courses of IV methylprednisolone, cyclophosphamide, rituximab and plasmapheresis.

Results:  All patients demonstrated rapid clinical improvement in their psychotic manifestations as well as reduction in steroid dose and need for plasmapheresis and anti-psychotic medications. No patient had recurrence of psychosis during a follow up period of 5 to 53 months. No severe side effects or adverse events were observed.

Conclusion:  NPSLE with psychosis that is resistant to cyclophosphamide, rituximab and plasmapheresis is a potentially devastating complication of SLE. Plasma cell depletion with bortezomib when used as adjunct therapy to conventional immunosuppression may be effective in some patients with refractory NPSLE and psychosis. In our pediatric case series, after initiation of bortezomib, patients had demonstrable improvement in their psychosis within 1-2 weeks and were able to reduce concomitant SLE therapies and discontinue anti-psychotic medication over time. In this pediatric case series, bortezomib was well tolerated, in keeping with adult case reports of its use in refractory SLE. Further investigation is needed to determine the therapeutic role of bortezomib in pediatric-onset SLE.