Background/Purpose Cyclophosphamide (CYC) is often used in severe neuropsychiatric systemic lupus erythematosus. However, data on its use rely on small case series and a single randomized controlled trial with a limited number of patients and short follow-up.

Methods SLE patients with active neuropsychiatric involvement from two tertiary European centers, who received CYC during the past 15 years and had regular follow-up were identified. Outcome at most recent follow-up visit (Likert scale from 1: remission to 6: worsening) and recurrences of the neuropsychiatric manifestation were assessed. Long-term complications of CYC therapy were also documented, with a focus on malignancies and severe infections.

Results CYC was administered in 44 non-thrombotic neuropsychiatric events experienced by 43 patients (Table 1). Median age at NPSLE occurrence was 45 years (range 14-68 years), time lag from SLE onset was 1 year (range 0-7 years), and positivity for antiphospholipid antibodies was 42.9%. Most common indications were psychosis (9 cases), stroke (6 cases) and myelopathy, seizure disorder and polyneuropathy (5 cases each). In 95% of cases, CYC was administered as monthly intravenous pulses (the remaining 5% received oral CYC) and was chosen as first line immunosuppressive therapy in 36/44 events (81.8%). In the remaining 8 cases, CYC was used as second-line after non-response to other immunosuppressants [azathioprine (AZA) in 7/8 and steroid monotherapy in 1/8)]. The median number of CYC pulses was 8 (range 2-18) with a median cumulative dose of CYC of 7.1 gr (range 2-27 gr). After a median follow-up of 40.0 months (range 1-173), 85.4% of events had favorable outcome (Likert score <4, indicating at least moderate improvement from baseline). Recurrences of the neuropsychiatric manifestation occurred in 13.2% of events. No difference in outcome was observed when CYC was given as first or second line therapy. A total of 4 events (stroke, aseptic meningitis, myelopathy and psychosis) did not respond to CYC and were treated with rituximab as rescue therapy. In cases that responded to CYC after the induction phase, maintenance therapy consisted of AZA in 73.7%, bimonthly and quarterly pulses of CY in 21.0%, and mycophenolate mofetil in 5.3%. No malignancies were observed in our cohort, yet there were two cases of severe infections (one HBV reactivation and one fatal case of disseminated tuberculosis).

Conclusion In a large case-series with long follow-up, cyclophosphamide was effective for severe non-thrombotic NPSLE but vigilant monitoring for infections is warranted.

Table 1