#2400 Combination cyclophosphamide and rituximab with early glucocorticoid withdrawal for the treatment of ANCA-associated vasculitis

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Abstract Background and Aims Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a multisystem, autoimmune disorder with variable presentation and organ involvement. Glucocorticoids are the mainstay of treatment for AAV, but their use is associated with significant morbidity. Recent trials have evaluated glucocorticoid-sparing regimens for AAV, however minimal glucocorticoid dose and optimal duration of therapy remain unclear. A few data suggest that induction treatment with a combination of cyclophosphamide and rituximab in patients with AAV and kidney involvement may allow a rapid glucocorticoid taper. Here, we present long-term follow-up of a large cohort of patients with AAV who received combination cyclophosphamide and rituximab induction treatment with a rapidly reducing and withdrawing oral glucocorticoid taper. Methods In a tertiary referral centre with a dedicated Vasculitis Service, we identified patients with AAV treated with combination intravenous (i.v.) cyclophosphamide and i.v. rituximab induction therapy. We analysed biochemical, histological, and outcome data, including time to remission, relapse rate, and renal recovery. A secondary analysis evaluated whether outcomes differed based on cumulative glucocorticoid dose. Results Overall, 112 patients (67 [IQR 56–76] years; 57% male) received combination i.v. cyclophosphamide (median dose 1g) and i.v. rituximab (median dose 2g). 85% (95/112) had kidney involvement (baseline eGFR 24 [13–52] mL/min/1.73 m2; urine protein: creatinine ratio 101 [36–199] mg/mmol). 107 patients (96%) achieved treatment-induced disease remission (median time to remission 77 [64–92] days). The remaining five patients (5%) died with active vasculitis within four months of diagnosis. In those with kidney involvement, the greatest improvement in kidney function (eGFR at diagnosis versus at 12 months: 24 [13–52] mL/min/1.73 m2versus 45 [31–69] mL/min/1.73 m2, P < 0.001) was seen in those with more severe kidney disease at diagnosis (Fig. 1). 75 patients had a kidney biopsy at diagnosis, of which 19 (25%) had an interval kidney biopsy at a median time interval of 143 (117–186) days. Presentation biopsies demonstrated a broad range of renal risk based on both the Berden classification and ANCA Renal Risk Score. However, following treatment interval biopsies were in-keeping with a lower risk for future kidney failure than presentation biopsies (Fig. 1). Over a median follow-up of 2.9 [1.7–4.3] years, five patients experienced a relapse (median time to disease relapse 3.1 [2.2–3.2] years). All 112 patients were treated with oral glucocorticoids (median duration 12 [8–40] weeks; median dose 1,680 [1,050–2,835] mg). Patients treated with <12 weeks of glucocorticoids (median dose 1,050 [761–1,470] mg) had a lower prevalence of eosinophilic granulomatosis with polyangiitis (0% versus 10.7%; P = 0.042) and a lower baseline CRP (24 versus 67 mg/L; P = 0.08) compared to those receiving glucocorticoids for >12 weeks (median dose 2,835 [2,126–3,290] mg). In addition, those treated with <12 weeks of glucocorticoids had a shorter time to disease remission (71 [57–85] days versus 81 [70–101] days; P = 0.008) with no difference in AAV relapse rate (0% versus 8.9%; P = 0.088), and fewer serious infections requiring hospitalisation (16.1% versus 33.9%; P = 0.029). Conclusion Early withdrawal of oral glucocorticoid therapy in patients with severe AAV treated with combination cyclophosphamide and rituximab induction immunosuppression is safe and effective and may reduce morbidity, in particular serious infections. These findings should be confirmed in future randomised trials.

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