Credit: Original article published here.
A new study published in JAMA Network Open suggests patients with granulomatosis with polyangiitis (GPA) are more likely to achieve remission if treated with rituximab for induction therapy compared to cyclophosphamide [1]. Previous clinical trials, such as the RAVE trial [2], demonstrated that rituximab was noninferior to cyclophosphamide for induction of remission in severe ANCA-associated analysis (AAV), with neither treatment having a specific advantage for GPA in adjusted analysis. However, post-hoc analysis showed higher remission rate for rituximab than cyclophosphamide in those with PR3 ANCA antibodies. Given some trial limitations with enrollment of patients with both GPA and microscopic polyangiitis, the authors of this study sought to perform an emulation target trial with observational data to compare rituximab vs cyclophosphamide efficacy at inducing remission in a large number of unselected patients with GPA.
Puéchal et al performed a comparative effectiveness study using observational data from 32 French hospitals as part of the French Vasculitis Study Group Registry. Groups were determined according to treatments received. They included patients with newly diagnosed or relapsing GPA by ACR Classification Criteria and/or Chapel Hill Consensus Conference nomenclature with active disease who received at least 1 infusion of rituximab or cyclophosphamide over a 10-year period, from 2008 to 2018. Patients with limited GPA, alveolar hemorrhage with respiratory failure, serum creatinine greater than 4.0 mg/dL, and those on concomitant treatment of plasma exchange, methotrexate, mycophenolate mofetil or azathioprine were excluded.
Two induction strategies were compared: (1) rituximab 4 weekly infusions of 375 mg/m2 or 1g 2 weeks apart, and (2) cyclophosphamide infusion of 0.6g/m2 on Days 1, 15, and 29 and then 0.7 g/m2 every 21 days. After achieving remission, maintenance treatments included azathioprine, methotrexate or low-dose (500mg) rituximab infusion every 6 months through month 24. The primary outcome of the study was the remission rate at month 6 (+/- 2 months), defined as BVAS score of 0 as well as a low dose of prednisone (10mg per day or less). Secondary outcomes included percentage of patients achieving BVAS score of 0 at 6 months, the rate of patients who were retrained without failure at 24 months, and safety outcomes at 6 months.
The study included 194 patients with GPA, of which 61 received rituximab and 133 received cyclophosphamide as induction therapy. Around 81% were positive for PR3-ANCA and 85% had newly diagnosed GPA. In weighted analysis, the primary outcome (remission) was reached for 73.1% of patients on rituximab compared to 40.1% of patients receiving cyclophosphamide (RR 1.82). Similar results were observed when analysis was restricted to those with newly diagnosed GPA or those with a more recent treatment. Additionally, there were several secondary outcomes analyzed. There was no increased toxicity signal observed in rituximab compared to cyclophosphamide recipients. Additionally, the number of patients who achieved BVAS of 0 at 6 (+/-2 months), regardless of prednisone dose, was 85.5% of the rituximab group vs 82.6% of the cyclophosphamide group.
This data demonstrates evidence to support the hypothesis that rituximab could be superior to cyclophosphamide for induction of remission (prednisone dose of 10mg/day or less) in GPA. In the discussion, authors highlight that prior clinical trials combined both types of ANCA-associated vasculitis due to their rarity, and thus were not powered to detect differences about a specific intervention’s efficacy within a single disease. This study offers new clinical data in a larger subset of patients with specifically GPA, most of whom with PR3-positive ANCA. The limitations of the study include this is an observational analysis, without randomization to the particular treatment arms. Although the rituximab and cyclophosphamide groups were balanced, there may be unmeasured confounding affecting the primary outcome. Finally, patients with more severe disease (alveolar hemorrhage with respiratory failure or creatinine above 4.0 mg/dL), with limited GPA, and on concomitant therapy as part of induction regimen were excluded.
Ultimately, this observational target trial emulation study suggests that patients with GPA are able to achieve remission (defined as prednisone dose of 10mg/day or less) more frequently when treated with rituximab compared to cyclophosphamide for induction therapy. Particularly given some of the known toxicities of cyclophosphamide, this data providers further evidence regarding overall efficacy of rituximab for many patients with GPA.
References:
[1] Puéchal X, Iudici M, Perrodeau E et al. Rituximab vs Cyclophosphamide Induction Therapy for Patients With Granulomatosis With Polyangiitis. JAMA network open 2022;5(11):e2243799.
[2] Stone JH, Merkel PA, Spiera R, et al; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCAassociated vasculitis. N Engl J Med. 2010;363(3):221-232
