NEW evidence from a large European target trial emulation study suggests that adding cyclophosphamide to glucocorticoids does not reduce relapse risk in patients with eosinophilic granulomatosis with polyangiitis (EGPA) who lack poor-prognosis factors, even when severe disease manifestations are present.
Current treatment recommendations for EGPA stratify therapy according to disease severity and prognostic risk. While glucocorticoids (GCs) alone are recommended for patients without severe manifestations, the combination of GCs plus cyclophosphamide (CYC) is often used in more severe disease, regardless of poor-prognosis status as defined by the 1996 Five Factor Score (FFS). However, direct comparative evidence supporting this escalation strategy in patients with an FFS of 0 has been limited.
Emulating a Target Trial in EGPA
To address this gap, investigators emulated a target trial using observational data from a European multicentre retrospective cohort. The analysis included 250 patients with newly diagnosed EGPA, all of whom had an FFS of 0 at diagnosis and were treated with either GCs alone (n=177) or GCs plus CYC (n=73). The primary outcome was overall relapse at 12 months.
To minimise confounding inherent in observational data, the authors used inverse probability of treatment weighting, allowing for a more balanced comparison between treatment strategies. A prespecified subgroup analysis focused on patients with severe disease manifestations not captured by the FFS.
No Relapse Reduction With Cyclophosphamide
After adjustment, the addition of cyclophosphamide to glucocorticoids did not reduce the risk of relapse at 12 months compared with glucocorticoids alone. Importantly, this lack of benefit persisted in the subgroup of patients with severe manifestations, challenging the assumption that disease severity alone justifies upfront cyclophosphamide use in the absence of poor-prognosis factors.
These findings suggest that cyclophosphamide, a drug associated with significant short- and long-term toxicity, may not provide additional efficacy in this specific EGPA population.
Implications for Clinical Practice
The authors note that their results support current guideline recommendations favouring glucocorticoids alone in EGPA patients without severe manifestations or poor-prognosis factors. However, the data also raise important questions about the routine use of cyclophosphamide in patients who present with severe features but retain a favourable prognostic profile.
By leveraging a target trial emulation framework, the study strengthens causal inference from real-world data and provides clinically relevant insights in a rare disease where randomised trials are difficult to conduct. The authors conclude that treatment decisions in EGPA should be guided not only by disease severity, but also by validated prognostic factors, balancing potential benefits against the risks of overtreatment.
Reference
Sorin B et al. Glucocorticoids vs glucocorticoids plus cyclophosphamide in eosinophilic granulomatosis with polyangiitis without poor-prognosis factors: a target trial emulation study. Oxford Rheumatol. 2025;64,(10):5238-44.
