Overlapping forms of granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis: Insights from a European multicenter study

Abstract

Background: Granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA) are distinct forms of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). Increasing evidence suggests overlapping features, particularly in proteinase 3 (PR3)-ANCA-positive EGPA and GPA with eosinophilia. This study aimed to characterize overlapping EGPA/GPA forms and assess their clinical and therapeutic implications.

Methods: We conducted a European, multicenter, observational study, including 135 patients with overlapping EGPA/GPA features. Definitions were based on ACR/EULAR classification criteria and other clinical and biological findings. Clinical, biological, and histological characteristics were analyzed using unsupervised hierarchical clustering approach. Comparisons were made with established EGPA and GPA control cohorts.

Results: Three clusters emerged: Cluster 1, a hybrid phenotype (pulmonary nodules, PR3-ANCA positivity, high relapse rate); Cluster 2, a systemic inflammatory phenotype (constitutional symptoms, PR3-ANCA positivity, moderate renal involvement); and Cluster 3, a severe vasculitis form (severe renal disease, alveolar hemorrhage). Including typical EGPA and GPA control cohorts revealed two main clusters a posteriori: an EGPA cluster and a GPA cluster. Cluster 1 overlapped with both EGPA and GPA clusters, whereas Clusters 2 and 3 predominantly aligned with GPA. Kaplan-Meier analysis revealed that Cluster 1 and the typical EGPA cohort had the best overall survival, whereas Cluster 3 had the poorest survival. Relapse-free survival was highest in typical EGPA and poorest in Cluster 3 and typical GPA.

Conclusion: This study delineates the heterogeneity of EGPA/GPA overlap and underscores the need for personalized treatment approaches. Future prospective studies should explore targeted therapies, including rituximab and IL-5 blockade, in these overlapping AAV subtypes.

Keywords: ANCA‐associated vasculitides; eosinophilic granulomatosis with polyangiitis; granulomatosis with polyangiitis; overlapping forms.

Fig. 1

Flow chart of the study. ACR, American College of Rheumatology; EGPA, eosinophilic granulomatosis with polyangiitis; EULAR, European Alliance of Associations for Rheumatology; FVSG, French Vasculitis Study Group; GPA, granulomatosis with polyangiitis.

Fig. 2

Hierarchical cluster analysis with dendrogram (a) and principal component analysis (b) of patients with eosinophilic granulomatosis with polyangiitis (EGPA)/granulomatosis with polyangiitis (GPA) overlapping forms. Panel a. Dendrogram showing sample clustering based on hierarchical clustering with logarithmic transformation of the distance metric. Three major clusters were identified and are highlighted in distinct colors. Panel b. Principal component projection of the clustered samples, illustrating the spatial separation of the three groups along the first two dimensions (Dim1: 62.6% variance explained, Dim2: 35%).

Fig. 3

Hierarchical cluster analysis in principal component between overlapping forms of eosinophilic granulomatosis with polyangiitis (EGPA)/granulomatosis with polyangiitis (GPA), GPA and EGPA control cohorts. Panel a displays the distribution of patients according to cluster analysis. Patients with overlap forms of EGPA and GPA are represented by three distinct clusters (Clusters 1–3, shown in different colors). Typical EGPA and GPA control cohorts are also represented by specific colors. In addition, the a posteriori clustering distinguishes two main groups: the EGPA cluster and the GPA cluster, depicted by circles and triangles, respectively. Panel b shows Cluster 1 overlapping equally with both of the two main patients’ populations, that is, the a posteriori EGPA (51.1%) and GPA (48.9%) clusters. Panel c shows Clusters 2 (89.3%) and 3 (100%) corresponding predominantly to the a posteriori GPA cluster. Panel d shows that almost all typical EGPA patients (99.1%) overlapped with the a posteriori EGPA cluster, whereas almost all typical GPA patients (96.1%) overlapped with the a posteriori GPA cluster. Panel e illustrates the two a posteriori clusters, that is, the “EGPA cluster” and the “GPA cluster.”

Fig. 4

Overall survival (a) and relapse‐free survival (b) curves in the clusters of eosinophilic granulomatosis with polyangiitis (EGPA)/granulomatosis with polyangiitis (GPA) overlapping forms patients, and EGPA and GPA control cohorts patients. Kaplan–Meier survival curves comparing overlap clusters (Clusters 1–3) with typical EGPA and GPA cohorts. (Top) Overall survival probability over a 10‐year follow‐up. (Bottom) Relapse‐free survival probability over a 10‐year follow‐up. Both analyses demonstrate significant differences across groups (log‐rank test, p < 0.0001).