Granulomatosis with Polyangiitis

Galectin-10 is a member of the lectin family and one of the most abundant cytoplasmic proteins in human eosinophils. Except for some myeloid leukemia cells, basophils, and minor T cell populations, galectin-10 is exclusively present in eosinophils in the human body. Galectin-10 forms Charcot-Leyden crystals, which are observed in various eosinophilic diseases. Accumulating studies have indicated that galectin-10 acts as a new biomarker for disease activity, diagnosis, and treatment effectiveness in asthma, eosinophilic esophagitis, rhinitis, sinusitis, atopic dermatitis, and eosinophilic granulomatosis with polyangiitis. The extracellular release of galectin-10 is not mediated through conventional secretory processes (piecemeal degranulation or exocytosis), but rather by extracellular trap cell death (ETosis), which is an active cell death program. Eosinophils undergoing ETosis rapidly disintegrate their plasma membranes to release the majority of galectin-10. Therefore, elevated galectin-10 levels in serum and tissue suggest a high degree of eosinophil ETosis. To date, several studies have shown that galectin-10/Charcot-Leyden crystals are more than just markers for eosinophilic inflammation, but play functional roles in immunity. In this review, we focus on the close relationship between eosinophils and galectin-10, highlighting this protein as a potential new biomarker in eosinophilic diseases.

ObjectiveTo assess markers of neutrophil activation such as calprotectin and N-formyl methionine (fMET) in anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) and large-vessel vasculitis (LVV).MethodsLevels of fMET, and calprotectin, were measured in the plasma of healthy controls (n=30) and patients with AAV (granulomatosis with polyangiitis (GPA, n=123), microscopic polyangiitis (MPA, n=61)), and LVV (Takayasu's arteritis (TAK, n=58), giant cell arteritis (GCA, n=68)), at times of remission or flare. Disease activity was assessed by physician global assessment. In vitro neutrophil activation assays were performed in the presence or absence of formyl peptide receptor 1 (FPR1) inhibitor cyclosporine H.ResultsLevels of calprotectin, and fMET were elevated in patients with vasculitis as compared to healthy individuals. Levels of fMET correlated with markers of systemic inflammation: C-reactive protein (r=0.82, pConclusionCirculating fMET appears to propagate neutrophil activation in AAV and LVV. Inhibition of fMET-mediated FPR1 signaling could be a novel therapeutic intervention for systemic vasculitides.

ImportanceResults of randomized clinical trials have demonstrated rituximab's noninferiority to cyclophosphamide as induction therapy for antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV), with neither treatment having a specific advantage for granulomatosis with polyangiitis (GPA). However, post hoc analysis results have suggested that rituximab might be more effective than cyclophosphamide in inducing remission in patients with proteinase 3-positive AAV.ObjectiveTo compare the effectiveness of rituximab and cyclophosphamide in inducing GPA remission in a large population of unselected patients.Design, setting, and participantsThis comparative effectiveness study used multicenter target trial emulation observational data from 32 French hospitals in the French Vasculitis Study Group Registry. Groups were determined according to treatments received, without any intervention from the investigators. Inverse probability of treatment weighting was used to correct for baseline imbalance between groups. Participants included patients with newly diagnosed or relapsing GPA who satisfied American College of Rheumatology classification criteria and/or Chapel Hill Consensus Conference nomenclature. Data were analyzed from October 1, 2021, to May 31, 2022.ExposuresAt least 1 infusion of rituximab or cyclophosphamide for induction therapy between April 1, 2008, and April 1, 2018.Main outcomes and measuresThe primary outcome was remission rate at month 6 (±2 months), with remission defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and prednisone dose of 10 mg/d or less. The BVAS is a validated tool for small-vessel vasculitis and used to assess the level of disease activity, with a numerical weight attached to each involved organ system. The BVAS has a range of 0 to 63 points; a score of 0 indicates no disease activity. Subgroup analyses included the primary outcome for patients with a new diagnosis, for most recently treated patients, and for patients with myeloperoxidase-ANCA positivity.ResultsAmong 194 patients with GPA included in the analysis (mean [SD] age, 54 [15] years; 110 men [56.7%]), 165 (85.1%) had a new diagnosis, and 147 of 182 with data available (80.8%) had proteinase 3-ANCA positivity. Sixty-one patients received rituximab and 133 received cyclophosphamide for induction therapy. In the weighted analysis, the primary outcome was reached for 73.1% of patients receiving rituximab vs 40.1% receiving cyclophosphamide (relative risk [RR], 1.82 [95% CI, 1.22-2.73]; risk difference, 33.0% [95% CI, 12.2%-53.8%]; E value for RR, 3.05). Similar results were observed in the subgroup of patients with newly diagnosed GPA and those with a more recent treatment. In the subset of 27 patients with myeloperoxidase-ANCA-positive GPA, 8 of 10 rituximab recipients and 8 of 17 cyclophosphamide recipients met the primary end point (unweighted RR, 1.73 [95% CI, 0.96-3.11]).Conclusions and relevanceIn this comparativeness effectiveness study using clinical data, rituximab induction therapy for GPA was more frequently associated with remission than cyclophosphamide. These results inform clinical decision-making concerning the choice of remission induction therapy for this subset of patients with AAV.

BackgroundGranulomatosis 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.MethodsWe 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.ResultsThree 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.ConclusionThis 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.