Long-term outcomes of 118 patients with eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome) enrolled in two prospective trials
Introduction
Eosinophilic granulomatosis with polyangiitis (EGPA) (Churg–Strauss syndrome), a rare eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis predominantly affecting small-to-medium–sized vessels, is associated with asthma and eosinophilia [1]. Extrapulmonary manifestations can be serious and life-threatening when heart, central nervous system (CNS), gastrointestinal tract and/or kidneys are affected. EGPA is associated with antineutrophil cytoplasm antibodies (ANCA) in <40% of the patients [2], [3]. The majority of ANCA-positive patients have a perinuclear (p-ANCA) fluorescence pattern and their IgG recognize myeloperoxidase (MPO), as assessed by enzyme-linked immunosorbent assay (ELISA). ANCA status distinguishes between 2 EGPA phenotypes: positive patients more frequently suffer from renal disease, peripheral nervous system involvement and/or alveolar hemorrhage, while ANCA-negative patients have more common cardiac involvement, lung infiltrate(s) and/or systemic manifestations [2], [3], [4], [5]. Despite treatment efficacy, relapses remain frequent and treatment has to be reinitiated or intensified. However, no prospective studies have assessed long-term EGPA outcomes and data are lacking on relapses, and their risk factors and outcomes [4].
Between 1994 and 2005, the French Vasculitis Study Group (FVSG) conducted 2 randomized–controlled, investigator-initiated trials on EGPA patients [6], [7] that validated therapeutic strategies based on the baseline Five-Factor Score (FFS) [8], [9]. For patients without poor-prognosis factors (1996 FFS = 0), corticosteroids (CS) alone, as induction and maintenance therapy, was evaluated in the CHUSPAN study, which found an excellent 5-year survival rate of 92% [7], further validating the FFS. However, only 56% of the patients achieved complete remission, and one-third (35%) eventually required immunosuppressant(s) (IS), 17% because CS alone failed and 25% because of relapse(s) [7]. Among CHUSPAN-study patients with at least 1 poor-prognosis factor (1996 FFS ≥ 1), 88% achieved remission with pulse cyclophosphamide (CYC) and CS [6]. However, without maintenance therapy, their relapse rates were high, 86% or 74%, respectively for those who had received 6 or 12 CYC pulses. Furthermore, CS use was prolonged, with 81% of the patients still taking low doses for asthma and relapse prevention at the last follow-up visit. Nevertheless, 5-year overall survival reached 97% [6].
Herein, we analyzed the long-term follow-up of a large cohort of prospectively followed EGPA patients, who had received homogenous therapeutic interventions. The outcomes of the 118 EGPA patients, with or without poor-prognosis factors, enrolled in 2 prospective clinical trials [6], [7] were examined, focusing on survival, disease-free survival, relapses, their clinical and laboratory findings, therapeutic responses, relapse outcomes and factors predictive of high risk of relapse.
Section snippets
Patient population
Patients included in this study were treated in France, Belgium, and the UK. The Institutional Review Board (Comité Consultatif pour la Protection des Personnes Participant à la Recherche Biomédicale) of the Hospices Civiles de Lyon approved the protocols (of both initial trials), which were conducted in accordance with the Declaration of Helsinki. Each participant gave signed informed consent. All the patients had EGPA satisfying the classification criteria established by the American College
Baseline characteristics
Among the 122 EGPA patients included in these 2 prospective trials [6], [7], 4 were excluded from the analysis because of missing follow-up data (Fig. 1). After receiving the protocol-assigned treatment regimen, 108/118 patients achieved remission; 10 (9%, 5 without and 5 with poor-prognosis factors) patients required second- or third-line therapy before 7 of them (5 without and 2 with poor-prognosis factors) achieved remission. Hence, 115/118 (97%) patients achieved remission; the remaining 3
Discussion
The results of this study demonstrated good survival of a large cohort of EGPA patients enrolled in 2 clinical trials, regardless of their initial vasculitis severity, who were treated according to their FFS and prospectively followed for a mean of >80 months [6], [7], [17]. Moreover, the therapeutic strategy based on distinguishing between patients with baseline FFS = 0 or higher validated the prognostic value of this score and supported the accuracy of this approach adapted to EGPA severity,
Conclusion
In summary, we prospectively confirmed that, after >80 months of follow-up, the therapeutic strategy distinguishing baseline EGPA severity as FFS = 0 or FFS ≥ 1 is accurate. Despite an excellent survival rate, relapses remain frequent, especially in patients with initial anti-MPO ANCA-positivity and eosinophilia <3000/mm3.
Role of the funding sources
ClinicalTrials.gov no. NCT00399399.
Supported by: Société Nationale Française de Médecine Interne (SNFMI), the Hospices Civiles de Lyon, the Groupe d’Intérêt Scientifique Maladies Rares (INSERM), the Assistance Publique des Hôpitaux de Paris, the Groupe d'Études et de Recherche sur les Maladies Orphelines Pulmonaires (GERMOP) and the FVSG. The Ministère de la Recherche and the Institut National de la Recherche Médicale provided grants, which were used to monitor the therapeutic studies.
Acknowledgments
FVSG members (city) who included patients are: Gilles Adam (Bourges), Marie-Hélène André (Bobigny), Jean-Pierre Arène (Hôpital Cochin, Paris), Elisabeth Aslangul (Hôpital Européen Georges-Pompidou), Alain Audebert (Nantes), Jean-Paul Battesti (Bobigny), Christophe Berranger (Saint-Nazaire), Boris Bienvenu (Caen), Anne-Sophie Blanchet (Lyon), Daniel Blockmans (Leuven, Belgium), Marc Bonnefoy (Angoulème), Eric Boulet (Pontoise), Eric Briens (Saint-Brieuc), Philippe Brun (Valence), Marie-Paule
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