Elsevier

Journal of Autoimmunity

Volume 43, June 2013, Pages 60-69
Journal of Autoimmunity

Long-term outcomes of 118 patients with eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome) enrolled in two prospective trials

https://doi.org/10.1016/j.jaut.2013.03.003Get rights and content

Highlights

  • In eosiphilic granulomatosis with polyangiitis (EGPA), 40% patients have ANCA.

  • Survival rate is very good when treatment is stratified according to the FFS.

  • EGPA-related mortality is essentially related to cardiomyopathy.

  • Relapses are more frequent in patients with anti-MPO antibodies.

  • Relapses are more frequent in patients with baseline eosinophilia <3000/mm3.

Abstract

The purpose of this study was to assess the outcomes of 118 patients with eosinophilic granulomatosis with polyangiitis (EGPA) enrolled in 2 prospective, randomized, open-label clinical trials (1994–2005), with or without Five-Factor Score (FFS)-defined poor-prognosis factors, focusing on survival, disease-free survival, relapses, clinical and laboratory findings, therapeutic responses, and factors predictive of relapse. Forty-four patients with FFS ≥ 1 were assigned to receive 6 or 12 cyclophosphamide pulses plus corticosteroids and the seventy-four with FFS = 0 received corticosteroids alone, with immunosuppressant adjunction when corticosteroids failed. Patients were followed (2005–2011) under routine clinical care in an extended study and data were recorded prospectively. Mean ± SD follow-up was 81.3 ± 39.6 months. Among the 118 patients studied, 29% achieved long-term remission and 10% died. Among the 115 patients achieving a first remission, 41% experienced ≥1 relapses, 26.1 ± 26.8 months after treatment onset, with 57% of relapses occurring when corticosteroid-tapering reached <10 mg/day. Treatment achieved new remissions in >90%, but relapses recurred in 38%. Overall survival was good, reaching 90% at 7 years, regardless of baseline severity. Age ≥65 years was the only factor associated with a higher risk of death during follow-up. The risk of relapse was higher for patients with anti-myeloperoxidase antibodies and lower for those with >3000 eosinophils/mm3. Sequelae remained frequent, usually chronic asthma and peripheral neuropathy. In conclusion, EGPA patients' survival rate is very good when treatment is stratified according to the baseline FFS. Relapses are frequent, especially in patients with anti-myeloperoxidase antibodies and baseline eosinophilia <3000/mm3.

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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