Does Adding Azathioprine to Glucocorticoid Induction Increase the Remission Rate and Prevent Relapses in Patients with Systemic Necrotizing Vasculitides without Poor-Prognosis Factors? a Multicenter, Double-Blind Randomized Controlled Trial

Xavier Puéchal¹, Christian Pagnoux², Gabriel Baron³, Thomas Quémeneur⁴, Antoine Néel⁵, Christian Agard⁵, François Lifermann⁶, Eric Liozon⁷, Marc Ruivard⁸, Pascal Godmer⁹, Nicolas Limal¹⁰, Arsène Mékinian¹¹, Thomas Papo¹², Anne-Marie Ruppert¹³, Anne Bourgarit-Durand¹⁴, Boris Bienvenu¹⁵, Loïck Geffray¹⁶, Jean-Luc Saraux¹⁷, Elisabeth Diot¹⁸, Bruno Crestani¹², Xavier Delbrel¹⁹, Laurent Sailler²⁰, Pascal Cohen¹, Véronique Le Guern²¹, Benjamin Terrier¹, Matthieu Groh²¹, Claire Le Jeunne²¹, Luc Mouthon²¹, Philippe Ravaud³ and Loïc Guillevin for The French Vasculitis Study Group²¹, ¹Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, Paris, France, ²Mount Sinai Hospital, Toronto, ON, Canada, ³Hôpital Hôtel Dieu, Paris, France, ⁴CH Valenciennes, Valenciennes, France, ⁵CHU Nantes, Nantes, France, ⁶CH Dax, Dax, France, ⁷CHU Limoges, Limoges, France, ⁸CHU Clermont-Ferrand, Clermont–Ferrand, France, ⁹CH Vannes, Vannes, France, ¹⁰CHU Créteil, Créteil, France, ¹¹Service de médecine interne. Hôpital Saint-Antoine., Paris, France, ¹²CHU Bichat, Paris, France, ¹³CHU Tenon, Paris, France, ¹⁴CHU Bondy, Bondy, France, ¹⁵Internal Medicine, Hospital Caen, Caen, France, ¹⁶CH Lisieux, Lisieux, France, ¹⁷CH Eaubonne, Eaubonne, France, ¹⁸CHU Tours, Tours, France, ¹⁹CH Pau, Pau, France, ²⁰CHU Toulouse, Toulouse, France, ²¹National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, AP–HP, Université Paris Descartes, Paris, France

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: azathioprine, randomized trials and systemic vasculitides

Session Information

Date: Sunday, November 8, 2015

Title: Vasculitis I

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Glucocorticoids (GC) achieve remission in most patients with systemic necrotizing vasculitides (SNVs) without poor-prognosis factors based on the 1996 Five-Factor Score (FFS; comprising creatininemia >140 µmol/L, proteinuria >1 g/24 h, specific gastrointestinal, cardiomyopathy and CNS involvement). However, more than a third of them relapse, mainly during the first 2 years after treatment onset. This study aimed to determine whether combined GC and azathioprine (AZA) could achieve higher remission and lower relapse rates than GC alone in patients with newly diagnosed eosinophilic granulomatosis with polyangiitis (EGPA), microscopic polyangiitis (MPA) or polyarteritis nodosa (PAN), without increasing adverse events.

Methods: All patients included in this multicenter, prospective, randomized, double-blind trial received GC, initially 1 mg/kg/day, then gradually tapered over 12 months (asthmatic patients’ doses were lowered as much as possible while controlling asthma symptoms) and were randomly assigned to receive concomitant 12 months of oral AZA (2 mg/kg/day, increased after 3 months to 3 mg/kg/day for insufficient responses, defined as BVAS >6, persistently elevated acute-phase reactants, eosinophilia >1×10⁹/L or manifestations, with FFS always 0) or placebo. Patients were followed for another 12 months, for 24 months of follow-up. The primary endpoint was combined remission-induction failures and minor or major relapses at month (M) 24. Analyses used a modified intent-to-treat strategy and were adjusted according to the vasculitis.

Results: Among the 101 eligible patients, 95(51 EGPA, 25 MPA, 19 PAN) met the inclusion criteria and received at least 1 dose of AZA (n=46) or placebo (n=49). At endpoint, 21 (45.6%) AZA-arm patients had remission-treatment failures and/or relapses compared to 24 (49.0%) placebo recipients (odds ratio [OR], 0.96; [95% CI, 0.41–2.24]). Secondary endpoints were also comparable between arms: initial remission rate (80.4% vs. 81.6%; OR, 0.90 [0.31–2.70]) and numbers of patients with minor (26.7% vs. 25.0%) or major relapses (13.3% vs. 10.4%) (OR, 1.45 [0.61–3.44]). Two (4.1%) AZA-arm patients died (1 sudden death at M12 while in complete remission, 1 86-year-old died of congestive heart failure). Mean and cumulative GC doses and area under the curve for GC use were also comparable between arms. At least 1 serious treatment-related adverse event occurred in 8 (17.4%) AZA-arm and 3 (6.1%) placebo-arm patients (OR, 3.22 [0.69-14.29]). For EGPA patients, neither the primary endpoint nor the numbers with exacerbated asthma/rhinosinusal disease differed between arms.

Conclusion: At study M24, AZA adjunction to GC induction did not lower the absolute risk of treatment failure or relapse in patients with non-severe SNVs, compared to GC alone, had no steroid-sparing effect, and, did not reduce EGPA patients’ rate of asthma/rhinosinusal disease exacerbations (CHUSPAN2 trial was funded by French Ministry of Health PHRC P060243 and sponsored by AP–HP; ClinicalTrials.gov number, NCT00647166).

Disclosure: X. Puéchal, None; C. Pagnoux, None; G. Baron, None; T. Quémeneur, None; A. Néel, None; C. Agard, None; F. Lifermann, None; E. Liozon, None; M. Ruivard, None; P. Godmer, None; N. Limal, None; A. Mékinian, None; T. Papo, None; A. M. Ruppert, None; A. Bourgarit-Durand, None; B. Bienvenu, None; L. Geffray, None; J. L. Saraux, None; E. Diot, None; B. Crestani, None; X. Delbrel, None; L. Sailler, None; P. Cohen, None; V. Le Guern, None; B. Terrier, None; M. Groh, None; C. Le Jeunne, None; L. Mouthon, None; P. Ravaud, None; L. Guillevin for The French Vasculitis Study Group, None.

To cite this abstract in AMA style:

Puéchal X, Pagnoux C, Baron G, Quémeneur T, Néel A, Agard C, Lifermann F, Liozon E, Ruivard M, Godmer P, Limal N, Mékinian A, Papo T, Ruppert AM, Bourgarit-Durand A, Bienvenu B, Geffray L, Saraux JL, Diot E, Crestani B, Delbrel X, Sailler L, Cohen P, Le Guern V, Terrier B, Groh M, Le Jeunne C, Mouthon L, Ravaud P, Guillevin for The French Vasculitis Study Group L. Does Adding Azathioprine to Glucocorticoid Induction Increase the Remission Rate and Prevent Relapses in Patients with Systemic Necrotizing Vasculitides without Poor-Prognosis Factors? a Multicenter, Double-Blind Randomized Controlled Trial [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/does-adding-azathioprine-to-glucocorticoid-induction-increase-the-remission-rate-and-prevent-relapses-in-patients-with-systemic-necrotizing-vasculitides-without-poor-prognosis-factors-a-multicenter/. Accessed .

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