Clémence Thery-Casari1, Romain Euvrard1, Sabine Mainbourg2, Stéphane Durupt3, Quitterie Reynaud4, Isabelle Durieu4, Alexandre Belot5, Hervé Lobbes6, Natalia Cabrera7, Jean-Christophe Lega8. 1. Department of Internal and Vascular Medicine, National Referral Centre for Rare Juvenile Rheumatological and Autoimmune Diseases (RAISE), Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Faculty of Medicine, Université de Lyon, Université Lyon 1, France; Lyon Immunopathology Federation (LIFE), University of Lyon, Hospices Civils de Lyon, France. 2. Department of Internal and Vascular Medicine, National Referral Centre for Rare Juvenile Rheumatological and Autoimmune Diseases (RAISE), Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Faculty of Medicine, Université de Lyon, Université Lyon 1, France; Lyon Immunopathology Federation (LIFE), University of Lyon, Hospices Civils de Lyon, France; Université de Lyon, Université Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Evolutive UMR 5558, F-69622 Villeurbanne, France. 3. Department of Internal and Vascular Medicine, National Referral Centre for Rare Juvenile Rheumatological and Autoimmune Diseases (RAISE), Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Lyon Immunopathology Federation (LIFE), University of Lyon, Hospices Civils de Lyon, France. 4. Department of Internal and Vascular Medicine, National Referral Centre for Rare Juvenile Rheumatological and Autoimmune Diseases (RAISE), Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Faculty of Medicine, Université de Lyon, Université Lyon 1, France; Lyon Immunopathology Federation (LIFE), University of Lyon, Hospices Civils de Lyon, France; Univ Lyon, Health Services and Performance Research EA7425, Claude Bernard University Lyon, F-69003, France. 5. Department of Internal and Vascular Medicine, National Referral Centre for Rare Juvenile Rheumatological and Autoimmune Diseases (RAISE), Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Faculty of Medicine, Université de Lyon, Université Lyon 1, France; INSERM U1111, National Referral Centre for rare Juvenile Rheumatological and Autoimmune Diseases (RAISE) and Department of Paediatric Rheumatology, Lyon University Hospital, University of Lyon, France. 6. Department of Internal and Vascular Medicine, National Referral Centre for Rare Juvenile Rheumatological and Autoimmune Diseases (RAISE), Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Internal Medicine Department, University Hospital Clermont-Ferrand, 1 place Lucie et Raymond Aubrac, 63003 Clermont-Ferrand, France. 7. Faculty of Medicine, Université de Lyon, Université Lyon 1, France; Lyon Immunopathology Federation (LIFE), University of Lyon, Hospices Civils de Lyon, France; Université de Lyon, Université Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Evolutive UMR 5558, F-69622 Villeurbanne, France. 8. Department of Internal and Vascular Medicine, National Referral Centre for Rare Juvenile Rheumatological and Autoimmune Diseases (RAISE), Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Faculty of Medicine, Université de Lyon, Université Lyon 1, France; Lyon Immunopathology Federation (LIFE), University of Lyon, Hospices Civils de Lyon, France; Université de Lyon, Université Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Evolutive UMR 5558, F-69622 Villeurbanne, France. Electronic address: jean-christophe.lega@chu-lyon.fr.
Abstract
INTRODUCTION: The efficacy of rituximab (RTX) for remission induction and maintenance in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) is now established, but the safety, particularly concerning severe infection risk, is not well known. OBJECTIVE: The purpose of this meta-analysis is to assess the prevalence and incidence of severe infections and the factors explaining heterogeneity in AAV patients treated with RTX. METHODS: PubMed and Embase were searched up to December 2017. Prevalence and incidence was pooled using a random-effects model in case of significant heterogeneity (I2 > 50%). Severe infection was defined as severe when it led to hospitalization, intravenous antibiotics therapy, and/or death. The heterogeneity was explored by subgroup analyses and meta-regression. RESULTS: The included studies encompassed 1434 patients with a median age of 51.9 years. The overall prevalence and incidence of severe infections was 15.4% (95% CI [8.9; 23.3], I2 = 90%, 33 studies) and 6.5 per 100 person-years (PY) (95% CI [2.9; 11.4], I2 = 76%, 18 studies), respectively. The most common infections were bacterial (9.4%, 95% CI [5.1; 14.8]). The prevalence of opportunistic infection was 1.5% (95% CI [0.5; 3.1], I2 = 58%) including pneumocytis jirovecii infections (0.2%, 95% CI [0.0; 0.6], I2 = 0), irrespective of prophylaxis administration. Mortality related to infection was estimated at 0.7% (95% CI [0.2; 1.2], I2 = 27%). The RTX cumulative dose was positively associated with prevalence of infections (13 studies, prevalence increase of 4% per 100 mg, p < .0001). The incidence of infection was negatively associated with duration of follow-up (8 studies, incidence decrease of 9% per year, p = .03). CONCLUSION: Prevalence and incidence of severe infections, mainly bacterial ones, were high in AAV patients treated with RTX. This meta-analysis highlights the need for prospective studies to stratify infectious risk and validate cumulative RTX dose and duration of follow-up as modifying factors.
INTRODUCTION: The efficacy of rituximab (RTX) for remission induction and maintenance in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) is now established, but the safety, particularly concerning severe infection risk, is not well known. OBJECTIVE: The purpose of this meta-analysis is to assess the prevalence and incidence of severe infections and the factors explaining heterogeneity in AAV patients treated with RTX. METHODS: PubMed and Embase were searched up to December 2017. Prevalence and incidence was pooled using a random-effects model in case of significant heterogeneity (I2 > 50%). Severe infection was defined as severe when it led to hospitalization, intravenous antibiotics therapy, and/or death. The heterogeneity was explored by subgroup analyses and meta-regression. RESULTS: The included studies encompassed 1434 patients with a median age of 51.9 years. The overall prevalence and incidence of severe infections was 15.4% (95% CI [8.9; 23.3], I2 = 90%, 33 studies) and 6.5 per 100 person-years (PY) (95% CI [2.9; 11.4], I2 = 76%, 18 studies), respectively. The most common infections were bacterial (9.4%, 95% CI [5.1; 14.8]). The prevalence of opportunistic infection was 1.5% (95% CI [0.5; 3.1], I2 = 58%) including pneumocytis jirovecii infections (0.2%, 95% CI [0.0; 0.6], I2 = 0), irrespective of prophylaxis administration. Mortality related to infection was estimated at 0.7% (95% CI [0.2; 1.2], I2 = 27%). The RTX cumulative dose was positively associated with prevalence of infections (13 studies, prevalence increase of 4% per 100 mg, p < .0001). The incidence of infection was negatively associated with duration of follow-up (8 studies, incidence decrease of 9% per year, p = .03). CONCLUSION: Prevalence and incidence of severe infections, mainly bacterial ones, were high in AAV patients treated with RTX. This meta-analysis highlights the need for prospective studies to stratify infectious risk and validate cumulative RTX dose and duration of follow-up as modifying factors.