Severe infections in patients with anti-neutrophil cytoplasmic antibody-associated vasculitides receiving rituximab: A meta-analysis

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Highlights

  • Prevalence and incidence of severe infections, mainly bacterial ones, were high in AAV patients treated with RTX.

  • The prevalence of opportunistic infection was 1.5%, including pneumocytis jirovecii infections (0.2%).

  • The RTX cumulative dose might be positively associated with prevalence of infections. The incidence of infection might be negatively associated with duration of follow-up.

  • This meta-analysis highlights the need for further prospective multi-center studies to stratify infectious risk to target high risk patients that may benefit from prophylaxis.

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

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are auto-immune diseases with potential life-threatening complications. [1]. They are characterized by necrotizing vasculitis, typically affecting small vessels, particularly respiratory tracts and kidneys [2]. AAV include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA) [2]. In most patients, circulating ANCA react with neutrophil proteinase-3 (PR3) or myeloperoxidase (MPO), the former being associated with a higher risk of relapse at follow-up [3,4].

The introduction of cyclophosphamide (CYC) in addition to glucocorticoids as therapy for remission induction in AAV significantly improves prognosis, with remission in approximately 70 to 90% of patients [[5], [6], [7]]. Since there is a high relapse rate, CYC use can be extended or repeated, leading to a high toxicity level [5,8,9]. Over the last decades, effective and potentially less toxic alternatives have been investigated. Rituximab (RTX) induces selective depletion of B lymphocytes by targeting the CD20+ surface antigen [10,11]. There is evidences that B-cell response is involved in the pathogenesis of AAV, because of ANCA pathogenicity [[12], [13], [14], [15], [16]].

Two randomized trials assessing remission induction [3,17] and one trial concerned with remission maintenance [18] found that RTX is effective in AAV treatment. In the RAVE trial, RTX was shown to be equally effective as oral CYC for standard remission induction in severe AAV (GPA and MPA), with similar infection rates for patients under RTX or CYC [3]. However, observational studies have described severe and opportunistic infections in patients treated with RTX, questioning the safety of RTX use in daily practice [[19], [20], [21], [22], [23], [24]]. The heterogeneity [21,[25], [26], [27]] and small size of the samples [20,[22], [23], [24]] in such studies limit the accurate analysis of infection rates in this population.

The aim of the present meta-analysis was to assess the infection rate (prevalence and incidence) and the factors explaining heterogeneity in AAV patients treated with RTX.

Section snippets

Literature research

PubMed and Embase were searched for original articles published in English up to December 2017. The search equation in PubMed and Embase was: “rituximab”[MeSH Terms] AND (“churg and strauss”[MeSH Terms] OR “eosinophilic granulomatosis with polyangiitis” OR “eosinophilic granulomatosis polyangiitis” OR “Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis” [MeSH Terms] OR “microscopic polyangiitis” OR “wegener's granulomatosis” OR “granulomatosis with polyangiitis”).

Additional articles

Study characteristics

The literature search strategy identified 1253 citations. The screening of titles and abstracts identified 255 potentially relevant records (Appendix 1). Following eligibility assessment of full-text articles, 40 studies were finally included: 32 (80%) studies were consecutive, 7 (18%) prospective, 7 (18%) multi-centered, and 3 (1%) were extracted from active arms of randomized trials (Table 1).

The included studies encompassed 1434 patients with a median age of 51.9 years, comprising 51%

Discussion

An overall severe infection prevalence of 15.4% and an incidence of 6.5 events per 100 PY, mainly related to bacterial infection, are reported herein. Despite the high incidence of severe infections, the infection related mortality is above 1 per 100 PY. These estimations were limited by a high degree of heterogeneity and partially explained by RTX cumulative dose for prevalence and duration of follow-up for incidence.

Severe infections are nowadays one of the first cause of mortality in AAV, as

Conclusion

In conclusion, infection prevalence and incidence rate were high in AAV patients treated with RTX, mainly from bacterial cause. This meta-analysis highlights the need for further prospective multi-center studies to stratify infectious risk to target high risk patients that may benefit from prophylaxis. Except for Pneumocystosis jirovecii infection, prophylaxis against opportunistic infections would not be necessary.

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