Severe infections in patients with anti-neutrophil cytoplasmic antibody-associated vasculitides receiving rituximab: A meta-analysis
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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Cited by (29)
Adverse effect of Pneumocystis Jirovecii infection associated with rituximab therapy for autoimmune disease are more frequently reported in older vs. younger patient
2023, TherapiesCitation Excerpt :More specifically, in our study, PJ infections were proportionally more frequently reported in older patients than other RTX ADRs. PJ infection is a well-known AE of RTX used in case of malignant pathology [26], but is also described in the treatment of autoimmune disease [27,28]. However, to our knowledge a higher rate of PJ infection in older patients treated for autoimmune disease has not been previously reported.
Outcomes in ANCA-associated vasculitis patients with end-stage kidney disease on renal replacement therapy—A meta-analysis
2023, Seminars in Arthritis and RheumatismHypogammaglobulinemia, late-onset neutropenia, and infections following rituximab
2023, Annals of Allergy, Asthma and ImmunologyAdding low dose cyclophosphamide to rituximab for remission-induction may prolong relapse-free survival in patients with ANCA vasculitis: A retrospective study
2023, Journal of Translational AutoimmunityCitation Excerpt :Importantly, this was not associated with an increased risk of infections in our study and the observed infection rates were in concordance with previous studies [4,12]. It has been reported that serious infectious complications mainly present as respiratory tract infections in patients with AAV treated with RTX, which is consistent with results of the current study [25]. Immunosuppressive therapy does not only increase infection risk, but also decreases the ability of the immune system to adequately detect and kill malignant cells [26,27].
Old known and possible new biomarkers of ANCA-associated vasculitis
2022, Journal of AutoimmunityCitation Excerpt :Within the first year after diagnosis, infection forms the most important risk of death, whereas thereafter cardiovascular disease and malignancies come to the fore and become common causes of death. Even rituximab, a chimeric monoclonal antibody against the CD20 antigen on B lymphocytes, considered to be - in comparison to cyclophosphamide - an at least equally effective but potentially less toxic alternative immunotherapy for AAV, has been associated with severe infections, increased infection related mortality and with a series of other devastating, life threatening side effects [14–18]. There is therefore an urgent need to identify and establish more precise risk factors for this purpose.
ANCA and anti-glomerular basement membrane double-positive patients: A systematic review of the literature
2021, Autoimmunity ReviewsCitation Excerpt :Therefore, in the age of the modern paradigm of personalized medicine, the search for double positivity for both ANCAs and anti-GBM antibodies must be systematic as soon as one of the two eponymous entities is suspected. Moreover, the recognition of this disease as a unique entity should be discussed, and further studies should focus on the best therapeutic strategy in these patients since, for example, rituximab [123–127], plasmapheresis [102,107] or anti-C5a receptor [128] are differentially validated and/or used in both eponymous diseases. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.