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Patients with antineutrophil cytoplasm antibody–associated vasculitis (AAV) requiring dialysis at diagnosis are at risk for developing end-stage renal disease (ESRD) or dying. Short-term results of a trial comparing plasma exchange (PLEX) to intravenous methylprednisolone (IV MeP) suggested PLEX improved renal recovery. Here we conducted long-term follow-up to see if this trend persisted. A total of 137 patients with newly diagnosed AAV and a serum creatinine over 500μmol/l or requiring dialysis were randomized such that 69 received PLEX and 68 received IV MeP in addition to cyclophosphamide and oral glucocorticoids. The patients were followed for a median of 3.95 years. In each group there were 35 deaths, while 23 PLEX and 33 IV MeP patients developed ESRD. The hazard ratio for PLEX compared to IV MeP for the primary composite outcome of death or ESRD was 0.81 (95% confidence interval 0.53–1.23). The hazard ratio for all-cause death was 1.08 with a subhazard ratio for ESRD of 0.64 (95% confidence interval 0.40–1.05). Thus, although short-term results with PLEX are encouraging, the long-term benefits remain unclear. Further research is required to determine the role of PLEX in AAV. Given the poor outcomes of patients with severe AAV, improved treatment is urgently needed.

Among patients with severe antineutrophil cytoplasmic antibody–associated vasculitis, plasma exchange did not reduce the incidence of death or end-stage kidney disease. A reduced-dose regimen of oral glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD.

Key Points The current view of the neutrophil as a short-lived, homogeneous cell type with a role limited to the elimination of pathogens during the innate immune response has begun to change. Recent studies have revealed that the lifespan of a neutrophil in circulation might be much longer, and that differential subpopulations of neutrophils and their reservoirs (marginal pools) might exist (although it still remains to be determined whether these subpopulations are functional or lineage-restricted). The classical cascade of neutrophil recruitment has been updated recently to reflect our better understanding of how this process occurs in the blood under shear stress conditions (for example, neutrophils have been found to form tethers and slings to anchor themselves to the vasculature). In addition, our understanding has improved regarding what are preferable sites of neutrophil extravasation. It is also now clear that there are exceptions to this classical cascade in a number of organs, such as the liver, lung and brain, where some steps of the cascade do not occur and/or different molecules are used by neutrophils. Furthermore, we recognize there might be differences between sterile and infectious inflammation. Once extravasated, neutrophils follow a hierarchy of chemotactic molecules to reach the site of inflammation, following first 'intermediate' chemoattractants (endogenous chemokines) and then later 'end-target' chemoattractants (bacterial peptides or complement components). The process of chemotaxis is controlled by multiple intracellular signalling pathways (mitogen-activated protein kinase-dependent) controlling 'go' and 'stop' signals. Despite the pre-existing dogma that neutrophils leave the vasculature and die, it has been revealed that some extravasated neutrophils might re-enter circulation, leading to the dissemination of inflammation to other organs and subsequent tissue injury. In other cases, transmigrating cells may play an important part in the resolution of inflammation. In fact, neutrophils were shown to participate in wound healing and to actively limit self-recruitment through the release of endogenous molecules that inhibit integrin activation or cytoskeletal changes. Newly described roles of neutrophils cover their involvement in adaptive immunity by controlling the activation of T and B cells, and through the presentation of antigens to professional antigen-presenting cells in lymph nodes. Neutrophil extracellular trap (NET) formation, a strategy of pathogen eradication discovered less than a decade ago, has now been described to occur in vivo not only during acute (bacterial or viral) inflammation but also in numerous pathological conditions, such as autoimmune diseases, vascular diseases and cancer. Recently described mechanisms of NET formation indicate that neutrophils releasing NETs in vivo do not immediately die but rather keep performing functions such as chemotaxis and phagocytosis. It is becoming clear that the immune functions of neutrophils are more complex than once thought. Here, the authors provide an updated version of the classical neutrophil recruitment cascade and discuss the pro-inflammatory and anti-inflammatory roles of these cells in different immune settings. Neutrophils have traditionally been thought of as simple foot soldiers of the innate immune system with a restricted set of pro-inflammatory functions. More recently, it has become apparent that neutrophils are, in fact, complex cells capable of a vast array of specialized functions. Although neutrophils are undoubtedly major effectors of acute inflammation, several lines of evidence indicate that they also contribute to chronic inflammatory conditions and adaptive immune responses. Here, we discuss the key features of the life of a neutrophil, from its release from bone marrow to its death. We discuss the possible existence of different neutrophil subsets and their putative anti-inflammatory roles. We focus on how neutrophils are recruited to infected or injured tissues and describe differences in neutrophil recruitment between different tissues. Finally, we explain the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites.

ObjectiveTo evaluate whether the classification of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) according to ANCA type (anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) antibodies) predicts treatment response.MethodsTreatment responses were assessed among patients enrolled in the Rituximab in ANCA-associated Vasculitis trial according to both AAV diagnosis (granulomatosis with polyangiitis (GPA)/microscopic polyangiitis (MPA)) and ANCA type (PR3-AAV/MPO-AAV). Complete remission (CR) was defined as disease activity score of 0 and successful completion of the prednisone taper.ResultsPR3-AAV patients treated with rituximab (RTX) achieved CR at 6 months more frequently than did those randomised to cyclophosphamide (CYC)/azathioprine (AZA) (65% vs 48%; p=0.04). The OR for CR at 6 months among PR3-AAV patients treated with RTX as opposed to CYC/AZA was 2.11 (95% CI 1.04 to 4.30) in analyses adjusted for age, sex and new-onset versus relapsing disease at baseline. PR3-AAV patients with relapsing disease achieved CR more often following RTX treatment at 6 months (OR 3.57; 95% CI 1.43 to 8.93), 12 months (OR 4.32; 95% CI 1.53 to 12.15) and 18 months (OR 3.06; 95% CI 1.05 to 8.97). No association between treatment and CR was observed in the MPO-AAV patient subset or in groups divided according to AAV diagnosis.ConclusionsPatients with PR3-AAV respond better to RTX than to CYC/AZA. An ANCA type-based classification may guide immunosuppression in AAV.Trial registration numberNCT00104299; post-results.

ObjectivesA prospective randomised trial to compare two different durations of maintenance immunosuppressive therapy for the prevention of relapse in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV).MethodsPatients with AAV were recruited 18–24 months after diagnosis if they were in stable remission after cyclophosphamide/prednisolone-based induction followed by azathioprine/prednisolone maintenance therapy. They were randomised (1:1) to receive continued azathioprine/prednisolone to 48 months from diagnosis (continuation group) or to withdraw azathioprine/prednisolone by 24 months (withdrawal group). The primary endpoint was the relapse risk, from randomisation to 48 months from diagnosis.ResultsOne hundred and seventeen patients were randomised and 110 remained to the trial end. At entry, median serum creatinine was 116 μmol/L (range 58–372), 53% were ANCA positive. The percentage of patients presenting with relapse was higher in the withdrawal than in the continuation treatment group (63% vs 22%, p<0.0001, OR 5.96, 95% CI 2.58 to 13.77). ANCA positivity at randomisation was associated with relapse risk (51% vs 29%, p=0.017, OR 2.57, 95% CI 1.16 to 5.68). Renal function, ANCA specificity, vasculitis type and age were not predictive of relapse. Severe adverse events were more frequent in the continuation than withdrawal groups (nine vs three events), but the continuation group had better renal outcome (0 vs 4 cases of end-stage renal disease), with no difference in patient survival.ConclusionsProlonged remission maintenance therapy with azathioprine/prednisolone, beyond 24 months after diagnosis reduces relapse risk out to 48 months and improves renal survival in AAV.Trial registration numberISRCTN13739474

Neutrophil Extracellular Traps (NETs) are net-like structures composed of DNA-histone complexes and proteins released by activated neutrophils. In addition to their key role in the neutrophil innate immune response, NETs are also involved in autoimmune diseases, like systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and in other non-infectious pathological processes, as coagulation disorders, thrombosis, diabetes, atherosclerosis, vasculitis, and cancer. Recently, a large body of evidence indicates that NETs are involved in cancer progression and metastatic dissemination, both in animal models and cancer patients. Interestingly, a close correlation between cancer cell recruitment of neutrophils in the tumor microenvironment (Tumor Associated Neutrophils. TANs) and NET formation has been also observed either in primary tumors and metastatic sites. Moreover, NETs can also catch circulating cancer cells and promote metastasis. Furthermore, it has been reported that wake dormant cancer cells, causing tumor relapse and metastasis. This review will primarily focus on the pro-tumorigenic activity of NETs in tumors highlighting their ability to serve as a potential target for cancer therapy.

Objectives: To evaluate the relationship between different serum oxidative markers and the delta neutrophil index and hyperemesis gravidarum. Methods: One hundred pregnant women were enrolled in the study and divided into two groups. Group 1 included 50 women with hyperemesis gravidarum, while Group 2 (control group) included 50 pregnant women similar in age, gestational week, and body mass index. Serum oxidative markers and complete blood count inflammatory markers were compared. Results: Native thiol and total thiol were significantly lower in the Group 1 when compared with the control group (P=0.029 for native thiol; P=0.035 for total thiol). Moreover, ischemia-modified albumin (IMA) and catalase values were significantly higher in the Group 1 than in the control group (P=0.023 for IMA; P=0.021 for catalase). Index1% shows the disulfide/native thiol percent ratio and means that the Group 1 oxidant load is increased but not statistically significant. Myeloperoxidase, ferroxidase, and the delta neutrophil index did not differ significantly between the two groups (P=0.591, P=0.793, and P=0.52; respectively). Conclusions: According to our study, contrary to the literature, although there are differences in some values, when evaluated individually hyperemesis gravidarum does not impose an extra burden on maternal oxidant-antioxidant balance.

Background Wegener's granulomatosis and microscopic polyangiitis are antineutrophil cytoplasm antibodies (ANCA)-associated vasculitides with significant morbidity and mortality. The long-term survival of patients with ANCA associated vasculitis treated with current regimens is uncertain. Objective To describe the long-term patient survival and possible prognostic factors at presentation in an international, multicentre, prospectively recruited representative patient cohort who were treated according to strictly defined protocols at presentation and included the full spectrum of ANCA-associated vasculitis disease. Methods Outcome data were collected for 535 patients who had been recruited at the time of diagnosis to four randomised controlled trials between 1995 and 2002. Trial eligibility was defined by disease severity and extent, covered the spectrum of severity of ANCA-associated vasculitis and used consistent diagnostic criteria. Demographic, clinical and laboratory parameters at trial entry were tested as potential prognostic factors in multivariable models. Results The median duration of follow-up was 5.2 years and 133 (25%) deaths were recorded. Compared with an age- and sex-matched general population there was a mortality ratio of 2.6 (95% CI 2.2 to 3.1). Main causes of death within the first year were infection (48%) and active vasculitis (19%). After the first year the major causes of death were cardiovascular disease (26%), malignancy (22%) and infection (20%). Multivariable analysis showed an estimated glomerular filtration rate <15 ml/min, advancing age, higher Birmingham Vasculitis Activity Score, lower haemoglobin and higher white cell count were significant negative prognostic factors for patient survival. Conclusion Patients with ANCA-associated vasculitis treated with conventional regimens are at increased risk of death compared with an age- and sex-matched population.

The RITUXVAS trial reported similar remission induction rates and safety between rituximab and cyclophosphamide based regimens for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 12 months; however, immunosuppression maintenance requirements and longer-term outcomes after rituximab in ANCA-associated renal vasculitis are unknown. Forty-four patients with newly diagnosed ANCA-associated vasculitis and renal involvement were randomised, 3:1, to glucocorticoids plus either rituximab (375 mg/m(2)/week×4) with two intravenous cyclophosphamide pulses (n=33, rituximab group), or intravenous cyclophosphamide for 3-6 months followed by azathioprine (n=11, control group). The primary end point at 24 months was a composite of death, end-stage renal disease and relapse, which occurred in 14/33 in the rituximab group (42%) and 4/11 in the control group (36%) (p=1.00). After remission induction treatment all patients in the rituximab group achieved complete B cell depletion and during subsequent follow-up, 23/33 (70%) had B cell return. Relapses occurred in seven in the rituximab group (21%) and two in the control group (18%) (p=1.00). All relapses in the rituximab group occurred after B cell return. At 24 months, rates of the composite outcome of death, end-stage renal disease and relapse did not differ between groups. In the rituximab group, B cell return was associated with relapse. ISRCTN28528813.