Search

Relapse in ANCA-associated vasculitis (AAV) has been studied previously, but there are few studies on renal relapse in particular. Identifying patients at high risk of renal relapse may aid in optimizing clinical management. We investigated which clinical and histological parameters are risk factors for renal relapse in ANCA-associated glomerulonephritis (AAGN). Patients (n = 174) were newly diagnosed and had mild–moderate or severe renal involvement. Data were derived from two trials of the European Vasculitis Society: MEPEX and CYCAZAREM. The Cox regression model was used to identify parameters increasing the instantaneous risk (= rate) of renal relapse (useful for instant clinical decisions). For identifying predictors of renal relapse during follow-up, we used Fine & Gray’s regression model. Competing events were end-stage renal failure and death. The cumulative incidence of renal relapse at 5 years was 9.5% (95% CI: 4.8–14.3%). In the Cox model, sclerotic class AAGN increased the instantaneous risk of renal relapse. In Fine & Gray’s model, the absence of interstitial infiltrates at diagnosis was predictive for renal relapse. In this study we used two different models to identify possible relationships between clinical and histopathological parameters at time of diagnosis of AAV with the risk of experiencing renal relapse. Sclerotic class AAGN increased the instantaneous risk of renal relapse. This association is most likely due to the high proportion of sclerosed glomeruli reducing the compensatory capacity. The absence of interstitial infiltrates increased the risk of renal relapse which is a warning sign that patients with a relatively benign onset of disease may also be prone to renal relapse. Renal relapses occurring in patients with sclerotic class AAGN and renal relapses occurring in patients without interstitial infiltrates were mutually exclusive, which may indicate that they are essentially different. [ABSTRACT FROM AUTHOR]

Objectives 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. Methods Forty-four patients with newly diagnosed ANCA-associated vasculitis and renal involvement were randomised, 3:1, to glucocorticoids plus either rituximab (375 mg/m²/weekx4) with two intravenous cyclophosphamide pulses (n=33, rituximab group), or intravenous cyclophosphamide for 3-6 months followed by azathioprine (n=11, control group). Results 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. Conclusions 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. Trial registration number ISRCTN28528813. [ABSTRACT FROM AUTHOR]

Background Rituximab is a B cell depleting anti-CD20 monoclonal antibody. CD20 is not expressed on mature plasma cells and accordingly rituximab does not have immediate effects on immunoglobulin levels. However, after rituximab some patients develop hypogammaglobulinaemia. Methods We performed a single centre retrospective review of 177 patients with multisystem autoimmune disease receiving rituximab between 2002 and 2010. The incidence, severity and complications of hypogammaglobulinaemia were investigated. Results Median rituximab dose was 6 g (1-20.2) and total follow-up was 8012 patient-months. At first rituximab, the proportion of patients with IgG <6 g/L was 13% and remained stable at 17% at 24 months and 14% at 60 months. Following rituximab, 61/177 patients (34%) had IgG <6 g/L for at least three consecutive months, of whom 7/177 (4%) had IgG <3 g/L. Low immunoglobulin levels were associated with higher glucocorticoid doses during follow up and there was a trend for median IgG levels to fall after = 6 g rituximab. 45/115 (39%) with IgG ≥6 g/L versus 26/62 (42%) with IgG <6 g/L experienced severe infections (p = 0.750). 6/177 patients (3%) received intravenous immunoglobulin replacement therapy, all with IgG <5 g/L and recurrent infection. Conclusions In multi-system autoimmune disease, prior cyclophosphamide exposure and glucocorticoid therapy but not cumulative rituximab dose was associated with an increased incidence of hypogammaglobulinaemia. Severe infections were common but were not associated with immunoglobulin levels. Repeat dose rituximab therapy appears safe with judicious monitoring. [ABSTRACT FROM AUTHOR]

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a group of vasculitides characterized by small-to-medium-sized blood vessel vasculitis and the presence of ANCA. Although our understanding of the causes of AAV remains limited, new information supporting an autoimmune basis is emerging. This review highlights recent progresses in etiology, pathogenesis, classification, and treatment. A genome-wide association study has confirmed a role for genetic susceptibility in AAV, and links between environmental factors and AAV induction through abnormal neutrophil extracellular traps has been demonstrated. Ongoing international consensus initiatives have revised approaches to the classification of vasculitis that has been enhanced by the analysis of large-scale prospective clinical data sets. New autoantibodies to human lysosome-associated membrane protein-2 antibody, moesin, and plasminogen have been detected in AAV sera and a prognostic classification of renal biopsies developed. Clinical trial networks have extended the evidence base for the treatment of AAV, and rituximab has emerged as an alternative to cyclophosphamide for remission induction. Long-term outcomes following current treatment strategies have been determined and increased risks for cardiovascular and malignant disease reported. [ABSTRACT FROM AUTHOR]

Objective To optimise a strategy for identifying gene expression signatures differentiating systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibody-associated vasculitis that provide insight into disease pathogenesis and identify biomarkers. Methods 44 vasculitis patients, 13 SLE patients and 25 age and sex-matched controls were enrolled. CD4 and CD8 T cells, B cells, monocytes and neutrophils were isolated from each patient and, together with unseparated peripheral blood mononuclear cells (PBMC), were hybridised to spotted oligonucleotide microarrays. Results Using expression data obtained from purified cells a substantial number of differentially expressed genes were identified that were not detectable in the analysis of PBMC. Analysis of purified T cells identified a SLE-associated, CD4 T-cell signature consistent with type 1 interferon signalling driving the generation and survival of tissue homing T cells and thereby contributing to disease pathogenesis. Moreover, hierarchical clustering using expression data from purified monocytes provided significantly improved discrimination between the patient groups than that obtained using PBMC data, presumably because the differentially expressed genes reflect genuine differences in processes underlying disease pathogenesis. Conclusion Analysis of leucocyte subsets enabled the identification of gene signatures of both pathogenic relevance and with better disease discrimination than those identified in PBMC. This approach thus provides substantial advantages in the search for diagnostic and prognostic biomarkers in autoimmune disease. [ABSTRACT FROM PUBLISHER]

Autoimmune diseases are common and debilitating, but their severe manifestations could be reduced if biomarkers were available to allow individual tailoring of potentially toxic immunosuppressive therapy. Gene expression–based biomarkers facilitating such tailoring of chemotherapy in cancer, but not autoimmunity, have been identified and translated into clinical practice. We show that transcriptional profiling of purified CD8+ T cells, which avoids the confounding influences of unseparated cells, identifies two distinct subject subgroups predicting long-term prognosis in two autoimmune diseases, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a chronic, severe disease characterized by inflammation of medium-sized and small blood vessels, and systemic lupus erythematosus (SLE), characterized by autoantibodies, immune complex deposition and diverse clinical manifestations ranging from glomerulonephritis to neurological dysfunction. We show that the subset of genes defining the poor prognostic group is enriched for genes involved in the interleukin-7 receptor (IL-7R) pathway and T cell receptor (TCR) signaling and those expressed by memory T cells. Furthermore, the poor prognostic group is associated with an expanded CD8+ T cell memory population. These subgroups, which are also found in the normal population and can be identified by measuring expression of only three genes, raise the prospect of individualized therapy and suggest new potential therapeutic targets in autoimmunity. [ABSTRACT FROM AUTHOR]

Objective. To determine the safety and efficacy of prolonged treatment with 15-deoxyspergualin (DSG, gusperimus) in patients with relapsing WG. [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented which discusses proteasome inhibition as a potential treatment for IgA vasculitis and other autoimmune diseases.

Background: Current therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are limited by toxicity.Objective: To compare pulse cyclophosphamide with daily oral cyclophosphamide for induction of remission.Design: Randomized, controlled trial. Random assignments were computer-generated; allocation was concealed by faxing centralized treatment assignment to providers at the time of enrollment. Patients, investigators, and assessors of outcomes were not blinded to assignment.Setting: 42 centers in 12 European countries.Patients: 149 patients who had newly diagnosed generalized ANCA-associated vasculitis with renal involvement but not immediately life-threatening disease.Intervention: Pulse cyclophosphamide, 15 mg/kg every 2 to 3 weeks (76 patients), or daily oral cyclophosphamide, 2 mg/kg per day (73 patients), plus prednisolone.Measurement: Time to remission (primary outcome); change in renal function, adverse events, and cumulative dose of cyclophosphamide (secondary outcomes).Results: Groups did not differ in time to remission (hazard ratio, 1.098 [95% CI, 0.78 to 1.55]; P = 0.59) or proportion of patients who achieved remission at 9 months (88.1% vs. 87.7%). Thirteen patients in the pulse group and 6 in the daily oral group achieved remission by 9 months and subsequently had relapse. Absolute cumulative cyclophosphamide dose in the daily oral group was greater than that in the pulse group (15.9 g [interquartile range, 11 to 22.5 g] vs. 8.2 g [interquartile range, 5.95 to 10.55 g]; P < 0.001). The pulse group had a lower rate of leukopenia (hazard ratio, 0.41 [CI, 0.23 to 0.71]).Limitations: The study was not powered to detect a difference in relapse rates between the 2 groups. Duration of follow-up was limited.Conclusion: The pulse cyclophosphamide regimen induced remission of ANCA-associated vasculitis as well as the daily oral regimen at a reduced cumulative cyclophosphamide dose and caused fewer cases of leukopenia.Primary Funding Source: The European Union. [ABSTRACT FROM AUTHOR]

Background A 40-year-old man was referred to a specialist vasculitis center 4 years after being diagnosed with Wegener's granulomatosis. At the time of diagnosis he had presented with skin, ear, nose and throat involvement, pulmonary hemorrhage, and microscopic hematuria. Remission was achieved with plasma exchange and with daily oral prednisolone and cyclophosphamide. The patient was switched to maintenance treatment with azathioprine and prednisolone but suffered a relapse shortly afterwards. Further treatment with cyclophosphamide achieved a second remission, but the patient relapsed again despite remission-maintaining treatment with mycophenolate mofetil. Investigations Physical examination, laboratory testing, serological testing, culture of eye swabs and sputum, chest X-ray, chest CT scan, head M RI scan, bronchoscopy and bronchoalveolar lavage, and consultation with ophthalmological and otorhinolaryngological specialists. Diagnosis Refractory Wegener's granulomatosis with involvement of the eyes, upper and lower respiratory tracts, and kidneys. Management Disease activity was controlled following treatment with deoxyspergualin and oral steroids in addition to aggressive management of intercurrent infections with repeated courses of oral and intravenous antibiotics. Relapses that occurred when deoxyspergualin was discontinued were treated with repeated courses of deoxyspergualin or with pulsed intravenous cyclophosphamide. Remission was achieved with rituximab. Pulmonary disease was closely monitored with repeated bronchoscopy. [ABSTRACT FROM AUTHOR]

BACKGROUND Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by eosinophilic inflammation. Benralizumab, a monoclonal antibody against the interleukin-5α receptor expressed on eosinophils, may be an option for treating EGPA. METHODS We conducted a multicenter, double-blind, phase 3, randomized, active-controlled noninferiority trial to evaluate the efficacy and safety of benralizumab as compared with mepolizumab. Adults with relapsing or refractory EGPA who were receiving standard care were randomly assigned in a 1:1 ratio to receive benralizumab (30 mg) or mepolizumab (300 mg) subcutaneously every 4 weeks for 52 weeks. The primary end point was remission at weeks 36 and 48 (prespecifled noninferiority margin, -25 percentage points). Secondary end points included the accrued duration of remission, time to first relapse, oral glucocorticoid use, eosinophil count, and safety. RESULTS A total of 140 patients underwent randomization (70 assigned to each group). The adjusted percentage of patients with remission at weeks 36 and 48 was 59% in the benralizumab group and 56% in the mepolizumab group (difference, 3 percentage points; 95% confidence interval [CI], -13 to 18; P=0.73 for superiority), showing noninferiority but not superiority of benralizumab to mepolizumab. The accrued duration of remission and the time to first relapse were similar in the two groups. Complete withdrawal of oral glucocorticoids during weeks 48 through 52 was achieved in 41% of the patients who received benralizumab and 26% of those who received mepolizumab. The mean (±SD) blood eosinophil count at baseline was 306.0±225.0 per microliter in the benralizumab group and 384.9±563.6 per micro-liter in the mepolizumab group, decreasing to 32.4±40.8 and 71.8±54.4 per micro-liter, respectively, at week 52. Adverse events were reported in 90% of the patients in the benralizumab group and 96% of those in the mepolizumab group; serious adverse events were reported in 6% and 13%, respectively. CONCLUSIONS Benralizumab was noninferior to mepolizumab for the induction of remission in patients with relapsing or refractory EGPA. (Funded by AstraZeneca; MANDARA ClinicalTrials.gov number, NCT04157348.) [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "European Vasculitis Study Group (EUVAS). Mycophenolate Mofetil vs Azathioprine for Remission Maintenance in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Randomized Controlled Trial," by T. F. Hiemstra and colleagues in a 2010 issue, along with the reply of the authors.

In recent decades, insights into the molecular pathways involved in disease have revolutionized the treatment of autoimmune diseases. A plethora of targeted therapies have been identified and are at varying stages of clinical development in renal autoimmunity. Some of these agents, such as rituximab or avacopan, have been approved for the treatment of immune-mediated kidney disease, but kidney disease lags behind more common autoimmune disorders in new drug development. Evidence is accumulating as to the importance of adaptive immunity, including abnormalities in T-cell activation and signaling, and aberrant B-cell function. Furthermore, innate immunity, particularly the complement and myeloid systems, as well as pathologic responses in tissue repair and fibrosis, play a key role in disease. Collectively, these mechanistic studies in innate and adaptive immunity have provided new insights into mechanisms of glomerular injury in immune-mediated kidney diseases. In addition, inflammatory pathways common to several autoimmune conditions exist, suggesting that the repurposing of some existing drugs for the treatment of immune-mediated kidney diseases is a logical strategy. This new understanding challenges the clinical investigator to translate new knowledge into novel therapies leading to better disease outcomes. This review highlights promising immunomodulatory therapies tested for immune-mediated kidney diseases as a primary indication, details current clinical trials and discusses pathways that could be targeted in the future. [ABSTRACT FROM AUTHOR]

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 500 μmol/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. [ABSTRACT FROM AUTHOR]

The article focuses on a study which assesses whether immunosuppression preserves renal function in patients with idiopathic membranous nephropathy with declining renal function. The researchers randomly-assigned patients to receive supportive treatment only, supportive treatment plus 6 months of alternating cycles of prednisolone and chlorambucil, or supportive treatment plus 12 months of ciclosporin. Results showed a higher serious adverse events in prednisolone and chlorambucil group.

Primary focal segmental glomerulosclerosis (FSGS) is a disease with poor prognosis and high unmet therapeutic need. Here, we evaluated the safety and pharmacokinetics of single-dose infusions of fresolimumab, a human monoclonal antibody that inactivates all forms of transforming growth factor-β (TGF-β), in a phase I open-label, dose-ranging study. Patients with biopsy-confirmed, treatment-resistant, primary FSGS with a minimum estimated glomerular filtration rate (eGFR) of 25  ml/min per 1.73  m(2), and a urine protein to creatinine ratio over 1.8  mg/mg were eligible. All 16 patients completed the study in which each received one of four single-dose levels of fresolimumab (up to 4  mg/kg) and was followed for 112 days. Fresolimumab was well tolerated with pustular rash the only adverse event in two patients. One patient was diagnosed with a histologically confirmed primitive neuroectodermal tumor 2 years after fresolimumab treatment. Consistent with treatment-resistant FSGS, there was a slight decline in eGFR (median decline baseline to final of 5.85 ml/min per 1.73  m(2)). Proteinuria fluctuated during the study with the median decline from baseline to final in urine protein to creatinine ratio of 1.2  mg/mg with all three Black patients having a mean decline of 3.6  mg/mg. The half-life of fresolimumab was ∼14 days, and the mean dose-normalized Cmax and area under the curve were independent of dose. Thus, single-dose fresolimumab was well tolerated in patients with primary resistant FSGS. Additional evaluation in a larger dose-ranging study is necessary. [ABSTRACT FROM AUTHOR]

Objectives: Rituximab is used for remission induction and the prevention of relapse in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). This study evaluated the incidence of safety events and compared time to first serious adverse event (SAE) between a rituximab cohort and a cohort treated with non-rituximab therapies in a real-life setting., Methods: Rituximab surveillance study in vasculitis was a retrospective observational study of patients with AAV who received rituximab (MabThera) or other treatments between 2003 and 2017 at a specialist vasculitis clinic. The primary endpoint was time to first SAE., Results: 392 patients were enrolled: 247 in the rituximab and 145 in the control cohorts with a total follow up of 2217 person-years (mean study duration 5.7 years). Mean age was 61 years, 77% had granulomatosis with polyangiitis (GPA). There were differences in baseline characteristics (disease duration and prior immunosuppressive use) between groups. 134/247 patients (54%) in the rituximab and 58/145 (40%) of controls experienced at least one SAE. Time to first SAE was shorter in the rituximab group (hazard ratio (HR) 1.55, 95% CI 1.07-2.26, P  = 0.022). Predictors of first SAE were higher vasculitis damage index and the presence of chronic pulmonary or kidney disease. The risk of serious infection was higher in the rituximab group (relative risk (RR) 2.12, 95% CI 1.31-3.43)., Conclusion: Over 40% of patients with AAV experienced at least one SAE. Although shorter time to first SAE and higher risk of infection were observed in the rituximab group, baseline imbalances necessitate a careful interpretation of these results., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Rationale & Objective: Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on reducing treatment toxicities, notably through reduction of exposure to glucocorticoids. Glucocorticoid-sparing therapies such as avacopan are not widely available in many countries, and patients are exposed to high glucocorticoid doses. There is little data concerning what clinicians should accept as the lowest glucocorticoid dosing that can be used in induction therapy for AAV., Study Design: International, online survey., Setting & Participants: Clinicians in various countries with experience in managing vasculitis., Exposure and Outcomes: Survey questions to gauge interest and preferences in studying an induction of remission regimen for severe AAV using only 2 or 4 weeks of glucocorticoids without avacopan. Data collected included general opinions about standard of care for induction agents, glucocorticoids, and avacopan. Respondents were presented with 3 candidate trial designs, 2 of which proposed a combination of cyclophosphamide and rituximab induction., Analytical Approach: Using a 10-point Likert scale, respondents ranked each candidate trial on its usefulness in demonstrating whether a minimal glucocorticoid regimen would be safe and effective and their willingness to randomize into the trial., Results: There were 210 respondents to the survey. The candidate trials were rated moderate-to-high for usefulness to demonstrate safety and efficacy (scores 6-7/10), and moderate (scores 5-6/10) for willingness to randomize. Four-week glucocorticoid duration was preferred to 2 weeks, and combination cyclophosphamide-rituximab with 4-week glucocorticoids was the most preferred design. Forty-two percent of respondents felt avacopan had to be incorporated into a minimal GC trial design to want to recruit patients., Limitations: Representativeness of survey sample and generalizability of findings., Conclusions: Combination cyclophosphamide-rituximab may be the ideal way of studying minimal glucocorticoid use in severe AAV. Given its increasing uptake, incorporating avacopan into a potential trial design is important., (© 2024 The Authors.)

Rationale: Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The PEXIVAS (Plasma Exchange and Glucocorticoids in Severe Antineutrophil Cytoplasmic Antibody-Associated Vasculitis) (NCT00987389) trial was the largest in AAV and the first to enroll participants with DAH requiring mechanical ventilation. Objectives: Evaluate characteristics, treatment effects, and outcomes for patients with AAV with and without DAH. Methods: PEXIVAS randomized 704 participants to plasma exchange (PLEX) or no-PLEX and reduced or standard-dose glucocorticoids (GC). DAH status was defined at enrollment as no-DAH, nonsevere, or severe (room air oxygen saturation of ⩽ 85% as measured by pulse oximetry, or use of mechanical ventilation). Measurements and Main Results: At enrollment, 191 (27.1%) participants had DAH (61 severe, including 29 ventilated) and were younger, more frequently relapsing, PR3 (proteinase 3)-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH ( n  = 513; 72.9%). Among those with DAH, 8/95 (8.4%) receiving PLEX died within 1 year versus 15/96 (15.6%) with no-PLEX (hazard ratio, 0.52; confidence interval [CI], 0.21-1.24), whereas 13/96 (13.5%) receiving reduced GC died versus 10/95 (10.5%) with standard GC (hazard ratio, 1.33; CI, 0.57-3.13). When ventilated, ventilator-free days were similar with PLEX versus no-PLEX (medians, 25; interquartile range [IQR], 22-26 vs. 22-27) and fewer with reduced GC (median, 23; IQR, 20-25) versus standard GC (median, 26; IQR, 25-28). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191 (12.0%) with DAH died within 1 year versus 34/513 (6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments. Conclusions: Patients with AAV and DAH differ from those without DAH in multiple ways. Further data are required to confirm or refute a benefit of PLEX or GC dosing on mortality. Original clinical trial registered with www.clinicaltrials.gov (NCT00987389).

Significance Statement: Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. More than 1500 patients were collated in an international longitudinal study to revise the ANCA kidney risk score. The score showed satisfactory performance, mimicking the original study (Harrell's C=0.779). In the development cohort of 959 patients, no additional parameters aiding the tool were detected, but replacing the GFR with creatinine identified an additional cutoff. The parameter interstitial fibrosis and tubular atrophy was modified to allow wider access, risk points were reweighted, and a fourth risk group was created, improving predictive ability (C=0.831). In the validation, the new model performed similarly well with excellent calibration and discrimination ( n =480, C=0.821). The revised score optimizes prognostication for clinical practice and trials., Background: Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. A retrospective international longitudinal cohort was collated to revise the ANCA renal risk score., Methods: The primary end point was ESKD with patients censored at last follow-up. Cox proportional hazards were used to reweight risk factors. Kaplan-Meier curves, Harrell's C statistic, receiver operating characteristics, and calibration plots were used to assess model performance., Results: Of 1591 patients, 1439 were included in the final analyses, 2:1 randomly allocated per center to development and validation cohorts (52% male, median age 64 years). In the development cohort ( n =959), the ANCA renal risk score was validated and calibrated, and parameters were reinvestigated modifying interstitial fibrosis and tubular atrophy allowing semiquantitative reporting. An additional cutoff for kidney function (K) was identified, and serum creatinine replaced GFR (K0: <250 µ mol/L=0, K1: 250-450 µ mol/L=4, K2: >450 µ mol/L=11 points). The risk points for the percentage of normal glomeruli (N) and interstitial fibrosis and tubular atrophy (T) were reweighted (N0: >25%=0, N1: 10%-25%=4, N2: <10%=7, T0: none/mild or <25%=0, T1: ≥ mild-moderate or ≥25%=3 points), and four risk groups created: low (0-4 points), moderate (5-11), high (12-18), and very high (21). Discrimination was C=0.831, and the 3-year kidney survival was 96%, 79%, 54%, and 19%, respectively. The revised score performed similarly well in the validation cohort with excellent calibration and discrimination ( n =480, C=0.821)., Conclusions: The updated score optimizes clinicopathologic prognostication for clinical practice and trials., (Copyright © 2023 by the American Society of Nephrology.)

Background: The Mepolizumab in Relapsing or Refractory EGPA (MIRRA) trial (GSK ID: 115921/NCT02020889) demonstrated that mepolizumab increased remission time and reduced oral corticosteroid (OCS) use compared with placebo in patients with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA). The present analysis investigated the impact of baseline characteristics on clinical outcomes and characterised the OCS-sparing effect of mepolizumab., Methods: In a phase 3, randomised controlled trial for patients with EGPA (MIRRA), patients received standard of care plus mepolizumab 300 mg or placebo every 4 weeks for 52 weeks. The accrued duration of remission, the proportion of patients in remission at weeks 36 and 48, and the proportion of patients with clinical benefit (remission, OCS or relapse-related) were assessed according to baseline EGPA characteristic subgroups ( post hoc ). Mepolizumab-related OCS-sparing benefits were also quantified., Results: Accrued duration of remission and the proportion of patients in remission at weeks 36 and 48 were greater with mepolizumab than placebo across the baseline subgroups of refractory disease, immunosuppressant use, EGPA duration, relapse number and OCS use ≤20 mg·day -1 . The proportion of patients with clinical benefit was greater with mepolizumab versus placebo (range 76-81% versus 25-39%), irrespective of immunosuppressant use or EGPA duration. Patients treated with mepolizumab versus placebo accrued significantly more weeks on OCS ≤4 mg·day -1 (OR 5.06, 95% CI 2.47-10.38) and had a mean of 1423.1 mg less per-patient OCS exposure over 52 weeks., Conclusions: Mepolizumab treatment provided benefits to patients with EGPA across varying baseline clinical characteristics and can be considered an OCS-sparing treatment in EGPA., Competing Interests: Conflict of interest: D.R.W. Jayne has received research grants and consultancy fees from AstraZeneca, Aurinia, BMS, Boehringer Ingelheim, Chemocentryx, GSK, Janssen, Novartis, Roche/Genentech, Takeda and Vifor; speaker fees from Amgen, Vifor and GSK; and was supported by the National Institute for Health and Care Research Cambridge Biomedical Research Centre. Conflict of interest: B. Terrier reports consulting fees from AstraZeneca, Vifor and GSK; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from AstraZeneca, Vifor, GSK and Boehringer Ingelheim; and support for attending meetings and/or travel from Vifor and GSK. Conflict of interest: B. Hellmich reports personal fees for lectures or advisory services from Amgen, AstraZeneca, BMS, Boehringer Ingelheim Chugai, InflaRx, GSK, Pfizer, Phadia, MSD, Roche, Novartis and Vifor, outside the submitted work. Conflict of interest: P. Khoury received research funding from the American Partnership for Eosinophilic Disorders. Conflict of interest: J.H. Bentley is an employee of GSK and owns stocks/shares in GSK. Conflict of interest: L. Baylis, J. Steinfeld, S.W. Yancey and N. Kwon were employees of GSK at the time of this study and own stocks/shares in GSK. Conflict of interest: M.E. Wechsler has research grants with the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute, and is a consultant with GSK, Genentech, Sanofi, Regeneron, AstraZeneca, Teva, Novartis, Boehringer Ingelheim, Sentien and Equillium. Conflict of interest: P. Akuthota has research grants with the National Heart, Lung, and Blood Institute, and the American Partnership for Eosinophilic Disorders; and declares himself as a paid instructor for AstraZeneca, and consultant for AstraZeneca, GSK, Sanofi; and has received grant/research support from GSK, AstraZeneca and Regeneron., (Copyright ©The authors 2024.)

Updated guidelines on the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) were released in 2021 by the American College of Rheumatology jointly with the Vasculitis Foundation and, subsequently, in 2022 by the European Alliance of Associations for Rheumatology. In addition, in 2021, the Kidney Disease: Improving Global Outcomes had released updated recommendations on the treatment of AAV with glomerulonephritis (AAV-GN). Kidney involvement is particularly relevant in microscopic polyangiitis and granulomatosis with polyangiitis, but is less frequent in eosinophilic granulomatosis with polyangiitis. The management of AAV-GN has been a focus for drug development and change over the past 10 years. Avoidance of progression to end-stage kidney disease (ESKD) or kidney failure is one of the main unmet needs in the management of AAV, with ESKD having a major impact on morbidity, health costs and mortality risk. Relevant changes in AAV-GN management are related to remission-induction treatment of patients with severe kidney disease, the use of glucocorticoids and avacopan, and remission-maintenance treatment. All the documents provide guidance in accordance with the evidence-based standard of care available at the time of their release. With our work we aim to (i) show the progress made and identify the differences between guidelines and recommendations, (ii) discuss the supporting rationale for those, and (iii) identify gaps in knowledge that could benefit from additional research and should be revised in subsequent updates., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Systemic lupus erythematosus is a chronic autoimmune disease characterized by loss of tolerance against nuclear and cytoplasmic self-antigens, induction of immunity and tissue inflammation. Lupus nephritis (LN), the most important predictor of morbidity in SLE, develops in almost 30% of SLE patients at disease onset and in up to 50-60% within the first 10 years. Firstly, in this review, we put the pathogenic mechanisms of the disease into a conceptual frame, giving emphasis to the role of the innate immune system in this loss of self-tolerance and the induction of the adaptive immune response. In this aspect, many mechanisms have been described such as dysregulation and acceleration of cell-death pathways, an aberrant clearance and overload of immunogenic acid-nucleic-containing debris and IC, and the involvement of antigen-presenting cells and other innate immune cells in the induction of this adaptive immune response. This result in a clonal expansion of autoreactive lymphocytes with generation of effector T-cells, memory B-cells and plasma cells that produce autoantibodies that will cause kidney damage. Secondly, we review the immunological pathways of damage in the kidney parenchyma, initiated by autoantibody binding and immune complex deposition, and followed by complement-mediated microvascular injury, activation of kidney stromal cells and the recruitment of leukocytes. Finally, we summarize the rationale for the treatment of LN, from conventional to new targeted therapies, focusing on their systemic immunologic effects and the minimization of podocytary damage., Competing Interests: Declaration of Competing Interest MX received lecture fees from GSK. JGP discloses honoraria from AstraZeneca, Abbvie, Galápagos, GSK, Janssen, ElyLilly, Pfizer, and Advisory for Galapagos and Sanofi. RC discloses honoraria and advisory from AstraZeneca, Celgene, GSK, Janssen, ElyLilly, Pfizer, UCB and Rubió. AK discloses consulting from CSL Vifor, Otsuka, Catalyst Biosciences, Walden Biosciences, GSK and Delta4. DJ received consultancy fees from Astra-Zeneca, BMS, Boehringer-Ingelheim, Chemocentryx, GSK, NICE, Novartis, Otsuka, Roche/Genentech, Takeda, UCB&Vifor; lecture fees from Amgen, Kessai, Vifor; and has stock options from Aurinia. Also, he received research grants from GSK, Roche/Genentech, EU, MRC, NIHR, Versus Arthritis. HJA received consultancy and lecture fees from Otsuka, GSK, Novartis, Janssen, AstraZeneca, Roche, and Vifor. FH received grants from GSK and Roche. GE received research funding from GSK and payments for presentations and advice from GSK and Otsuka. LFQ received honoraria from GSK, Otsuka, CSL Vifor and is on the advisory board of GSK, Otsuka, Alexion, Novartis and CSL Vifor. GMLL, FT, AE, CS, JR and AGH have nothing to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To investigate the occurrence of cardiovascular events (CVEs) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, China, Turkey, Russia, the United Kingdom, and the USA., Methods: Patients with a definite diagnosis of AAV who were followed for ≥ 3 months and had sufficient documentation were included. Data on myocardial infarction (MI) and stroke were collected retrospectively from tertiary vasculitis centers. Univariate and multivariate Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs., Results: Over a median follow-up of 62.0 months (IQR 22.6-100.0), CVEs (mostly MIs) occurred in 245 (10.7%) of 2286 patients with AAV, with a higher frequency in China and the UK. On multivariate regression analysis, older age (55-64.9 yrs, HR 2.93, 95% CI 1.99-4.31), smoking (HR 1.98, 95% CI 1.48-2.64), Chinese origin (HR 4.24, 95% CI 3.07-5.85), and pulmonary (HR 1.50, 95% CI 1.09-2.06) and kidney (HR 3.02, 95% CI 2.08-4.37) involvement were independent variables associated with a higher occurrence of CVEs., Conclusion: We showed that geographic region and both traditional and disease-specific (kidney involvement in particular) factors were independently associated with CVEs. Proper assessment and management of modifiable cardiovascular (CV) risk factors are essential for prevention of CV morbidity in patients with AAV., (Copyright © 2023 by the Journal of Rheumatology.)

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is characterised by inflammation and destruction of small to medium sized blood vessels. In the previously reported ADVOCATE study, a phase 3 double-blind, double-dummy randomised controlled trial of patients with newly diagnosed or relapsing ANCA-associated vasculitis, the oral selective complement 5a receptor inhibitor avacopan was shown to be non-inferior with regard to remission induction at week 26 and superior with regard to sustained remission at week 52, compared with a prednisone taper in a standard of care regimen. In this Article, we report an in-depth analysis of prespecified and exploratory patient-reported outcomes from the ADVOCATE study, measuring health-related quality of life and health utilities., Methods: We did a post-hoc analysis of patient-reported outcome data from the ADVOCATE study (NCT02994927) of patients with newly diagnosed or relapsing ANCA-associated vasculitis. We analysed summary scores and individual domain scores for the prespecified health-related quality of life outcomes from ADVOCATE, which were evaluated at weeks 26 and 52 by use of the Medical Outcomes Survey 36-Item Short Form Health Survey (SF-36) version 2, the EuroQol 5-Dimensions 5-Levels Questionnaire (EQ-5D-5L), and the EQ-5D health utility measure, assessed in the modified intention-to-treat population. We also calculated the Short Form 6 Dimension (SF-6D) score as an additional health utility measure. We evaluated the proportion of patients who reported scores that met or exceeded minimum clinically important differences in health-related quality of life, and we compared scores to normative values (age-specific and sex-specific scores from healthy populations from the USA matched to the protocol population). We also evaluated the proportion of patients who reported scores that met or exceeded minimum important difference in health utility scores., Findings: 331 patients were enrolled in the ADVOCATE trial, of whom 166 were in the avacopan group and 165 were in the prednisone standard of care group. In the avacopan group, the mean age was 61·2 years (SD 14·6), 98 (59%) of 166 patients were men, 68 (41%) were women, and 138 (83%) were White; in the prednisone group, the mean age was 60·5 years (14·5), 88 (54%) of 164 patients were men, 76 (46%) were women, and 140 (85%) were White. Patients treated with avacopan received approximately 2500 mg less median total prednisone up to week 52. Least squares means difference from baseline in physical component summary scores were significantly greater in patients in the avacopan group compared with those in the prednisone group at weeks 26 and 52, as well as in five of eight SF-36 domains at week 26 and two of eight SF-36 domains at week 52. The proportion of patients reporting scores equal to or greater than normative values was higher in the avacopan group than in the prednisone group across all SF-36 domains at both week 26 and 52, although the differences were not statistically significant with the exception of the role physical and vitality domains at week 26. Least squares means change from baseline in EQ-5D-5L visual analogue scale, EQ-5D health utility scores, and SF-6D health utility scores were significantly greater at week 52 in the avacopan group compared with the prednisone group., Interpretation: Patients with ANCA-associated vasculitis who received avacopan reported statistically significant and clinically meaningful improvements in health-related quality of life at 26 and 52 weeks and in health utility EQ-5D and SF-6D scores at 52 weeks. These patient-reported outcomes complement investigator assessments and support the efficacy of avacopan in patients with ANCA-associated vasculitis with use of lower prednisone doses., Funding: ChemoCentryx., Competing Interests: Declaration of interests VS received consulting fees from Abbvie, Alpine Immune Sciences, Alumis, Amgen, Aria, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, ChemoCentryx, Endo, Equillium, Ermium, Genentech–Roche, Gilead, GlaxoSmithKline, Horizon, Inmedix, Kiniksa, Lilly, Merck, MiMedx, Novartis, Omeros, Pfizer, Priovant, Regeneron, R-Pharm, Samsung, Sandoz, Sanofi, Scipher, Setpoint, Sorrento, Spherix, and Tonix. VS received honoraria from Arthros, Purdue, Cleveland Clinic, and Lupus Forum; participated on a data safety monitoring board or advisory board for Abbvie, AstraZeneca, Bayer, Endo, and Tonix; and has been a member of Outcome Measures in Rheumatology, Group for Research and Assessment of Psoriasis and Psoriatic Arthritis, and International Dermatology Measures. DRWJ reports personal fees from Astra Zeneca, Boehringer, ChemoCentryx, Novartis, and CSL Vifor, and grants and personal fees from GlaxoSmithKline and Roche. AH received honorarium from ChemoCentryx. HY was an employee of, and reports stock and stock options from, ChemoCentryx, and is currently an employee of Amgen. PB reports consulting fees and stock and stock options from ChemoCentryx. PAM reports grants from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, ChemoCentryx, CSL Behring, Dynacure, EMDSerono, Forbius, GlaxoSmithKline, Immagene, InflaRx, Jannsen, Jubilant, Kyverna, Magenta, MiroBio, Mitsubishi, Neutrolis, Novartis, NS Pharma, Otsuka, Q32, Regeneron, Sparrow, and Takeda; and consulting fees from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, CSL Behring, Dynacure, EMDSerono, Forbius, GlaxoSmithKline, Immagene, InflaRx, Jannsen, Jubilant, Kyverna, Magenta, MiroBio, Mitsubishi, Neutrolis, Novartis, NS Pharma, Otsuka, Q32, Regeneron, Sparrow, and Takeda; and royalties from UpToDate., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Quantifying glucocorticoid toxicity is crucial to efforts to reduce it. The Glucocorticoid Toxicity Index (GTI) measures toxicity effectively in clinical trials by calculating two scores: the cumulative worsening score (CWS) and the aggregate improvement score (AIS). However, in clinical practice, high patient volumes limit the time available for standardised assessments. We aimed to compare the GTI with an abbreviated version of the GTI, the GTI-Metabolic Domains (GTI-MD), which could help to address this issue by using data that are collected easily at routine visits and do not require additional effort from clinicians., Methods: We did a post-hoc analysis of data from ADVOCATE, a randomised, double-blind, double-dummy, phase 3 trial in which avacopan replaced a standard prednisone taper in patients with antineutrophil cytoplasmic antibody-associated vasculitis. We calculated the cumulative worsening score (CWS) and aggregate improvement score (AIS) for each domain of the GTI-MD-comprising the BMI, glucose tolerance, blood pressure, and lipid metabolism domains of the GTI-to test its ability to differentiate the avacopan and prednisone groups by glucocorticoid toxicity. Data from two additional disease cohorts, one comprising patients with asthma and the other comprising patients with autoimmune blistering disease, constituted the validation set., Findings: Complete data were available for 321 (97%) of the 330 participants comprising the intention-to-treat population in the ADVOCATE trial at week 13, and 307 (93%) at week 26; data from these individuals were included in our post-hoc analysis. In ADVOCATE, 98 (59%) of 166 participants in the avacopan group were men and 68 (41%) were women, 88 (54%) of 164 in the prednisone group were men and 76 (46%) were women; the mean age of participants was 61·2 years [SD 14·6] in the avacopan group and 60·5 years [14·5] in the prednisone group. The validation cohort included 159 patients (89 with glucocorticoid-dependent asthma, of whom 40 [45%] were men and 49 [55%] were women, and 70 with autoimmune blistering disease of the skin, of whom 30 [43%] were men and 40 [57%] were women). The Spearman's rank correlation coefficient in ADVOCATE for the GTI-MD CWS with the GTI CWS for the treatment groups combined was 0·78 (95% CI 0·75-0·81; p<0·0001). The corresponding correlation for the AIS was 0·73 (0·69-0·77, p<0·0001). The GTI-MD distinguished the groups by glucocorticoid toxicity at both 13 weeks and 26 weeks. The mean GTI-MD CWS was lower in the avacopan group than in the prednisone group, consistent with less toxicity (15·9 vs 23·0 at 13 weeks [p=0·0010]; 26·7 vs 31·7 at 26 weeks [p=0·0092]). The GTI-MD AIS values were also consistent with less toxicity in the avacopan group (2·5 vs 13·0 at 13 weeks [p=0·0003], 4·4 vs 10·1 at 26 weeks [p=0·027]). A GTI-MD score of 0 corresponded to a low likelihood of toxicity in the other GTI domains. In the validation set, the Spearman's rank correlation coefficient for the GTI-MD CWS with the GTI CWS was 0·61 (95% CI 0·50-0·70; p<0·0001) and the corresponding correlation for the AIS was 0·58 (0·47-0·68; p<0·0001)., Interpretation: The GTI-MD correlates well with the full GTI and could be incorporated readily into routine clinic workflows without additional input from the clinician. Using the GTI-MD on the background of electronic medical records systems could help clinicians to monitor glucocorticoid toxicity longitudinally, with the goals of preventing the burden of chronic, treatment-related harms and reducing long-term costs to health systems., Funding: ChemoCentryx., Competing Interests: Declaration of interests NJP reports consulting fees from FVC Health and Alosa Health, unrelated to the current work. DRWJ reports consultancy fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, ChemoCentryx (now Amgen), GSK, NICE, Novartis, Otsuka, Roche/Genentech, Takeda, UCB, Vifor Pharma, Catalyst Pharmaceuticals, Medscape, and Chinook Therapeutics; lecture fees from Amgen, Vifor Pharma, and Medscape; board member fees from and stock options in Aurinia Pharmaceuticals; commercial research grants from GSK and Roche/Genentech; and non-commercial research grants from the EU, the Medical Research Council, the National Institute for Health and Care Research, and Versus Arthritis. PAM reports consulting with AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ChemoCentryx (now Amgen), CSL Behring, Dynacure, EMD Serono, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, Immagene, InflaRx, Janssen Pharmaceuticals, Kiniksa Pharmaceuticals, Kyverna Therapeutics, Magenta Therapeutics, MiroBio, Neutrolis, Novartis, Pfizer, Regeneron, Sparrow Pharmaceuticals, Takeda, and Talaris Therapeutics; research support from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ChemoCentryx (now Amgen), Eicos Sciences, Forbius, Genentech/Roche, Genzyme/Sanofi, GSK, InflaRx, Sanofi, and Takeda; and royalties from UpToDate. PB reports consulting fees from ChemoCentryx (now Amgen) and owns stock and stock options in ChemoCentryx (now Amgen). PJM reports honoraria from GSK. LGH reports sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GSK, and Napp Pharmaceuticals; advisory board fees from Novartis, Hoffman la Roche/Genentech, Sanofi, GSK, AstraZeneca, Teva Pharmaceuticals, Theravance Biopharma, and Circassia Group; institutional grant funding from MedImmune, Novartis UK, Roche/Genentech, and GSK; and is the academic lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma, which involves industrial partnerships with Amgen, Genetech/Hoffman la Roche, AstraZeneca, MedImmune, GSK, Aerocrine, and Vitalograph. DM reports consultation fees and investigator support from argenx, AstraZeneca, Janssen Pharmaceuticals, Pfizer, Principia Biopharma, and Roche; royalties from UpToDate; and speaker's fees from argenx, Janssen Pharmaceuticals, and Principia Biopharma. MNS is the CEO of Steritas, which holds the licensing rights to the Glucocorticoid Toxicity Index, and owns stock in Steritas (the intellectual property of the GTI is owned by the Massachusetts General Hospital. The intellectual property of the GTI-MD is co-owned by the Massachusetts General Hospital and Steritas. The sole licensing rights to the GTI and GTI-MD worldwide are controlled by Steritas). HY reports employment with and owning stock and stock options in ChemoCentryx (now Amgen). JHS reports consulting fees from ChemoCentryx (now Amgen), Amgen, Roche/Genentech, Sanofi, Bristol-Myers Squibb, AbbVie, InflaRx, Kyverna Therapeutics, Novartis, Q32 Bio, Steritas, Zenas BioPharma, Horizon Therapeutics, argenx, Spruce BioSciences, and PPD; owning stock in Steritas; commercial research grants from Roche/Genentech, Sanofi, Bristol-Myers Squibb; royalties from UpToDate; non-commercial research grants from National Institutes of Health/National Institute of Allergy and Infectious Diseases; and is the co-founder of Steritas and the unpaid chair of its scientific advisory board, with no fiduciary responsibility at the company. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To evaluate mepolizumab's efficacy in eosinophilic granulomatosis with polyangiitis (EGPA) with and without a vasculitic phenotype., Methods: The MIRRA study (NCT02020889/GSK ID: 115921) included adults with relapsing/refractory EGPA and 4 or more weeks of stable oral glucocorticoids (OG). Patients received mepolizumab (300 mg subcutaneously every 4 weeks) or placebo, plus standard of care for 52 weeks. This post hoc analysis assessed EGPA vasculitic phenotype using antineutrophil cytoplasmic antibody (ANCA) history, baseline Birmingham Vasculitis Activity Score (BVAS), and Vasculitis Damage Index (VDI) score. Coprimary endpoints included accrued remission over 52 weeks and proportion in remission at Week 36 and Week 48. Remission was defined as a BVAS equal to 0 and an OG dose of 4 or more mg/day of a prednisone equivalent. Types of relapses (vasculitis, asthma, and sino-nasal) and EGPA vasculitic characteristics (by study remission status) were also assessed., Results: A total of 136 patients were included (n = 68, mepolizumab and placebo). Irrespective of history of ANCA positivity status, baseline BVAS, or baseline VDI, the accrued remission duration and the proportion of patients in remission at Weeks 36 and 48 were greater with mepolizumab compared with placebo. With mepolizumab, remission at both Week 36 and Week 48 was achieved by 54% of patients with and 27% of patients without a history of ANCA positivity compared with 0% and 4%, respectively (placebo); 45% of patients with a BVAS of 0 and 22% of patients with BVAS of greater than 0 compared with 5% and 2%, respectively (placebo); and 29% of patients with a VDI score of less than 5 and 37% of patients with a VDI score of 5 or more compared with 6% and 0%, respectively (placebo). Mepolizumab reduced all types of relapses as compared with placebo. Baseline vasculitic characteristics (neuropathy, glomerulonephritis, alveolar hemorrhage, palpable purpura, and ANCA positivity) were generally similar among patients with and without remission., Conclusion: Mepolizumab is associated with clinical benefits for patients with and without a vasculitic EGPA phenotype., (© 2023 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, characterized by asthma, eosinophilia and granulomatous or vasculitic involvement of several organs. The diagnosis and management of EGPA are often challenging and require an integrated, multidisciplinary approach. Current practice relies on recommendations and guidelines addressing the management of ANCA-associated vasculitis and not specifically developed for EGPA. Here, we present evidence-based, cross-discipline guidelines for the diagnosis and management of EGPA that reflect the substantial advances that have been made in the past few years in understanding the pathogenesis, clinical subphenotypes and differential diagnosis of the disease, as well as the availability of new treatment options. Developed by a panel of European experts on the basis of literature reviews and, where appropriate, expert opinion, the 16 statements and five overarching principles cover the diagnosis and staging, treatment, outcome and follow-up of EGPA. These recommendations are primarily intended to be used by healthcare professionals, pharmaceutical industries and drug regulatory authorities, to guide clinical practice and decision-making in EGPA. These guidelines are not intended to limit access to medications by healthcare agencies, nor to impose a fixed order on medication use., (© 2023. Springer Nature Limited.)