RARE DISEASE
Anti-neutrophil cytoplasmic antibody-associated vasculitis
Anti-neutrophil cytoplasmic antibody-associated vasculitis
Anti-neutrophil cytoplasmic antibody-associated vasculitis
Synonyms: AAV, ANCA-associated vasculitis, Antineutrophil cytoplasmic antibody-associated vasculitis
Synonyms: AAV, ANCA-associated vasculitis, Antineutrophil cytoplasmic antibody-associated vasculitis
Synonyms: AAV, ANCA-associated vasculitis, Antineutrophil cytoplasmic antibody-associated vasculitis
Drug discovery
4
drugs
With orphan designations
Overview
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) encompasses rare autoimmune disorders (granulomatosis with polyangiitis [GPA], microscopic polyangiitis [MPA], eosinophilic granulomatosis with polyangiitis [EGPA]) characterized by necrotizing inflammation of small-to-medium vessels. ANCAs targeting PR3 or MPO trigger neutrophil activation, leading to organ damage (e.g., kidneys, lungs). Diagnosis hinges on clinical features, ANCA testing, and histopathology. Treatment involves glucocorticoids combined with cyclophosphamide or rituximab for induction, followed by maintenance therapy. Emerging biologics (e.g., avacopan) aim to reduce glucocorticoid-related toxicity [1][3][6][13]. Relapses and treatment-related adverse effects contribute to morbidity [1][8][14].
Therapies
Induction: High-dose glucocorticoids + rituximab/cyclophosphamide; plasma exchange for severe renal involvement [1][3][13].
Maintenance: Rituximab/azathioprine/methotrexate for ≥24 months; extended therapy for high-risk relapses [3][8][13].
Emerging therapies: Avacopan (complement C5a inhibitor) for glucocorticoid-sparing effects; mepolizumab for refractory EGPA [5][8][18].
Categories: rare circulatory system diseases, rare respiratory diseases, rare systemic and rheumatological diseases, rare systemic or rheumatologic diseases of childhood, rare transplant-related disorders
Research Papers
1,852 drug discovery papers about Anti-neutrophil cytoplasmic antibody-associated vasculitis, with 5 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,852 drug discovery papers about Anti-neutrophil cytoplasmic antibody-associated vasculitis, with 5 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-19 | Rituximab With or Without Avacopan in ANCA-Associated Vasculitis With Severe Renal Involvement.
Avacopan has shown efficacy as a glucocorticoid-sparing therapy in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but its benefit in patients with severe renal involvement treated with rituximab remains uncertain. We conducted a retrospective comparative cohort study at Mayo Clinic including patients with AAV and estimated glomerular filtration rate (eGFR) < 30 ml/min per 1.73 m2 at induction treated with rituximab plus avacopan (n = 30) or rituximab alone (n = 120) between 2010 and 2025. Coprimary outcomes were time to renal remission (no > 25% eGFR decline and hematuria ≤ 10 red blood cells per high-power field [RBC/HPF]), analyzed by Kaplan-Meier and Cox proportional hazards regression, and longitudinal eGFR trajectory, analyzed by linear mixed-effects models. Baseline characteristics were well balanced. Median eGFR was 15.0 and 16.0 mL/min/1.73 m2 and dialysis was required at baseline in 13.3% and 12.5% in the avacopan and rituximab groups, respectively. Avacopan significantly reduced cumulative prednisone exposure at 12 months (1.8 vs 4.3 g; P < 0.001) and shortened time to prednisone discontinuation (3.3 vs 7.3 months; log-rank P < 0.001). On adjusted Cox regression, renal remission did not differ significantly between groups (hazard ratio [HR], 0.74, 95% confidence interval [CI], 0.45-1.21; P = 0.232). Longitudinal eGFR trajectories did not differ significantly between groups. One patient (3.3%) discontinued avacopan because of drug-induced liver injury, with transaminase normalization after discontinuation. In our cohort of patients with AAV and severe renal involvement treated with rituximab-based induction, avacopan did not improve renal remission rates or longitudinal eGFR trajectory in comparison to glucocorticoids but achieved significant and faster glucocorticoid reduction with an acceptable safety profile.
2026-09-19 | Infection Risk Associated with Steroid-Sparing Therapies in GCA, PMR, and ANCA-Associated Vasculitis: A Systematic Review.
Giant cell arteritis (GCA), polymyalgia rheumatica (PMR), and ANCA-associated vasculitis (AAV) often require prolonged glucocorticoid therapy. Steroid-sparing biologic and small molecule therapies reduce glucocorticoid exposure, but may increase infection risk, particularly in older adults. We evaluated infection risk associated with these therapies with concomitant glucocorticoid treatment, versus glucocorticoid treatment alone, in vasculitis/PMR clinical trials. We searched PubMed, Embase, Cochrane, and ClinicalTrials.gov using terms related to GCA, PMR, AAV, biologics (tocilizumab, sarilumab), small molecule therapies (upadacitinib, avacopan), glucocorticoids, and infection outcomes. We included randomized controlled trials (RCTs) comparing biologics or small molecules plus glucocorticoid (active intervention) versus glucocorticoid monotherapy (comparator) reporting infection outcomes. We calculated the relative risk (RR) of infection and difference in glucocorticoid dose between the comparator and active intervention groups. We included 10 RCTs (1,487 patients total, enrolling adults averaged ≥50 years): 4 tocilizumab, 3 avacopan, 2 sarilumab, and 1 upadacitinib. When the active intervention had much lower glucocorticoid dosing than the comparator, the RR for infection was either close to 1 or <1. When the active intervention glucocorticoid dose was comparable to the comparator, the RR for infection was >1. Steroid-sparing therapies reduced glucocorticoid exposure with varying magnitudes but were not consistently associated with lower infection risk. These findings underscore the heightened risk of infection when these novel therapies are used in combination with glucocorticoids when the glucocorticoid dose cannot be adequately tapered, particularly in older adults.
2026-09-18 | Reduced severe infection risk with avacopan in ANCA-associated vasculitis: a multicentre REVEAL cohort with time-varying exposure modelling.
To evaluate the association between avacopan (AVA) use and recurrent relapse and severe infection in patients with ANCA-associated vasculitis, with particular attention to time-varying treatment and glucocorticoid exposure. In this multicentre retrospective cohort study, AVA use was modelled as a time-varying exposure. Stabilized inverse probability of treatment weighting was used to adjust for baseline differences. Recurrent relapse and severe infection, defined as an infection requiring hospitalisation, were analysed using time-dependent Cox proportional hazards models based on the Andersen-Gill formulation. Exploratory models additionally incorporated time-varying and cumulative prednisolone exposure. A total of 387 patients were included, of whom 52 received AVA and 335 did not. AVA exposure was associated with a lower estimated risk of severe infection (adjusted HR 0.22, 95% CI 0.07-0.68; P = 0.008), whereas no statistically significant difference in recurrent relapse risk was observed. AVA use was also associated with lower prednisolone exposure over time. This association with severe infection remained directionally consistent in glucocorticoid-adjusted models, although its magnitude varied depending on model specification. In this multicentre real-world cohort, AVA exposure was associated with a lower estimated risk of severe infection and reduced glucocorticoid exposure, whereas no statistically significant reduction in recurrent relapse risk was observed. These findings suggest that an AVA-containing treatment strategy may be associated with improved infection-related outcomes in routine practice, although the observational design precludes causal inference.
2026-09-15 | Clinical outcomes after relapse during rituximab-based maintenance in ANCA-associated vasculitis: A single-center retrospective cohort study.
Relapse during rituximab (RTX)-based maintenance therapy remains a clinical problem in ANCA-associated vasculitis (AAV). Mycophenolate mofetil (MMF) has been investigated as an alternative; however, evidence regarding its use after relapse during RTX-based maintenance is limited. We aimed to retrospectively describe clinical outcomes in patients with AAV who relapsed during RTX-based maintenance according to whether MMF was included in the initial post-relapse treatment strategy. We retrospectively analyzed 17 patients with AAV who experienced their first relapse during RTX-based maintenance after remission induction. Baseline was defined as the time of the first relapse. Post-relapse treatment included glucocorticoid escalation and/or RTX re-administration; patients were categorized according to whether MMF was additionally included in the initial treatment strategy (MMF-added group, n = 9; MMF-not-added group, n = 8). All outcomes were evaluated descriptively. In the MMF-added group, MMF was initiated at a median of 0.4 months after the first relapse (interquartile range [IQR], 0.3-0.4 months; range, 0.3-0.5 months). The median age was 76 years (IQR, 73-81 years); 16 patients (94.1%) were MPO-ANCA-positive. During a median follow-up of 28 months (IQR, 21-33 months), all patients achieved remission after post-relapse treatment intensification. No second relapse occurred in the MMF-added group, whereas three patients in the MMF-not-added group experienced a second relapse. Glucocorticoids were discontinued in all nine patients in the MMF-added group, whereas in the MMF-not-added group, all eight patients continued glucocorticoids while they were managed without MMF. Severe infections requiring hospitalization occurred in none of the patients in the MMF-added group and in three patients in the MMF-not-added group. Because treatment allocation was non-randomized and post-relapse treatment strategies differed with respect to RTX scheduling, concomitant therapies, and physician-directed glucocorticoid tapering, the independent effect of MMF could not be determined. Therefore, these descriptive and hypothesis-generating findings warrant confirmation in future prospective studies.
2026-09-11 | Complement in Kidney Disease: Core Curriculum 2026.
The complement cascade is part of the innate immune system, and it provides an important line of defense against infections. Inappropriate or excessive activation of this system, however, is also a driver of kidney inflammation in many diseases. Complement inhibitory drugs have now been approved by the US Food and Drug Administration for the treatment of 5 renal diseases: atypical hemolytic uremic syndrome, C3 glomerulopathy, immune-complex membranoproliferative glomerulonephritis, antineutrophil cytoplasmic antibody-associated vasculitis, and IgA nephropathy. Ongoing clinical trials are testing new anticomplement drugs and additional renal indications for complement inhibitors. Most immunosuppressive drugs do not directly block complement activation, and the use of complement inhibitors for renal indications is likely to expand in the coming years. Complement activation in renal diseases also generates plasma, urine, and tissue biomarkers, and laboratory evaluation of the complement system is an important part of the clinical work-up of patients with these inflammatory and autoimmune conditions. It is essential, therefore, that nephrologists are familiar with the available anticomplement drugs and with complement diagnostics.
cell therapies
2026-09-09 | Therapeutic plasma exchange in paediatric ANCA-associated vasculitis: a multicentre real-world experience.
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a rare but potentially life-threatening condition in children, often presenting with severe multi-organ involvement. Although standard induction therapy includes cyclophosphamide or rituximab with glucocorticoids, the role of therapeutic plasma exchange (TPE) in paediatric AAV remains uncertain. This study sought to describe the clinical characteristics, indications and outcomes of paediatric AAV patients treated with TPE in real-world practice and to compare them with patients managed without TPE. This retrospective multicentre study included children (<18 years) diagnosed with AAV according to EULAR/PRINTO/PRES criteria. Patients were classified into TPE-treated (TPE+) and non-TPE-treated (TPE-) groups. Demographic features, organ involvement, laboratory parameters, Paediatric Vasculitis Activity Score (PVAS), treatments, adverse events and outcomes were analysed. Twenty-six paediatric AAV patients were included, of whom 11 (42.3%) underwent TPE. At diagnosis, the TPE+ group had significantly higher disease activity (median PVAS 12 vs 7, P = 0.004) and more severe kidney involvement, with higher serum creatinine and lower estimated glomerular filtration rate. Severe pulmonary, gastrointestinal, cardiovascular and cutaneous manifestations occurred predominantly in the TPE+ group. The primary indication for TPE was severe kidney involvement. TPE was associated with a significant reduction in PVAS (median 12.0-4.5, P = 0.007). Clinical improvement was observed in most acute organ-threatening manifestations, although persistent abnormalities remained common among patients with severe baseline kidney involvement. One patient died from catheter-related Pseudomonas aeruginosa sepsis during treatment. TPE is selectively used as an adjunctive therapy in children with severe or refractory AAV, particularly in those with advanced kidney involvement. Although disease activity and acute organ-threatening manifestations improved following TPE, persistent renal abnormalities remained frequent, reflecting the severity of baseline kidney disease.
2026-05-25 | Chimeric autoantibody receptor T cells for targeted depletion of myeloperoxidase-specific anti-neutrophil cytoplasmic antibody-producing B cells.
Anti-neutrophil cytoplasmic antibody (ANCA) vasculitides are autoimmune disorders driven by autoantibodies against neutrophil granule proteins, myeloperoxidase (MPO) and proteinase 3, which cause necrotizing small-vessel inflammation with prominent lung and kidney involvement, resulting in pulmonary hemorrhage and glomerulonephritis. Current remission-induction regimens rely on broad immunosuppression and global B cell depletion, which are effective but associated with substantial infection risk and relapse that often necessitates repetitive, long-term treatment. Here, we develop MPO chimeric autoantibody receptor (CAAR) T cells as a target-specific therapy to eliminate MPO-autoreactive B cells. MPO CAAR T cells selectively eliminated anti-MPO BCR-expressing B cell lines in vitro and in vivo. In primary murine autoreactive B cell cultures, MPO CAAR T cells suppressed anti-MPO IgG production without inducing global B cell depletion. Together, these findings support MPO CAAR T cells as a precision approach to eliminate pathogenic B cells in ANCA vasculitis, potentially eliminating the need for generalized humoral immunosuppression.
2026-04-23 | Severe autoimmune diffuse alveolar hemorrhage in children; early diagnosis and initiation of therapeutic plasma exchange may improve clinical outcomes.
Diffuse alveolar hemorrhage (DAH) is a rare but life-threatening pulmonary complication in children, presenting with hemoptysis, anemia, diffuse infiltrates, and respiratory failure. Autoimmune diseases such as systemic lupus erythematosus (SLE) and ANCA-associated vasculitis (AAV) account for 30%-40% of pediatric DAH cases. Pediatric evidence is limited to case reports and small series. We aimed to characterize the clinical course, management, and outcomes of pediatric patients with autoimmune DAH requiring intensive care. We conducted a retrospective cohort study at a single tertiary pediatric institution, identifying 6 patients admitted to the ICU from 2013 to 2024 with DAH secondary to SLE or AAV. All six patients (5 females; age 14-17) were critically ill. Five required MV (median 18 days, IQR: 18-25), two required high-frequency oscillatory ventilation (HFOV) (6, 10 days), and three required VV-ECMO (8, 9, and 45 days). Four had new-onset autoimmune diagnoses on admission. All received high-dose corticosteroids and therapeutic plasma exchange (TPE) (mean 6.5 ± 2.6 sessions); adjunctive therapies included cyclophosphamide, rituximab, IVIG, mycophenolate mofetil, and hydroxychloroquine. TPE was initiated within 24 h of DAH diagnosis in most cases. Two patients with less severe presentations had delayed initiation, and one progressed to HFOV. All patients on ECMO were successfully decannulated; one died from Pseudomonal sepsis post-decannulation. The remaining patients survived to discharge. Autoimmune DAH in pediatric patients carries high morbidity, often requiring advanced respiratory support and multimodal immunosuppression. Early diagnostics work up and initiation of TPE may improve outcomes. Further prospective pediatric study would be necessary to guide standardized treatment protocols.
2026-04-16 | Management of Antineutrophil Cytoplasmic Antibody-Associated Alveolar Hemorrhage: A Bayesian Reanalysis of the PEXIVAS Trial.
The Plasma Exchange and Glucocorticoids in Severe Antineutrophil Cytoplasmic Antibody-Associated Vasculitis (PEXIVAS) trial evaluated plasma exchange (PLEX) and glucocorticoid dose in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study reanalyzed the PEXIVAS trial using Bayesian methods to focus on patients with diffuse alveolar hemorrhage (DAH). In the PEXIVAS trial, adults with AAV and kidney injury and/or DAH were randomized to receive PLEX or no PLEX and reduced- or standard-dose glucocorticoids. This study evaluated 1-year survival and severe infection among participants with DAH, no DAH, and severe DAH (oxygen saturation ≤ 85% on room air or mechanical ventilation) across multiple priors. The secondary outcome was severe infection (leading to hospitalization, intravenous antibiotics, or death). This study calculated mean hazard ratios (HRs) for survival and odds ratios (ORs) for infection, 95% credible intervals (CrIs), and probabilities of survival benefit (HR < 1) and infection (OR > 1). Among 704 participants (191 with DAH and 61 with severe DAH), using noninformative priors, the probability of improved survival was 93% for participants with DAH receiving PLEX (HR 0.52; 95% CrI 0.21-1.26) and 67% for those without DAH (HR 0.86; 95% CrI 0.43-1.71). Participants receiving reduced-dose glucocorticoids had a 98% probability of improved survival without DAH (HR 0.46; 95% CrI 0.22-0.95) but a 12% probability with severe DAH (HR 2.02; 95% CrI 0.64-6.35). Plasma exchange increased the odds of severe infection (OR 1.25; 95% CrI 0.92-1.70; 92% probability of OR > 1), whereas reduced-dose glucocorticoids decreased the odds of infection (OR 0.85; 95% CrI 0.63-1.15; 85% probability of OR < 1). Results were consistent across priors. Patients with AAV and DAH may benefit from PLEX. Reduced-dose glucocorticoids improve survival for individuals without DAH but may be harmful in patients with severe DAH.
2026-04-09 | CAR-T cell therapy for ANCA-associated vasculitis: Rationale, current evidence, and future directions.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a relapsing, autoantibody-driven disease in which current therapies often fail to achieve durable remission or are limited by cumulative toxicity. Although CD20-directed B-cell depletion has transformed AAV management, persistent autoreactive B-cells and long-lived, tissue-resident plasma cells contribute to refractory disease and relapse. Chimeric antigen receptor (CAR) T-cell therapy offers a mechanistically distinct approach through deep and sustained depletion of pathogenic B-cell lineages and potential "immune reprogramming." Emerging clinical experience in autoimmune diseases, coupled with preclinical models and early case reports in AAV, has demonstrated rapid disease control, marked reductions in ANCA levels, and prolonged immunologic quiescence following CD19 CAR-T therapy. While safety signals in autoimmune populations appear favorable, critical questions remain regarding the durability of response, long-term immunologic consequences, optimal CAR constructs, and patient selection. This review summarizes the immunopathogenic rationale, existing evidence, safety considerations, and future directions for CAR-based therapies in AAV.
proteins
2026-07-16 | The Effect of Teriparatide in a Brown Tumor Patient With Pathological Hip Fracture: A Case Report and Literature Review.
A 32-year-old man with end-stage renal disease (ESRD) from anti-neutrophil cytoplasmic antibody-associated vasculitis and tertiary hyperparathyroidism, presented with progressive right hip pain. A giant cell-rich lesion biopsy confirmed Brown tumor. Despite cinacalcet and vitamin D, hyperparathyroidism persisted, necessitating parathyroidectomy complicated by hungry bone syndrome and a pathological right hip fracture. Surgical fixation and prosthetic replacement were deferred due to high risk factors such as, ESRD and fracture pattern, as well as potential for postoperative implant failure and infection. Teriparatide was initiated to promote bone remodeling, leading to pain relief and radiographic improvement. To our knowledge, this is the first reported long-bone Brown tumor successfully treated with teriparatide.
2026-06-20 | Soluble CD95L triggers Caspase-10-driven reactive oxygen species production in neutrophils and aggravates anti-neutrophil cytoplasmic antibody-vasculitis.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a severe autoimmune disease that lacks effective targeted therapies. T cell and neutrophil activation are associated with tissue lesions in ANCA-associated vasculitis responsible for the necrotizing vasculitis of small blood vessels. Although the aberrant release of reactive oxygen species (ROS) by neutrophils contribute to the disruption of the endothelial barrier, the underlying molecular mechanisms of this oxidative burst remain unclear. Here, we observe that blood vessels in the inflamed organs of patients with AAV express CD95L, which is cleaved by metalloproteases to release soluble CD95L (sCD95L). sCD95L stimulates ROS production in AAV neutrophils via a caspase-driven mechanism. Proteomic analysis reveals that the deubiquitinase OTULIN is a caspase substrate in sCD95L-exposed neutrophils. Caspase-10 cleaves OTULIN after its aspartates at positions 31 and 54 to unleash the activity of E3 ligase complex LUBAC and trigger mitochondrion-dependent ROS production in AAV neutrophils. Inhibition of the CD95-mediated non-apoptotic signaling abrogates ROS production in AAV neutrophils and alleviates clinical symptoms in AAV and crescentic glomerulonephritis mouse models, indicating that CD95 and CD95L represent attractive molecular targets for patients with AAV.
2026-02-18 | Structures of proteinase 3 and the CD177 receptor complex reveal a major autoantibody epitope.
Granulomatosis with polyangiitis is a life-threatening systemic vasculitis, characterised by anti-neutrophil cytoplasmic autoantibodies (ANCA) most commonly against proteinase 3 (PR3), a protease expressed intracellularly and on the surface of neutrophils. Most cell surface PR3 is bound to the receptor CD177; however, the molecular mechanism of the interactions is not well understood. Here, we present crystal structures of CD177 in complex with PR3 and unliganded CD177. We describe a mainly hydrophobic binding interface between PR3 and CD177, involving the first two Ly6/uPAR (LU) domains of CD177. These form a globular structure which is connected to downstream domains via a flexible linker. Using a panel of PR3-ANCA-positive patient samples, we show that a significant proportion of ANCAs target the CD177-binding site of PR3 in these samples. Structure-guided mutation of the CD177-binding site on PR3 is effective in reducing PR3-ANCA binding. The results demonstrate that the CD177-binding surface of PR3 harbours a major PR3-ANCA epitope, and that the extent of binding to this surface varies between different patients.
2026-01-05 | Similar and yet not quite the same: unmasking distinct type I interferon signatures in ANCA vasculitis.
Antineutrophil cytoplasmic autoantibody-associated vasculitides can be classified by clinical phenotype or antineutrophil cytoplasmic autoantibody specificity, with overlapping yet distinct characteristics. Transcriptomic analyses of kidney biopsies from 2 French antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) cohorts revealed a pronounced type I interferon signature in microscopic polyangiitis (microscopic polyangiitis/myeloperoxidase-AAV) compared with granulomatosis with polyangiitis (granulomatosis with polyangiitis/proteinase 3-AAV). Among biopsies with high interferon scores, 66% were myeloperoxidase-AAV and 28% proteinase 3-AAV. The interferon score was associated with decreased kidney survival. These findings highlight AAV patient heterogeneity and support targeted treatment approaches.
2025-09-12 | A stronger type I interferon signature distinguishes ANCA-associated vasculitis phenotypes and predicts kidney prognosis.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) causes severe multisystemic organ damage. The main phenotypes, microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), share similarities but differ in clinical presentation and outcome. To uncover their molecular differences, we performed transcriptomic profiling of kidney tissue, then focused on type I interferon (IFN-I) pathway activation in kidney and blood and its clinical implications. We analyzed two independent cohorts (Maine-Anjou and RENVAS registries) totaling 193 patients with AAV and glomerulonephritis. NanoString nCounter transcriptomic profiling, and serum inflammatory molecules quantification were conducted. Comparative analyses of MPA vs. GPA (and MPO-AAV vs. PR3-AAV) were validated using independent public datasets (including kidney spatial transcriptomic datasets, European cDNA Renal Biobank and blood from the RAVE trial). The kidney IFN-I signature found in AAV-GN is upregulated in MPA/MPO-AAV compared to GPA/PR3-AAV and controls. Quantitative PCR, MxA immunohistochemistry, and analysis of external datasets confirmed these findings. This IFN-I signature, close to the one found in lupus nephritis, is linked to the extent of pDC infiltration. Kidney IFN-I activation correlated with increased kidney fibrosis, independently of kidney function. High kidney IFN-I signatures were linked to lower kidney survival, independently of kidney function and pathological scores. MPA kidneys also exhibited higher mast cell and T-cell infiltration. Systemic analyses showed elevated IFNα and interferon related inflammatory molecules in all patients with AAV, but a stronger IFN-I gene signature was found in immune cells from MPA. Our study identifies an IFN-I signature in AAV, especially in MPA/MPO-AAV, underscoring its potential role in disease heterogeneity and kidney pathology. IFN-I emerges as a potential prognostic biomarker and therapeutic target in AAV, particularly for MPA. Further studies are needed to clarify its mechanisms and explore IFN-I modulation in clinical trials.
antibodies
2026-09-23 | Steroid-sparing strategies in respiratory diseases: efficacy and safety of current therapeutic options.
Glucocorticoids (GCs) are a fundamental component in the management of numerous respiratory diseases because of their anti-inflammatory and immunosuppressive effects. Growing recognition of the cumulative toxicity associated with systemic glucocorticoid (SGC) therapy has intensified interest in therapeutic strategies aimed at reducing steroid exposure. The wider availability of targeted therapies has created new opportunities to reduce SGC exposure while maintaining disease control. This review summarises the current evidence for the efficacy and safety of steroid-sparing therapies in selected respiratory diseases, including ANCA-associated vasculitis, allergic bronchopulmonary aspergillosis, pulmonary sarcoidosis, and asthma. Available steroid-sparing therapies differ in efficacy, strength of supporting evidence, and safety profiles. However, broader implementation of several agents remains limited by restricted indications, insufficient long-term safety data, and high treatment costs. The benefits of reducing SGC exposure should be interpreted in the context of the safety profiles of alternative therapies, which may themselves be associated with substantial toxicity. Consequently, steroid-sparing strategies should encompass more than simple dose reduction and be part of personalised treatment plans aimed at maintaining long-term disease control while minimising overall treatment-related toxicity. Although targeted therapies continue to advance, their ability to fully replace the broad therapeutic effects of GCs remains limited.
2026-09-23 | Distinct molecular signature in relapsed patients with ANCA-associated vasculitis.
The pathogenesis of relapses in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) remains ill defined. We aimed to identify whether there are any differences in the molecular profile between patients with relapsing versus new-onset disease. Whole blood RNA sequencing in 21 patients with MPA or GPA and 12 age-matched/sex-matched healthy controls was performed; 11 patients had active disease, either newly diagnosed (treatment-naïve, n=6) or relapsed (off-therapy, n=5) and 10 were in remission, either on (n=4) or off (n=6) maintenance therapy. Differential gene expression and functional enrichment analysis were conducted. Relapsing patients with MPA/GPA exhibited a distinct molecular profile compared with healthy controls, newly diagnosed patients or those in remission. Specifically, patients with a major relapse displayed a unique pattern of 41 neutrophil degranulation-associated genes, encoding neutrophil granular proteins, proteins mediating neutrophil adhesion and chemotaxis and proteins involved in myelopoiesis. In this well-defined MPA/GPA cohort, we report for the first time a distinct relapse-associated transcriptional signature consistent with enhanced neutrophil activity. Therapies targeting neutrophil activation could represent a novel approach for preventing or treating relapses in MPA/GPA.
2026-09-08 | From immune dysregulation to renal injury: mechanistic insights and translational opportunities in immune-mediated nephropathies.
Immune-mediated nephropathies are a mechanistically diverse group of kidney disorders in which dysregulated innate and adaptive immunity drive sustained inflammation, tissue injury, and progressive fibrosis. The kidney is not a passive target of these processes but an active immunological organ, where crosstalk between resident parenchymal cells and infiltrating leukocytes shapes both initiation and progression of disease. Advances in immunogenetics and molecular pathology have allowed several previously idiopathic entities-lupus nephritis, IgA nephropathy, ANCA-associated vasculitis, membranous nephropathy, and complement-mediated glomerulopathies-to be reclassified along mechanism-based lines. This review synthesizes the current understanding of their immunopathology, with emphasis on convergent signaling networks and on translational implications for diagnosis, risk stratification, and targeted therapy. We adopted an evidence-based narrative approach, integrating clinical and experimental findings from immunology, nephrology, immunogenetics, and multi-omics. Key domains examined included immune tolerance, immune-complex biology, complement dysregulation, the renal immune microenvironment, cytokine and chemokine networks, non-coding RNA regulation, and immune-derived renal biomarkers. Comparative analysis was used to distinguish shared immune programs from disease-specific cascades across the major nephritic syndromes. Synthesizing evidence from over 150 peer-reviewed publications (2015-2025) across five major immune-mediated nephropathies, several recurrent immune modules emerge: autoantibody generation, complement activation, macrophage M1/M2 repolarization, and NLRP3 inflammasome priming. These converge on canonical signaling axes (TLR-MyD88, NF-κB, JAK-STAT, cGAS-STING, TGF-β/Smad), linking immune activation to glomerular injury and interstitial fibrosis. Established biomarkers (anti-dsDNA, anti-PLA2R, Gd-IgA1) guide diagnosis and risk stratification, while lncRNA signatures and exosomal cargo represent emerging non-invasive monitoring tools. Mechanism-targeted therapies-B-cell depletion, complement inhibition, and inflammasome modulation-are reshaping the treatment landscape. Immune-mediated nephropathies arise from the interaction between systemic immune dysregulation and a nephron-specific immune microenvironment. Distinguishing the shared immune programs from disease-defining cascades provides a rational basis for stratification and precision medicine. Integrated serologic, urinary, histologic, genetic, and multi-omics biomarkers can support earlier diagnosis and dynamic treatment adjustment. Therapy that targets the dominant pathogenic axis in each patient-rather than broad immunosuppression-offers the most realistic route to delaying end-stage renal disease, reducing toxicity, and improving long-term outcomes.
2026-08-19 | Immunoglobulin replacement therapy in antineutrophil cytoplasmic antibody-associated vasculitis with rituximab-associated hypogammaglobulinemia: infection outcomes and disease course in a retrospective cohort.
To evaluate whether immunoglobulin replacement therapy (IgR), initiated for infection prophylaxis in patients with ANCA-associated vasculitis (AAV) receiving rituximab, is associated with changes in infection burden, disease activity, and the ability to de-escalate immunosuppression. We performed a retrospective single-center study of 16 patients with AAV treated with rituximab who developed secondary hypogammaglobulinemia (IgG <600 mg/dL) and subsequently received IgR between 2014 and 2024. Patients receiving IgR for primary immunodeficiency were excluded. Data collected included demographics, ANCA serotype, relapse history, infection burden, immunosuppressive regimen, and serum IgG levels before and after IgR. Primary outcomes were infections and disease relapse before versus after IgR initiation. Secondary outcomes included changes in serum IgG and rituximab use. Prior to IgR, mean IgG was 287 ± 98 mg/dL, 14/14 patients tested had impaired vaccine responses, and 13/16 (81%) experienced recurrent or severe infections. Seven patients (44%) had at least one disease relapse while on rituximab maintenance. After IgR, mean IgG increased to 1018 ± 234 mg/dL, with normalization in 14/15 (93%). Recurrent or severe infections decreased to 1/16 (6%). Following IgR initiation, no disease relapses were observed during a median follow-up of 29.0 months (IQR 14.5-61.4; range 2.8-127.8), despite rituximab discontinuation in 10 patients and dose-interval extension in the remaining 6 patients. IgR was discontinued in 3 patients without relapse. In this cohort of AAV patients with rituximab-associated hypogammaglobulinemia, IgR demonstrated improved immunoglobulin levels and reduced infection burden and was associated with sustained disease remission despite immunosuppression de-escalation. Further studies are needed to determine whether IgR influences disease activity in AAV.
2026-08-14 | Clinical and electrodiagnostic features of nerve conduction study-classified peripheral neuropathy in symptomatic patients with antineutrophil cytoplasmic antibody-associated vasculitis: a single-centre cohort study.
This study investigated the clinical and electrodiagnostic features of vasculitic peripheral neuropathy (VPN) in symptomatic patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) who underwent nerve conduction studies (NCS) within 3 months after AAV diagnosis. Among 323 patients with AAV, 97 presenting with clinical symptoms suggestive of VPN and with the availability of results of NCS performed within 3 months after AAV diagnosis were included in this study. VPN was classified based on the case definition and guidelines proposed by the Brighton Collaboration Vasculitic Peripheral Neuropathy Working Group in 2017. Of the 97 patients, 12 underwent nerve biopsy. At AAV diagnosis, the median age of the 97 patients was 63.0 years (57% women), consisting of 48 patients with microscopic polyangiitis (MPA), 20 with granulomatosis with polyangiitis (GPA), and 29 with eosinophilic granulomatosis with polyangiitis (EGPA). Among symptomatic AAV patients who underwent early NCS, 55 patients (56.7%) were classified as having electrodiagnostically supported VPN. The most common type of VPN was a mixed type (83.6%), and the most frequently affected nerve was the peroneal nerve (70.9%). The concordance rate between NCS and nerve biopsy findings was 75% based on histological evidence of vasculitis. In this selected cohort of symptomatic AAV patients who underwent NCS within 3 months after diagnosis, more than half were classified as having electrodiagnostically supported VPN. NCS may provide adjunctive objective information for characterizing peripheral nerve involvement in clinically suspected VPN.
other
2026-06-29 | Pediatric case of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis with immunoglobulin a deposition diagnosed early through school urinary screening.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare but severe condition in children, and renal involvement in the form of ANCA-associated glomerulonephritis (AAGN) usually determines prognosis. Although AAGN is characterized by pauci-immune necrotizing crescentic glomerulonephritis, mesangial immunoglobulin A (IgA) deposition occurs in a subset of patients; however, pediatric cases remain exceptionally rare. We aimed to report a case of a 12-year-old girl who was asymptomatic and diagnosed through routine school urinalysis. She presented with hematuria and progressive proteinuria, accompanied by elevated myeloperoxidase (MPO)-ANCA levels, while renal function was preserved. Renal biopsy revealed a cellular crescent with surrounding inflammatory cell infiltration, consistent with AAGN. Immunofluorescence microscopy demonstrated mesangial deposition of IgA, immunoglobulin M, and C3; however, there was no mesangial cell proliferation or matrix expansion to suggest typical IgA nephropathy. Based on the clinical course and pathological findings, the primary pathological process was considered to be AAGN rather than IgA nephropathy. The patient was treated with methylprednisolone pulse therapy, followed by rituximab and maintenance therapy with azathioprine. MPO-ANCA levels and proteinuria normalized, and no relapse has been observed. This case highlights the significance of early detection of pediatric renal-limited AAV and suggests that timely AAV-based immunosuppressive therapy promotes favorable outcomes in pediatric AAGN with IgA deposition.
2026-05-10 | Concurrent anti-neutrophil cytoplasmic antibody-associated nephritis and IgG4-related tubulointerstitial nephritis: a rare case.
Concurrent anti-neutrophil cytoplasmic antibody (ANCA)-associated nephritis and immunoglobulin G4 (IgG4)-related nephritis is a rare clinical entity with incompletely understood pathogenesis and progression. We describe the case of a 56-year-old woman, without significant past medical history, who presented with a recurrent low-grade fever for over 3 months, occasional non-productive cough, and acute renal insufficiency, but without chills. Empirical anti-infective therapy was ineffective. Laboratory evaluation revealed moderate anemia and microscopic hematuria without proteinuria on urinalysis. Immunological testing was positive for anti-myeloperoxidase (MPO) antibodies, supporting a preliminary diagnosis of ANCA-associated vasculitis with renal involvement. Renal biopsy demonstrated crescentic glomerulonephritis coexisting with tubulointerstitial nephritis (TIN), with predominant infiltration by IgG4-producing plasma cells, despite a normal serum IgG4 concentration. Following confirmation of no therapeutic contraindications, the patient received corticosteroids in combination with rituximab. At a 2-week follow-up, renal function had improved, erythrocyte sedimentation rate and C-reactive protein were normalized, and urinalysis was negative for occult blood and protein, indicating effective disease control. Cases with concurrent ANCA-associated vasculitis and IgG4-related renal disease are exceedingly uncommon. Their clinical manifestations are often atypical, and routine laboratory assessments are insufficient for differentiation, typically requiring integrated histopathological analysis for definitive diagnosis. Further clinical observations and laboratory studies are needed to clarify the pathogenesis, improve diagnostic accuracy, and establish optimal treatment strategies for this complex condition.
2026-03-10 | Predictors of glucocorticoid-free clinical remission in patients with newly diagnosed microscopic polyangiitis and granulomatosis with polyangiitis: a retrospective cohort study using a nationwide registry in Japan (J-CANVAS).
BACKGROUND: Glucocorticoids (GC) comprise a cornerstone in the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV); however, prolonged GC exposure leads to substantial toxicity and immune system-related complications. Hence, identifying treatment strategies that enable early GC withdrawal while maintaining disease control is of clinical importance. OBJECTIVES: To investigate the proportion and characteristics of patients achieving GC-free clinical remission (GFCR) 48 weeks after treatment initiation in patients with newly diagnosed microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA) and examine their long-term clinical outcomes (up to week 96). METHODS: We conducted a retrospective cohort study using clinical data from a multicenter, nationwide registry in Japan comprising patients with newly diagnosed MPA or GPA and at least 48 weeks of follow-up. GFCR was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 with complete GC withdrawal. Univariable and multivariable logistic regression analyses were used to identify independent predictors of GFCR at week 48, and a sensitivity analysis using a matched cohort was performed to validate robustness. RESULTS: A total of 728 patients were enrolled in the registry, of whom 544 were followed for ≥ 48 weeks; among them, 29 (5.3%) achieved GFCR at week 48. Use of rituximab (RTX) for induction therapy and avacopan within 48 weeks were independently associated with achieving GFCR (multivariable analysis, model 1: RTX: odds ratio [OR]: 3.9, 95% confidence interval [CI]: 1.5–10.0; avacopan: OR: 24.3, 95% CI: 5.8–101.9; both p < 0.01). Conversely, methylprednisolone pulse therapy was associated with a lower likelihood of achieving GFCR (multivariable analysis, model 1: OR: 0.08, 95% CI: 0.02–0.44; p < 0.01). Patient’s demographic and baseline disease characteristics were not predictive of GFCR. In the long-term (weeks 48 through 96), the rates of death, relapse, and serious infection were similar regardless of GFCR status at week 48. CONCLUSIONS: The use of RTX for induction therapy and avacopan within 48 weeks is independently associated with achieving GFCR at week 48 in patients with MPA and GPA, supporting their potential as key components of GC-sparing strategies in AAV. Prospective studies are needed to confirm these results and optimize treatment algorithms to ensure disease control and minimize GC-related toxicity.
2025-07-31 | Active and Mild Chronic Necrotizing Crescentic Glomerulonephritis With Severe Medullary Angiitis in an Elderly Male Patient: A Case Report.
Pauci-immune crescentic glomerulonephritis (GN) is a rapidly progressive form of GN typically associated with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and may present with rare but severe histologic findings such as medullary angiitis. We describe a 69-year-old male patient with no prior medical history who presented with worsening renal function following a recent hospitalization for what is thought to be pneumonia and presumed prerenal azotemia. On readmission, he was found to have an elevated serum creatinine of 5.42 mg/dL, significant hematuria and proteinuria, elevated inflammatory markers, and normocytic anemia. Further evaluation revealed positive P-ANCA at a 1:640 titer and elevated serum IgG. A renal biopsy confirmed the diagnosis of pauci-immune necrotizing crescentic GN with both acute and chronic features, severe medullary angiitis, and arterial nephrosclerosis. The patient was treated with intravenous pulse methylprednisolone, followed by rituximab and avacopan, resulting in significant improvement in renal function without the need for dialysis. This case highlights the diagnostic challenge of distinguishing intrinsic renal disease from prerenal azotemia in the setting of acute illness and underscores the importance of considering AAV in patients presenting with unexplained acute kidney injury and systemic inflammatory markers. Medullary angiitis, although infrequently reported, may be associated with more severe renal disease and should be recognized as a potential marker of disease severity. Early biopsy and prompt initiation of immunosuppressive therapy can lead to substantial renal recovery, even in the presence of chronic histologic damage.
2025-07-09 | Gene therapy enhances deoxyribonuclease I treatment in antimyeloperoxidase glomerulonephritis.
Extracellular DNA (ecDNA) released from injured and dying cells powerfully induces injurious inflammation. In this study we define the role of ecDNA in systemic vasculitis affecting the kidney, using human kidney biopsies and murine models of myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (MPO-ANCA GN). Twice daily administration of intravenous deoxyribonuclease I (ivDNase I) in 2 models of anti-MPO GN reduced glomerular deposition of ecDNA, histological injury, leukocyte infiltration, and NETosis. Comprehensive investigation into DNase I modes of action revealed that after exposure to MPO, DNase I reduced lymph node DC numbers and their activation status, resulting in decreased frequency of MPO-specific CD4+ effector T cells (IFN-γ and IL-17A producing) and reductions in dermal anti-MPO delayed type hypersensitivity responses. To overcome the translational obstacle of the short half-life of DNase I (<5 hours), we tested an adeno-associated viral vector encoding DNase I. This method of DNase I delivery was more effective, as in addition to the histological and antiinflammatory changes described above, a single vector treatment also reduced circulating MPO-ANCA titers and albuminuria. These results indicate ecDNA is a potent driver of anti-MPO GN and DNase I is a potential therapeutic that can be delivered using gene technology.
small molecules
2026-09-19 | Rituximab With or Without Avacopan in ANCA-Associated Vasculitis With Severe Renal Involvement.
Avacopan has shown efficacy as a glucocorticoid-sparing therapy in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but its benefit in patients with severe renal involvement treated with rituximab remains uncertain. We conducted a retrospective comparative cohort study at Mayo Clinic including patients with AAV and estimated glomerular filtration rate (eGFR) < 30 ml/min per 1.73 m2 at induction treated with rituximab plus avacopan (n = 30) or rituximab alone (n = 120) between 2010 and 2025. Coprimary outcomes were time to renal remission (no > 25% eGFR decline and hematuria ≤ 10 red blood cells per high-power field [RBC/HPF]), analyzed by Kaplan-Meier and Cox proportional hazards regression, and longitudinal eGFR trajectory, analyzed by linear mixed-effects models. Baseline characteristics were well balanced. Median eGFR was 15.0 and 16.0 mL/min/1.73 m2 and dialysis was required at baseline in 13.3% and 12.5% in the avacopan and rituximab groups, respectively. Avacopan significantly reduced cumulative prednisone exposure at 12 months (1.8 vs 4.3 g; P < 0.001) and shortened time to prednisone discontinuation (3.3 vs 7.3 months; log-rank P < 0.001). On adjusted Cox regression, renal remission did not differ significantly between groups (hazard ratio [HR], 0.74, 95% confidence interval [CI], 0.45-1.21; P = 0.232). Longitudinal eGFR trajectories did not differ significantly between groups. One patient (3.3%) discontinued avacopan because of drug-induced liver injury, with transaminase normalization after discontinuation. In our cohort of patients with AAV and severe renal involvement treated with rituximab-based induction, avacopan did not improve renal remission rates or longitudinal eGFR trajectory in comparison to glucocorticoids but achieved significant and faster glucocorticoid reduction with an acceptable safety profile.
2026-09-19 | Infection Risk Associated with Steroid-Sparing Therapies in GCA, PMR, and ANCA-Associated Vasculitis: A Systematic Review.
Giant cell arteritis (GCA), polymyalgia rheumatica (PMR), and ANCA-associated vasculitis (AAV) often require prolonged glucocorticoid therapy. Steroid-sparing biologic and small molecule therapies reduce glucocorticoid exposure, but may increase infection risk, particularly in older adults. We evaluated infection risk associated with these therapies with concomitant glucocorticoid treatment, versus glucocorticoid treatment alone, in vasculitis/PMR clinical trials. We searched PubMed, Embase, Cochrane, and ClinicalTrials.gov using terms related to GCA, PMR, AAV, biologics (tocilizumab, sarilumab), small molecule therapies (upadacitinib, avacopan), glucocorticoids, and infection outcomes. We included randomized controlled trials (RCTs) comparing biologics or small molecules plus glucocorticoid (active intervention) versus glucocorticoid monotherapy (comparator) reporting infection outcomes. We calculated the relative risk (RR) of infection and difference in glucocorticoid dose between the comparator and active intervention groups. We included 10 RCTs (1,487 patients total, enrolling adults averaged ≥50 years): 4 tocilizumab, 3 avacopan, 2 sarilumab, and 1 upadacitinib. When the active intervention had much lower glucocorticoid dosing than the comparator, the RR for infection was either close to 1 or <1. When the active intervention glucocorticoid dose was comparable to the comparator, the RR for infection was >1. Steroid-sparing therapies reduced glucocorticoid exposure with varying magnitudes but were not consistently associated with lower infection risk. These findings underscore the heightened risk of infection when these novel therapies are used in combination with glucocorticoids when the glucocorticoid dose cannot be adequately tapered, particularly in older adults.
2026-09-18 | Reduced severe infection risk with avacopan in ANCA-associated vasculitis: a multicentre REVEAL cohort with time-varying exposure modelling.
To evaluate the association between avacopan (AVA) use and recurrent relapse and severe infection in patients with ANCA-associated vasculitis, with particular attention to time-varying treatment and glucocorticoid exposure. In this multicentre retrospective cohort study, AVA use was modelled as a time-varying exposure. Stabilized inverse probability of treatment weighting was used to adjust for baseline differences. Recurrent relapse and severe infection, defined as an infection requiring hospitalisation, were analysed using time-dependent Cox proportional hazards models based on the Andersen-Gill formulation. Exploratory models additionally incorporated time-varying and cumulative prednisolone exposure. A total of 387 patients were included, of whom 52 received AVA and 335 did not. AVA exposure was associated with a lower estimated risk of severe infection (adjusted HR 0.22, 95% CI 0.07-0.68; P = 0.008), whereas no statistically significant difference in recurrent relapse risk was observed. AVA use was also associated with lower prednisolone exposure over time. This association with severe infection remained directionally consistent in glucocorticoid-adjusted models, although its magnitude varied depending on model specification. In this multicentre real-world cohort, AVA exposure was associated with a lower estimated risk of severe infection and reduced glucocorticoid exposure, whereas no statistically significant reduction in recurrent relapse risk was observed. These findings suggest that an AVA-containing treatment strategy may be associated with improved infection-related outcomes in routine practice, although the observational design precludes causal inference.
2026-09-15 | Clinical outcomes after relapse during rituximab-based maintenance in ANCA-associated vasculitis: A single-center retrospective cohort study.
Relapse during rituximab (RTX)-based maintenance therapy remains a clinical problem in ANCA-associated vasculitis (AAV). Mycophenolate mofetil (MMF) has been investigated as an alternative; however, evidence regarding its use after relapse during RTX-based maintenance is limited. We aimed to retrospectively describe clinical outcomes in patients with AAV who relapsed during RTX-based maintenance according to whether MMF was included in the initial post-relapse treatment strategy. We retrospectively analyzed 17 patients with AAV who experienced their first relapse during RTX-based maintenance after remission induction. Baseline was defined as the time of the first relapse. Post-relapse treatment included glucocorticoid escalation and/or RTX re-administration; patients were categorized according to whether MMF was additionally included in the initial treatment strategy (MMF-added group, n = 9; MMF-not-added group, n = 8). All outcomes were evaluated descriptively. In the MMF-added group, MMF was initiated at a median of 0.4 months after the first relapse (interquartile range [IQR], 0.3-0.4 months; range, 0.3-0.5 months). The median age was 76 years (IQR, 73-81 years); 16 patients (94.1%) were MPO-ANCA-positive. During a median follow-up of 28 months (IQR, 21-33 months), all patients achieved remission after post-relapse treatment intensification. No second relapse occurred in the MMF-added group, whereas three patients in the MMF-not-added group experienced a second relapse. Glucocorticoids were discontinued in all nine patients in the MMF-added group, whereas in the MMF-not-added group, all eight patients continued glucocorticoids while they were managed without MMF. Severe infections requiring hospitalization occurred in none of the patients in the MMF-added group and in three patients in the MMF-not-added group. Because treatment allocation was non-randomized and post-relapse treatment strategies differed with respect to RTX scheduling, concomitant therapies, and physician-directed glucocorticoid tapering, the independent effect of MMF could not be determined. Therefore, these descriptive and hypothesis-generating findings warrant confirmation in future prospective studies.
2026-09-11 | Complement in Kidney Disease: Core Curriculum 2026.
The complement cascade is part of the innate immune system, and it provides an important line of defense against infections. Inappropriate or excessive activation of this system, however, is also a driver of kidney inflammation in many diseases. Complement inhibitory drugs have now been approved by the US Food and Drug Administration for the treatment of 5 renal diseases: atypical hemolytic uremic syndrome, C3 glomerulopathy, immune-complex membranoproliferative glomerulonephritis, antineutrophil cytoplasmic antibody-associated vasculitis, and IgA nephropathy. Ongoing clinical trials are testing new anticomplement drugs and additional renal indications for complement inhibitors. Most immunosuppressive drugs do not directly block complement activation, and the use of complement inhibitors for renal indications is likely to expand in the coming years. Complement activation in renal diseases also generates plasma, urine, and tissue biomarkers, and laboratory evaluation of the complement system is an important part of the clinical work-up of patients with these inflammatory and autoimmune conditions. It is essential, therefore, that nephrologists are familiar with the available anticomplement drugs and with complement diagnostics.
cell therapies
2026-09-09 | Therapeutic plasma exchange in paediatric ANCA-associated vasculitis: a multicentre real-world experience.
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a rare but potentially life-threatening condition in children, often presenting with severe multi-organ involvement. Although standard induction therapy includes cyclophosphamide or rituximab with glucocorticoids, the role of therapeutic plasma exchange (TPE) in paediatric AAV remains uncertain. This study sought to describe the clinical characteristics, indications and outcomes of paediatric AAV patients treated with TPE in real-world practice and to compare them with patients managed without TPE. This retrospective multicentre study included children (<18 years) diagnosed with AAV according to EULAR/PRINTO/PRES criteria. Patients were classified into TPE-treated (TPE+) and non-TPE-treated (TPE-) groups. Demographic features, organ involvement, laboratory parameters, Paediatric Vasculitis Activity Score (PVAS), treatments, adverse events and outcomes were analysed. Twenty-six paediatric AAV patients were included, of whom 11 (42.3%) underwent TPE. At diagnosis, the TPE+ group had significantly higher disease activity (median PVAS 12 vs 7, P = 0.004) and more severe kidney involvement, with higher serum creatinine and lower estimated glomerular filtration rate. Severe pulmonary, gastrointestinal, cardiovascular and cutaneous manifestations occurred predominantly in the TPE+ group. The primary indication for TPE was severe kidney involvement. TPE was associated with a significant reduction in PVAS (median 12.0-4.5, P = 0.007). Clinical improvement was observed in most acute organ-threatening manifestations, although persistent abnormalities remained common among patients with severe baseline kidney involvement. One patient died from catheter-related Pseudomonas aeruginosa sepsis during treatment. TPE is selectively used as an adjunctive therapy in children with severe or refractory AAV, particularly in those with advanced kidney involvement. Although disease activity and acute organ-threatening manifestations improved following TPE, persistent renal abnormalities remained frequent, reflecting the severity of baseline kidney disease.
2026-05-25 | Chimeric autoantibody receptor T cells for targeted depletion of myeloperoxidase-specific anti-neutrophil cytoplasmic antibody-producing B cells.
Anti-neutrophil cytoplasmic antibody (ANCA) vasculitides are autoimmune disorders driven by autoantibodies against neutrophil granule proteins, myeloperoxidase (MPO) and proteinase 3, which cause necrotizing small-vessel inflammation with prominent lung and kidney involvement, resulting in pulmonary hemorrhage and glomerulonephritis. Current remission-induction regimens rely on broad immunosuppression and global B cell depletion, which are effective but associated with substantial infection risk and relapse that often necessitates repetitive, long-term treatment. Here, we develop MPO chimeric autoantibody receptor (CAAR) T cells as a target-specific therapy to eliminate MPO-autoreactive B cells. MPO CAAR T cells selectively eliminated anti-MPO BCR-expressing B cell lines in vitro and in vivo. In primary murine autoreactive B cell cultures, MPO CAAR T cells suppressed anti-MPO IgG production without inducing global B cell depletion. Together, these findings support MPO CAAR T cells as a precision approach to eliminate pathogenic B cells in ANCA vasculitis, potentially eliminating the need for generalized humoral immunosuppression.
2026-04-23 | Severe autoimmune diffuse alveolar hemorrhage in children; early diagnosis and initiation of therapeutic plasma exchange may improve clinical outcomes.
Diffuse alveolar hemorrhage (DAH) is a rare but life-threatening pulmonary complication in children, presenting with hemoptysis, anemia, diffuse infiltrates, and respiratory failure. Autoimmune diseases such as systemic lupus erythematosus (SLE) and ANCA-associated vasculitis (AAV) account for 30%-40% of pediatric DAH cases. Pediatric evidence is limited to case reports and small series. We aimed to characterize the clinical course, management, and outcomes of pediatric patients with autoimmune DAH requiring intensive care. We conducted a retrospective cohort study at a single tertiary pediatric institution, identifying 6 patients admitted to the ICU from 2013 to 2024 with DAH secondary to SLE or AAV. All six patients (5 females; age 14-17) were critically ill. Five required MV (median 18 days, IQR: 18-25), two required high-frequency oscillatory ventilation (HFOV) (6, 10 days), and three required VV-ECMO (8, 9, and 45 days). Four had new-onset autoimmune diagnoses on admission. All received high-dose corticosteroids and therapeutic plasma exchange (TPE) (mean 6.5 ± 2.6 sessions); adjunctive therapies included cyclophosphamide, rituximab, IVIG, mycophenolate mofetil, and hydroxychloroquine. TPE was initiated within 24 h of DAH diagnosis in most cases. Two patients with less severe presentations had delayed initiation, and one progressed to HFOV. All patients on ECMO were successfully decannulated; one died from Pseudomonal sepsis post-decannulation. The remaining patients survived to discharge. Autoimmune DAH in pediatric patients carries high morbidity, often requiring advanced respiratory support and multimodal immunosuppression. Early diagnostics work up and initiation of TPE may improve outcomes. Further prospective pediatric study would be necessary to guide standardized treatment protocols.
2026-04-16 | Management of Antineutrophil Cytoplasmic Antibody-Associated Alveolar Hemorrhage: A Bayesian Reanalysis of the PEXIVAS Trial.
The Plasma Exchange and Glucocorticoids in Severe Antineutrophil Cytoplasmic Antibody-Associated Vasculitis (PEXIVAS) trial evaluated plasma exchange (PLEX) and glucocorticoid dose in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study reanalyzed the PEXIVAS trial using Bayesian methods to focus on patients with diffuse alveolar hemorrhage (DAH). In the PEXIVAS trial, adults with AAV and kidney injury and/or DAH were randomized to receive PLEX or no PLEX and reduced- or standard-dose glucocorticoids. This study evaluated 1-year survival and severe infection among participants with DAH, no DAH, and severe DAH (oxygen saturation ≤ 85% on room air or mechanical ventilation) across multiple priors. The secondary outcome was severe infection (leading to hospitalization, intravenous antibiotics, or death). This study calculated mean hazard ratios (HRs) for survival and odds ratios (ORs) for infection, 95% credible intervals (CrIs), and probabilities of survival benefit (HR < 1) and infection (OR > 1). Among 704 participants (191 with DAH and 61 with severe DAH), using noninformative priors, the probability of improved survival was 93% for participants with DAH receiving PLEX (HR 0.52; 95% CrI 0.21-1.26) and 67% for those without DAH (HR 0.86; 95% CrI 0.43-1.71). Participants receiving reduced-dose glucocorticoids had a 98% probability of improved survival without DAH (HR 0.46; 95% CrI 0.22-0.95) but a 12% probability with severe DAH (HR 2.02; 95% CrI 0.64-6.35). Plasma exchange increased the odds of severe infection (OR 1.25; 95% CrI 0.92-1.70; 92% probability of OR > 1), whereas reduced-dose glucocorticoids decreased the odds of infection (OR 0.85; 95% CrI 0.63-1.15; 85% probability of OR < 1). Results were consistent across priors. Patients with AAV and DAH may benefit from PLEX. Reduced-dose glucocorticoids improve survival for individuals without DAH but may be harmful in patients with severe DAH.
2026-04-09 | CAR-T cell therapy for ANCA-associated vasculitis: Rationale, current evidence, and future directions.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a relapsing, autoantibody-driven disease in which current therapies often fail to achieve durable remission or are limited by cumulative toxicity. Although CD20-directed B-cell depletion has transformed AAV management, persistent autoreactive B-cells and long-lived, tissue-resident plasma cells contribute to refractory disease and relapse. Chimeric antigen receptor (CAR) T-cell therapy offers a mechanistically distinct approach through deep and sustained depletion of pathogenic B-cell lineages and potential "immune reprogramming." Emerging clinical experience in autoimmune diseases, coupled with preclinical models and early case reports in AAV, has demonstrated rapid disease control, marked reductions in ANCA levels, and prolonged immunologic quiescence following CD19 CAR-T therapy. While safety signals in autoimmune populations appear favorable, critical questions remain regarding the durability of response, long-term immunologic consequences, optimal CAR constructs, and patient selection. This review summarizes the immunopathogenic rationale, existing evidence, safety considerations, and future directions for CAR-based therapies in AAV.
proteins
2026-07-16 | The Effect of Teriparatide in a Brown Tumor Patient With Pathological Hip Fracture: A Case Report and Literature Review.
A 32-year-old man with end-stage renal disease (ESRD) from anti-neutrophil cytoplasmic antibody-associated vasculitis and tertiary hyperparathyroidism, presented with progressive right hip pain. A giant cell-rich lesion biopsy confirmed Brown tumor. Despite cinacalcet and vitamin D, hyperparathyroidism persisted, necessitating parathyroidectomy complicated by hungry bone syndrome and a pathological right hip fracture. Surgical fixation and prosthetic replacement were deferred due to high risk factors such as, ESRD and fracture pattern, as well as potential for postoperative implant failure and infection. Teriparatide was initiated to promote bone remodeling, leading to pain relief and radiographic improvement. To our knowledge, this is the first reported long-bone Brown tumor successfully treated with teriparatide.
2026-06-20 | Soluble CD95L triggers Caspase-10-driven reactive oxygen species production in neutrophils and aggravates anti-neutrophil cytoplasmic antibody-vasculitis.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a severe autoimmune disease that lacks effective targeted therapies. T cell and neutrophil activation are associated with tissue lesions in ANCA-associated vasculitis responsible for the necrotizing vasculitis of small blood vessels. Although the aberrant release of reactive oxygen species (ROS) by neutrophils contribute to the disruption of the endothelial barrier, the underlying molecular mechanisms of this oxidative burst remain unclear. Here, we observe that blood vessels in the inflamed organs of patients with AAV express CD95L, which is cleaved by metalloproteases to release soluble CD95L (sCD95L). sCD95L stimulates ROS production in AAV neutrophils via a caspase-driven mechanism. Proteomic analysis reveals that the deubiquitinase OTULIN is a caspase substrate in sCD95L-exposed neutrophils. Caspase-10 cleaves OTULIN after its aspartates at positions 31 and 54 to unleash the activity of E3 ligase complex LUBAC and trigger mitochondrion-dependent ROS production in AAV neutrophils. Inhibition of the CD95-mediated non-apoptotic signaling abrogates ROS production in AAV neutrophils and alleviates clinical symptoms in AAV and crescentic glomerulonephritis mouse models, indicating that CD95 and CD95L represent attractive molecular targets for patients with AAV.
2026-02-18 | Structures of proteinase 3 and the CD177 receptor complex reveal a major autoantibody epitope.
Granulomatosis with polyangiitis is a life-threatening systemic vasculitis, characterised by anti-neutrophil cytoplasmic autoantibodies (ANCA) most commonly against proteinase 3 (PR3), a protease expressed intracellularly and on the surface of neutrophils. Most cell surface PR3 is bound to the receptor CD177; however, the molecular mechanism of the interactions is not well understood. Here, we present crystal structures of CD177 in complex with PR3 and unliganded CD177. We describe a mainly hydrophobic binding interface between PR3 and CD177, involving the first two Ly6/uPAR (LU) domains of CD177. These form a globular structure which is connected to downstream domains via a flexible linker. Using a panel of PR3-ANCA-positive patient samples, we show that a significant proportion of ANCAs target the CD177-binding site of PR3 in these samples. Structure-guided mutation of the CD177-binding site on PR3 is effective in reducing PR3-ANCA binding. The results demonstrate that the CD177-binding surface of PR3 harbours a major PR3-ANCA epitope, and that the extent of binding to this surface varies between different patients.
2026-01-05 | Similar and yet not quite the same: unmasking distinct type I interferon signatures in ANCA vasculitis.
Antineutrophil cytoplasmic autoantibody-associated vasculitides can be classified by clinical phenotype or antineutrophil cytoplasmic autoantibody specificity, with overlapping yet distinct characteristics. Transcriptomic analyses of kidney biopsies from 2 French antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) cohorts revealed a pronounced type I interferon signature in microscopic polyangiitis (microscopic polyangiitis/myeloperoxidase-AAV) compared with granulomatosis with polyangiitis (granulomatosis with polyangiitis/proteinase 3-AAV). Among biopsies with high interferon scores, 66% were myeloperoxidase-AAV and 28% proteinase 3-AAV. The interferon score was associated with decreased kidney survival. These findings highlight AAV patient heterogeneity and support targeted treatment approaches.
2025-09-12 | A stronger type I interferon signature distinguishes ANCA-associated vasculitis phenotypes and predicts kidney prognosis.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) causes severe multisystemic organ damage. The main phenotypes, microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), share similarities but differ in clinical presentation and outcome. To uncover their molecular differences, we performed transcriptomic profiling of kidney tissue, then focused on type I interferon (IFN-I) pathway activation in kidney and blood and its clinical implications. We analyzed two independent cohorts (Maine-Anjou and RENVAS registries) totaling 193 patients with AAV and glomerulonephritis. NanoString nCounter transcriptomic profiling, and serum inflammatory molecules quantification were conducted. Comparative analyses of MPA vs. GPA (and MPO-AAV vs. PR3-AAV) were validated using independent public datasets (including kidney spatial transcriptomic datasets, European cDNA Renal Biobank and blood from the RAVE trial). The kidney IFN-I signature found in AAV-GN is upregulated in MPA/MPO-AAV compared to GPA/PR3-AAV and controls. Quantitative PCR, MxA immunohistochemistry, and analysis of external datasets confirmed these findings. This IFN-I signature, close to the one found in lupus nephritis, is linked to the extent of pDC infiltration. Kidney IFN-I activation correlated with increased kidney fibrosis, independently of kidney function. High kidney IFN-I signatures were linked to lower kidney survival, independently of kidney function and pathological scores. MPA kidneys also exhibited higher mast cell and T-cell infiltration. Systemic analyses showed elevated IFNα and interferon related inflammatory molecules in all patients with AAV, but a stronger IFN-I gene signature was found in immune cells from MPA. Our study identifies an IFN-I signature in AAV, especially in MPA/MPO-AAV, underscoring its potential role in disease heterogeneity and kidney pathology. IFN-I emerges as a potential prognostic biomarker and therapeutic target in AAV, particularly for MPA. Further studies are needed to clarify its mechanisms and explore IFN-I modulation in clinical trials.
antibodies
2026-09-23 | Steroid-sparing strategies in respiratory diseases: efficacy and safety of current therapeutic options.
Glucocorticoids (GCs) are a fundamental component in the management of numerous respiratory diseases because of their anti-inflammatory and immunosuppressive effects. Growing recognition of the cumulative toxicity associated with systemic glucocorticoid (SGC) therapy has intensified interest in therapeutic strategies aimed at reducing steroid exposure. The wider availability of targeted therapies has created new opportunities to reduce SGC exposure while maintaining disease control. This review summarises the current evidence for the efficacy and safety of steroid-sparing therapies in selected respiratory diseases, including ANCA-associated vasculitis, allergic bronchopulmonary aspergillosis, pulmonary sarcoidosis, and asthma. Available steroid-sparing therapies differ in efficacy, strength of supporting evidence, and safety profiles. However, broader implementation of several agents remains limited by restricted indications, insufficient long-term safety data, and high treatment costs. The benefits of reducing SGC exposure should be interpreted in the context of the safety profiles of alternative therapies, which may themselves be associated with substantial toxicity. Consequently, steroid-sparing strategies should encompass more than simple dose reduction and be part of personalised treatment plans aimed at maintaining long-term disease control while minimising overall treatment-related toxicity. Although targeted therapies continue to advance, their ability to fully replace the broad therapeutic effects of GCs remains limited.
2026-09-23 | Distinct molecular signature in relapsed patients with ANCA-associated vasculitis.
The pathogenesis of relapses in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) remains ill defined. We aimed to identify whether there are any differences in the molecular profile between patients with relapsing versus new-onset disease. Whole blood RNA sequencing in 21 patients with MPA or GPA and 12 age-matched/sex-matched healthy controls was performed; 11 patients had active disease, either newly diagnosed (treatment-naïve, n=6) or relapsed (off-therapy, n=5) and 10 were in remission, either on (n=4) or off (n=6) maintenance therapy. Differential gene expression and functional enrichment analysis were conducted. Relapsing patients with MPA/GPA exhibited a distinct molecular profile compared with healthy controls, newly diagnosed patients or those in remission. Specifically, patients with a major relapse displayed a unique pattern of 41 neutrophil degranulation-associated genes, encoding neutrophil granular proteins, proteins mediating neutrophil adhesion and chemotaxis and proteins involved in myelopoiesis. In this well-defined MPA/GPA cohort, we report for the first time a distinct relapse-associated transcriptional signature consistent with enhanced neutrophil activity. Therapies targeting neutrophil activation could represent a novel approach for preventing or treating relapses in MPA/GPA.
2026-09-08 | From immune dysregulation to renal injury: mechanistic insights and translational opportunities in immune-mediated nephropathies.
Immune-mediated nephropathies are a mechanistically diverse group of kidney disorders in which dysregulated innate and adaptive immunity drive sustained inflammation, tissue injury, and progressive fibrosis. The kidney is not a passive target of these processes but an active immunological organ, where crosstalk between resident parenchymal cells and infiltrating leukocytes shapes both initiation and progression of disease. Advances in immunogenetics and molecular pathology have allowed several previously idiopathic entities-lupus nephritis, IgA nephropathy, ANCA-associated vasculitis, membranous nephropathy, and complement-mediated glomerulopathies-to be reclassified along mechanism-based lines. This review synthesizes the current understanding of their immunopathology, with emphasis on convergent signaling networks and on translational implications for diagnosis, risk stratification, and targeted therapy. We adopted an evidence-based narrative approach, integrating clinical and experimental findings from immunology, nephrology, immunogenetics, and multi-omics. Key domains examined included immune tolerance, immune-complex biology, complement dysregulation, the renal immune microenvironment, cytokine and chemokine networks, non-coding RNA regulation, and immune-derived renal biomarkers. Comparative analysis was used to distinguish shared immune programs from disease-specific cascades across the major nephritic syndromes. Synthesizing evidence from over 150 peer-reviewed publications (2015-2025) across five major immune-mediated nephropathies, several recurrent immune modules emerge: autoantibody generation, complement activation, macrophage M1/M2 repolarization, and NLRP3 inflammasome priming. These converge on canonical signaling axes (TLR-MyD88, NF-κB, JAK-STAT, cGAS-STING, TGF-β/Smad), linking immune activation to glomerular injury and interstitial fibrosis. Established biomarkers (anti-dsDNA, anti-PLA2R, Gd-IgA1) guide diagnosis and risk stratification, while lncRNA signatures and exosomal cargo represent emerging non-invasive monitoring tools. Mechanism-targeted therapies-B-cell depletion, complement inhibition, and inflammasome modulation-are reshaping the treatment landscape. Immune-mediated nephropathies arise from the interaction between systemic immune dysregulation and a nephron-specific immune microenvironment. Distinguishing the shared immune programs from disease-defining cascades provides a rational basis for stratification and precision medicine. Integrated serologic, urinary, histologic, genetic, and multi-omics biomarkers can support earlier diagnosis and dynamic treatment adjustment. Therapy that targets the dominant pathogenic axis in each patient-rather than broad immunosuppression-offers the most realistic route to delaying end-stage renal disease, reducing toxicity, and improving long-term outcomes.
2026-08-19 | Immunoglobulin replacement therapy in antineutrophil cytoplasmic antibody-associated vasculitis with rituximab-associated hypogammaglobulinemia: infection outcomes and disease course in a retrospective cohort.
To evaluate whether immunoglobulin replacement therapy (IgR), initiated for infection prophylaxis in patients with ANCA-associated vasculitis (AAV) receiving rituximab, is associated with changes in infection burden, disease activity, and the ability to de-escalate immunosuppression. We performed a retrospective single-center study of 16 patients with AAV treated with rituximab who developed secondary hypogammaglobulinemia (IgG <600 mg/dL) and subsequently received IgR between 2014 and 2024. Patients receiving IgR for primary immunodeficiency were excluded. Data collected included demographics, ANCA serotype, relapse history, infection burden, immunosuppressive regimen, and serum IgG levels before and after IgR. Primary outcomes were infections and disease relapse before versus after IgR initiation. Secondary outcomes included changes in serum IgG and rituximab use. Prior to IgR, mean IgG was 287 ± 98 mg/dL, 14/14 patients tested had impaired vaccine responses, and 13/16 (81%) experienced recurrent or severe infections. Seven patients (44%) had at least one disease relapse while on rituximab maintenance. After IgR, mean IgG increased to 1018 ± 234 mg/dL, with normalization in 14/15 (93%). Recurrent or severe infections decreased to 1/16 (6%). Following IgR initiation, no disease relapses were observed during a median follow-up of 29.0 months (IQR 14.5-61.4; range 2.8-127.8), despite rituximab discontinuation in 10 patients and dose-interval extension in the remaining 6 patients. IgR was discontinued in 3 patients without relapse. In this cohort of AAV patients with rituximab-associated hypogammaglobulinemia, IgR demonstrated improved immunoglobulin levels and reduced infection burden and was associated with sustained disease remission despite immunosuppression de-escalation. Further studies are needed to determine whether IgR influences disease activity in AAV.
2026-08-14 | Clinical and electrodiagnostic features of nerve conduction study-classified peripheral neuropathy in symptomatic patients with antineutrophil cytoplasmic antibody-associated vasculitis: a single-centre cohort study.
This study investigated the clinical and electrodiagnostic features of vasculitic peripheral neuropathy (VPN) in symptomatic patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) who underwent nerve conduction studies (NCS) within 3 months after AAV diagnosis. Among 323 patients with AAV, 97 presenting with clinical symptoms suggestive of VPN and with the availability of results of NCS performed within 3 months after AAV diagnosis were included in this study. VPN was classified based on the case definition and guidelines proposed by the Brighton Collaboration Vasculitic Peripheral Neuropathy Working Group in 2017. Of the 97 patients, 12 underwent nerve biopsy. At AAV diagnosis, the median age of the 97 patients was 63.0 years (57% women), consisting of 48 patients with microscopic polyangiitis (MPA), 20 with granulomatosis with polyangiitis (GPA), and 29 with eosinophilic granulomatosis with polyangiitis (EGPA). Among symptomatic AAV patients who underwent early NCS, 55 patients (56.7%) were classified as having electrodiagnostically supported VPN. The most common type of VPN was a mixed type (83.6%), and the most frequently affected nerve was the peroneal nerve (70.9%). The concordance rate between NCS and nerve biopsy findings was 75% based on histological evidence of vasculitis. In this selected cohort of symptomatic AAV patients who underwent NCS within 3 months after diagnosis, more than half were classified as having electrodiagnostically supported VPN. NCS may provide adjunctive objective information for characterizing peripheral nerve involvement in clinically suspected VPN.
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2026-06-29 | Pediatric case of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis with immunoglobulin a deposition diagnosed early through school urinary screening.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare but severe condition in children, and renal involvement in the form of ANCA-associated glomerulonephritis (AAGN) usually determines prognosis. Although AAGN is characterized by pauci-immune necrotizing crescentic glomerulonephritis, mesangial immunoglobulin A (IgA) deposition occurs in a subset of patients; however, pediatric cases remain exceptionally rare. We aimed to report a case of a 12-year-old girl who was asymptomatic and diagnosed through routine school urinalysis. She presented with hematuria and progressive proteinuria, accompanied by elevated myeloperoxidase (MPO)-ANCA levels, while renal function was preserved. Renal biopsy revealed a cellular crescent with surrounding inflammatory cell infiltration, consistent with AAGN. Immunofluorescence microscopy demonstrated mesangial deposition of IgA, immunoglobulin M, and C3; however, there was no mesangial cell proliferation or matrix expansion to suggest typical IgA nephropathy. Based on the clinical course and pathological findings, the primary pathological process was considered to be AAGN rather than IgA nephropathy. The patient was treated with methylprednisolone pulse therapy, followed by rituximab and maintenance therapy with azathioprine. MPO-ANCA levels and proteinuria normalized, and no relapse has been observed. This case highlights the significance of early detection of pediatric renal-limited AAV and suggests that timely AAV-based immunosuppressive therapy promotes favorable outcomes in pediatric AAGN with IgA deposition.
2026-05-10 | Concurrent anti-neutrophil cytoplasmic antibody-associated nephritis and IgG4-related tubulointerstitial nephritis: a rare case.
Concurrent anti-neutrophil cytoplasmic antibody (ANCA)-associated nephritis and immunoglobulin G4 (IgG4)-related nephritis is a rare clinical entity with incompletely understood pathogenesis and progression. We describe the case of a 56-year-old woman, without significant past medical history, who presented with a recurrent low-grade fever for over 3 months, occasional non-productive cough, and acute renal insufficiency, but without chills. Empirical anti-infective therapy was ineffective. Laboratory evaluation revealed moderate anemia and microscopic hematuria without proteinuria on urinalysis. Immunological testing was positive for anti-myeloperoxidase (MPO) antibodies, supporting a preliminary diagnosis of ANCA-associated vasculitis with renal involvement. Renal biopsy demonstrated crescentic glomerulonephritis coexisting with tubulointerstitial nephritis (TIN), with predominant infiltration by IgG4-producing plasma cells, despite a normal serum IgG4 concentration. Following confirmation of no therapeutic contraindications, the patient received corticosteroids in combination with rituximab. At a 2-week follow-up, renal function had improved, erythrocyte sedimentation rate and C-reactive protein were normalized, and urinalysis was negative for occult blood and protein, indicating effective disease control. Cases with concurrent ANCA-associated vasculitis and IgG4-related renal disease are exceedingly uncommon. Their clinical manifestations are often atypical, and routine laboratory assessments are insufficient for differentiation, typically requiring integrated histopathological analysis for definitive diagnosis. Further clinical observations and laboratory studies are needed to clarify the pathogenesis, improve diagnostic accuracy, and establish optimal treatment strategies for this complex condition.
2026-03-10 | Predictors of glucocorticoid-free clinical remission in patients with newly diagnosed microscopic polyangiitis and granulomatosis with polyangiitis: a retrospective cohort study using a nationwide registry in Japan (J-CANVAS).
BACKGROUND: Glucocorticoids (GC) comprise a cornerstone in the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV); however, prolonged GC exposure leads to substantial toxicity and immune system-related complications. Hence, identifying treatment strategies that enable early GC withdrawal while maintaining disease control is of clinical importance. OBJECTIVES: To investigate the proportion and characteristics of patients achieving GC-free clinical remission (GFCR) 48 weeks after treatment initiation in patients with newly diagnosed microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA) and examine their long-term clinical outcomes (up to week 96). METHODS: We conducted a retrospective cohort study using clinical data from a multicenter, nationwide registry in Japan comprising patients with newly diagnosed MPA or GPA and at least 48 weeks of follow-up. GFCR was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 with complete GC withdrawal. Univariable and multivariable logistic regression analyses were used to identify independent predictors of GFCR at week 48, and a sensitivity analysis using a matched cohort was performed to validate robustness. RESULTS: A total of 728 patients were enrolled in the registry, of whom 544 were followed for ≥ 48 weeks; among them, 29 (5.3%) achieved GFCR at week 48. Use of rituximab (RTX) for induction therapy and avacopan within 48 weeks were independently associated with achieving GFCR (multivariable analysis, model 1: RTX: odds ratio [OR]: 3.9, 95% confidence interval [CI]: 1.5–10.0; avacopan: OR: 24.3, 95% CI: 5.8–101.9; both p < 0.01). Conversely, methylprednisolone pulse therapy was associated with a lower likelihood of achieving GFCR (multivariable analysis, model 1: OR: 0.08, 95% CI: 0.02–0.44; p < 0.01). Patient’s demographic and baseline disease characteristics were not predictive of GFCR. In the long-term (weeks 48 through 96), the rates of death, relapse, and serious infection were similar regardless of GFCR status at week 48. CONCLUSIONS: The use of RTX for induction therapy and avacopan within 48 weeks is independently associated with achieving GFCR at week 48 in patients with MPA and GPA, supporting their potential as key components of GC-sparing strategies in AAV. Prospective studies are needed to confirm these results and optimize treatment algorithms to ensure disease control and minimize GC-related toxicity.
2025-07-31 | Active and Mild Chronic Necrotizing Crescentic Glomerulonephritis With Severe Medullary Angiitis in an Elderly Male Patient: A Case Report.
Pauci-immune crescentic glomerulonephritis (GN) is a rapidly progressive form of GN typically associated with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and may present with rare but severe histologic findings such as medullary angiitis. We describe a 69-year-old male patient with no prior medical history who presented with worsening renal function following a recent hospitalization for what is thought to be pneumonia and presumed prerenal azotemia. On readmission, he was found to have an elevated serum creatinine of 5.42 mg/dL, significant hematuria and proteinuria, elevated inflammatory markers, and normocytic anemia. Further evaluation revealed positive P-ANCA at a 1:640 titer and elevated serum IgG. A renal biopsy confirmed the diagnosis of pauci-immune necrotizing crescentic GN with both acute and chronic features, severe medullary angiitis, and arterial nephrosclerosis. The patient was treated with intravenous pulse methylprednisolone, followed by rituximab and avacopan, resulting in significant improvement in renal function without the need for dialysis. This case highlights the diagnostic challenge of distinguishing intrinsic renal disease from prerenal azotemia in the setting of acute illness and underscores the importance of considering AAV in patients presenting with unexplained acute kidney injury and systemic inflammatory markers. Medullary angiitis, although infrequently reported, may be associated with more severe renal disease and should be recognized as a potential marker of disease severity. Early biopsy and prompt initiation of immunosuppressive therapy can lead to substantial renal recovery, even in the presence of chronic histologic damage.
2025-07-09 | Gene therapy enhances deoxyribonuclease I treatment in antimyeloperoxidase glomerulonephritis.
Extracellular DNA (ecDNA) released from injured and dying cells powerfully induces injurious inflammation. In this study we define the role of ecDNA in systemic vasculitis affecting the kidney, using human kidney biopsies and murine models of myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (MPO-ANCA GN). Twice daily administration of intravenous deoxyribonuclease I (ivDNase I) in 2 models of anti-MPO GN reduced glomerular deposition of ecDNA, histological injury, leukocyte infiltration, and NETosis. Comprehensive investigation into DNase I modes of action revealed that after exposure to MPO, DNase I reduced lymph node DC numbers and their activation status, resulting in decreased frequency of MPO-specific CD4+ effector T cells (IFN-γ and IL-17A producing) and reductions in dermal anti-MPO delayed type hypersensitivity responses. To overcome the translational obstacle of the short half-life of DNase I (<5 hours), we tested an adeno-associated viral vector encoding DNase I. This method of DNase I delivery was more effective, as in addition to the histological and antiinflammatory changes described above, a single vector treatment also reduced circulating MPO-ANCA titers and albuminuria. These results indicate ecDNA is a potent driver of anti-MPO GN and DNase I is a potential therapeutic that can be delivered using gene technology.
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Drug Discovery Landscape
4 orphan drug designations for Anti-neutrophil cytoplasmic antibody-associated vasculitis, including 2 approved therapies.
4 orphan drug designations for Anti-neutrophil cytoplasmic antibody-associated vasculitis, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
a humanized IgG4 mAb that binds to hC5aR1 and blocks C5a binding to C5aR1 resulting in inhibition of C5aR1 activation and downstream signaling | antibodies | FDA | — | Otsuka Pharmaceutical Development & Commercialization, Inc |
Gabexate | small molecules | FDA | — | RNR BioMedical Inc. |
avacopan [Tavneos] | small molecules | FDA | Approved | ChemoCentryx, Inc. |
rituximab [Rituxan] | antibodies | FDA | Approved | Genentech, Inc. |
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