The diseases themselves remain rare, but their consequences are anything but trivial. Although therapeutic advances have improved outcomes in recent years, management continues to be difficult because disease activity, irreversible damage, relapse risk and treatment-related toxicity can coexist and evolve differently within the same patient over time. That tension, between suppressing a dangerous immune attack and avoiding collateral harm from powerful immunosuppression, runs through nearly every contribution in the collection. The editorial frames the eleven studies as complementary pieces of a puzzle in which the biological context, clinical phenotype, risk profile and dynamic response to treatment of each patient matter more than any one-size-fits-all protocol.

One of the most striking findings concerns how autoimmunity may be initiated in the first place. The editorial draws a historical parallel with Goodpasture’s original description of a pulmonary renal syndrome following the influenza pandemic, a process that in retrospect may have represented a vasculitic event. Echoing that pattern, a study by Gabrie and colleagues identified a transient increase in AAV incidence during the COVID-19 pandemic, rising from 22.4 cases per million people in 2019 to 37.9 per million in 2021, before returning toward pre-pandemic levels in 2022. Approximately forty percent of patients diagnosed with AAV had experienced either SARS-CoV-2 infection or vaccination within the three months preceding their diagnosis. The authors interpret the pattern as consistent with transient immune priming, but the observational design cannot establish causality, and the editorial stresses that larger multicentre studies are needed before any firm conclusion can be drawn about a viral or vaccine trigger.

At a more mechanistic level, the collection probes the qualitative features of the autoimmune response rather than its mere presence. Chen and colleagues showed that B cells specific for myeloperoxidase, the MPO protein targeted by ANCA antibodies in many patients, can be detected in healthy individuals, in patients with active MPO-AAV and in patients in long-term remission. What differed between the groups were the immunogenomic characteristics and antibody output of those cells. Patients with disease displayed restricted B-cell receptor repertoires, greater clonotype overlap and distinct MPO epitope recognition. In other words, the mere presence of autoreactive B cells or circulating ANCA may be far less informative than the qualitative characteristics of the autoimmune response itself, a concept with potentially profound implications for how remission and relapse are defined biologically.

That theme of qualitative immune dysregulation is developed further in a review by García-Serrano and colleagues, who catalogue alterations across multiple immune checkpoint pathways, including PD-1/PD-L1, CTLA-4, ICOS, CD40-CD40L, LAG-3, TIM-3, BTLA and CD27. Several soluble and cellular checkpoint markers have been associated with disease activity, renal involvement or treatment response. Notably, lower soluble LAG-3 and higher soluble CD27 have been reported to predict rituximab treatment failure, offering a potential bridge between immunopathology and clinically useful biomarkers. The editorial cautions, however, that incorporating these markers into routine decision-making remains to be established, and that the leap from association to clinical utility requires prospective validation.

Clinical phenotypes are also challenging conventional disease classification. Xie and colleagues highlight the diagnostic and therapeutic complexity of patients with systemic lupus erythematosus who also have renal biopsy-proven AAV, in whom overlapping manifestations can obscure the distinction between lupus nephritis and pauci-immune glomerulonephritis. Wu and colleagues describe a case of MPO-ANCA-associated hypertrophic pachymeningitis that preceded renal involvement and subsequently evolved into a phenotype fulfilling criteria for microscopic polyangiitis, while also illustrating the potential role of individualised low-dose rituximab in refractory disease. These reports emphasise that AAV may manifest through organ-specific phenotypes that are not readily captured by conventional systemic disease categories, complicating both diagnosis and the interpretation of clinical trial data.

A central practical problem addressed in the collection is how to balance disease control against treatment-related harm. Wang and colleagues developed a nomogram incorporating age, albumin, cumulative prednisone exposure and baseline systemic immune-inflammation and systemic inflammation response indices, known as SII and SIRI, to estimate the risk of infection during the first six months of immunosuppressive treatment. In their cohort, 41.6 percent of patients developed an infection, predominantly respiratory, and the five-predictor model showed better discrimination than a clinical model alone. Complementing this approach, Rathmann and colleagues found hypogammaglobulinaemia in 45 percent of rituximab-treated patients, with lower baseline IgG independently predicting its subsequent development. Importantly, hypogammaglobulinaemia was not associated with an increased risk of severe infection in that cohort, supporting close immunoglobulin monitoring while illustrating the need to interpret laboratory abnormalities in their clinical context and to investigate differences between cohorts further.

Monitoring questions extend beyond conventional inflammatory markers and ANCA titres. A review by Colina surveys an expanding range of circulating, urinary and tissue biomarkers alongside advanced imaging techniques, including FDG-PET/CT, vessel-wall MRI, vascular ultrasound and magnetic resonance angiography. These approaches may become particularly relevant when clinical assessment, serology and tissue activity provide discordant signals, a common and frustrating scenario in AAV practice. The editorial draws a sharp distinction, however, between biomarkers and imaging modalities with sufficient evidence for clinical use and promising proof-of-concept approaches that still require validation. That distinction, the authors argue, is essential if increasingly sophisticated tools are to improve rather than complicate clinical decision-making.

On the treatment side, several contributions address how biological and clinical information might translate into therapy selection. Treppo and colleagues propose a phase-oriented framework distinguishing induction, consolidation and maintenance, with therapeutic intensity informed by disease severity, organ involvement, histopathology, ANCA specificity and patient-level vulnerability to toxicity. A small retrospective cohort reported by Ye and colleagues provides preliminary clinical experience with obinutuzumab, a newer anti-CD20 antibody, in AAV, including its use in both induction and maintenance, although its role remains uncertain. Emerging strategies including complement inhibition, FcRn blockade and cellular therapies are also of considerable interest, but their evidence base remains heterogeneous. Meanwhile, a post hoc analysis of the RITAZAREM trial by Prieto-González and colleagues identified a small subgroup with incomplete remission at month four, all of whom had previous PR3-ANCA positivity and ear, nose and throat involvement, and who relapsed more frequently during follow-up. The editorial is careful to note that the small sample size, post hoc design and overlap with the broader PR3-positive GPA phenotype make these findings hypothesis-generating rather than evidence of a distinct rituximab-resistant phenotype.

Taken together, the eleven contributions reinforce the view that AAV cannot be fully understood or managed as a homogeneous disorder, and that treatment response should not be considered binary. The field is moving toward an approach in which biological characterisation, clinical phenotyping, risk stratification and treatment selection are increasingly interconnected and individualised. The editorial closes with a challenge for the next phase of AAV research: not simply to identify more biomarkers or therapies, but to determine which biological signals meaningfully change clinical decisions and improve outcomes. If that integration succeeds, treatment intensity could ultimately be matched to disease biology, organ-specific risk, relapse potential and treatment-related vulnerability, bringing personalised medicine in ANCA-associated vasculitis closer to clinical reality.

Subject of Research: Immunopathology and individualised treatment strategies in ANCA-associated vasculitis

Article Title: Editorial: Comprehensive insights into ANCA vasculitis: from immunopathology to treatment strategies

Article References: Gabrie, L., Salama, A. D., & Zonozi, R. (2026). Editorial: Comprehensive insights into ANCA vasculitis: from immunopathology to treatment strategies. Frontiers in Medicine, 13, Article 2022704. https://doi.org/10.3389/fmed.2026.2022704

Image Credits: AI Generated

DOI: 10.3389/fmed.2026.2022704

Keywords: ANCA-associated vasculitis, autoimmunity, biomarkers, granulomatosis with polyangiitis, immunopathology, microscopic polyangiitis, precision medicine, rituximab, COVID-19, immune checkpoints, rheumatology, Editorial