The recent vasculitis conference delivered important advances in classification, pathogenesis, therapeutics, and precision medicine in ANCA-associated vasculitis (AAV) and related glomerular diseases. Below is a synthesis of key developments relevant to ISGD members.
Refining Classification in ANCA-Associated Vasculitis
The updated DCVAS initiative underpinned the 2022 ACR/EULAR classification criteria for AAV. With over 6,000 patients enrolled, DCVAS represents the largest vasculitis dataset assembled to date. Importantly, classification criteria are designed as research tools and are distinct from diagnostic criteria used in clinical care.
The 2022 criteria demonstrate strong concordance with ANCA serology, particularly PR3-ANCA in granulomatosis with polyangiitis and MPO-ANCA in microscopic polyangiitis. While the proportion of unclassified cases has decreased, double-classified cases persist. Histopathologic discordance remains a challenge, with occasional granulomatous inflammation classified as MPA, reflecting a serology-driven framework in which ANCA specificity may override pathology.
Data-driven subclassification approaches further refine disease heterogeneity. FAIRVASC analysis of 3,868 patients identified five clusters—young respiratory, inflammatory multisystem, PR3-renal, severe renal, and MPO-renal—which demonstrated superior prognostic power for mortality and renal survival compared with traditional diagnostic labels or serology alone. These findings support movement toward biologically informed stratification.
Regional Signatures and Epidemiologic Differences
Striking geographic differences were reported between Japanese and Western cohorts. Japanese patients are older at presentation, have higher MPO positivity, and exhibit greater pulmonary involvement, including interstitial lung disease (ILD). ILD is particularly common in Japanese MPA and strongly influences mortality.
Notably, approximately 5% of Japanese patients with idiopathic pulmonary fibrosis demonstrate baseline MPO positivity, and up to 20% may later develop MPA. These findings suggest genetic susceptibility and a broader immune-mediated pulmonary phenotype in East Asian populations. Understanding these regional signatures is essential for global trial design and prognostication.
Therapeutic Advances and Ongoing Questions
Glucocorticoids and Induction Therapy
Reduced-dose glucocorticoid regimens are now standard; however, caution is warranted in patients with creatinine >300 µmol/L and in those receiving rituximab induction. Plasma exchange has not demonstrated benefit for kidney outcomes or mortality in diffuse alveolar haemorrhage, though integration of biopsy data may yet refine patient selection.
Avacopan
Renal function at week 52 favoured avacopan in ADVOCATE, though baseline differences complicate interpretation. Severe disease subsets were underrepresented, and patients still received significant background glucocorticoids. Treatment is currently recommended for one year. Post-marketing surveillance in Japan identified higher-than-expected hepatobiliary toxicity, including cases of vanishing bile duct syndrome—an immune-mediated injury possibly related to drug-specific T cell responses. Vigilance in monitoring is warranted.
Rituximab Duration
Scheduled rituximab maintenance reduces relapse compared to on-demand therapy. Eighteen months of fixed-interval therapy appears comparable to 36 months. Emerging predictive models for relapse and infection risk should be incorporated into future randomized trials to individualize duration.
Relapse and Infection Risk
Relapse remains clinically significant, with 5- and 10-year relapse rates of 21% and 31%, respectively, and higher rates in GPA than MPA. Relapse correlates with accelerated GFR decline. While histologic sclerosis and baseline eGFR predict relapse, adding histology to clinical models did not substantially improve predictive accuracy.
Infection risk analysis from the RITAZAREM cohort identified pulmonary involvement, pulmonary fibrosis, and infection during induction as major risk factors. Trimethoprim-sulfamethoxazole prophylaxis showed a protective signal. Infection rates did not differ significantly between azathioprine and rituximab maintenance.
Emerging Immunotherapies: CAR-T Cells
Chimeric antigen receptor (CAR) T-cell therapy represents a novel strategy targeting autoreactive B cells and plasma cell niches inadequately depleted by rituximab. In preclinical models, CD19-targeted CAR-T cells reduced B cells and plasmablasts with favorable tissue responses. Early human experience demonstrated rapid PR3 decline and clinical remission in refractory disease, though B-cell reconstitution and serologic relapse may occur. This remains an evolving and promising field.
Genetics and Precision Medicine
AAV is genetically polygenic and strongly stratified by ANCA specificity. PR3-ANCA disease associates with HLA-DP, SERPINA1, and PRTN3 variants, whereas MPO-ANCA disease associates with HLA-DQ. Whole genome sequencing (WGS) now captures the majority of heritable risk, including rare and non-coding variants missed by GWAS and exome sequencing. Rare variants contribute approximately 20% of total heritability. Future work must move beyond susceptibility toward genetic predictors of treatment response and prognosis.
Transcriptomics and Spatial Biology
Kidney transcriptomic studies reveal a prominent type I interferon signature in MPO-ANCA disease, comparable in intensity to lupus nephritis. Spatial transcriptomics demonstrate plasma dendritic cell infiltration and proximity to interferon-stimulated T cells, suggesting mechanistic pathways and therapeutic targets.
Distinct spatial organization between PR3 and MPO disease was observed, with PR3 kidneys enriched for immune activation and MPO kidneys demonstrating greater tissue remodelling and macrophage-fibroblast crosstalk. These findings underscore biologically divergent pathways despite shared clinical phenotypes.
Special Populations and Related Conditions
Pediatric AAV is rare but often severe, with younger patients exhibiting more diffuse alveolar haemorrhage and intensive care requirements. Damage accrual appears higher in older pediatric patients at diagnosis.
Adult IgA vasculitis classification now uses revised EULAR-endorsed Ankara criteria for research. Three reproducible phenotypic clusters have been identified, with older patients demonstrating greater renal fibrosis and cardiovascular risk and younger patients demonstrating better prognosis but more relapses.
In eosinophilic granulomatosis with polyangiitis, early mepolizumab therapy (<3 months from diagnosis) is associated with higher remission rates and greater glucocorticoid-free survival, emphasizing timing over dose.
In anti-GBM disease, atypical variant anti-laminin 521 positivity is increasingly recognized. This may not be detected by regular ELISA based techniques which only detects NC1 alpha-3 chain of collagen type IV. Hence atypical anti GBM disease needs greater awareness for identification. A study to identify outcome with Imlifidase in anti GBM disease was a negative study with no outcome difference. Imlifidase (IgG-degrading enzyme) rapidly reduces circulating antibodies but did not demonstrate superior kidney survival compared with plasma exchange.
Conclusion
Collectively, these advances signal a transition from syndromic classification toward biologically stratified, precision-guided management in vasculitis. Integration of genomics, transcriptomics, spatial biology, and refined clinical phenotyping will be central to improving outcomes in glomerular disease worldwide. The ISGD community remains uniquely positioned to lead this translational evolution.
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