ANCA-associated vasculitis (AAV) is a heterogeneous autoimmune disease marked by varying organ involvement and outcomes. Plasma exchange, a method of removing native plasma and replacing it with crystalloid, albumin or donor plasma, can deplete autoantibodies and may help control autoimmune diseases rapidly. In AAV, several randomized controlled trials have been performed but, individually, had mixed results. The best data available, through meta-analysis, suggest the effects of plasma exchange in AAV are limited to improving kidney outcomes with a low likelihood of other benefits but also an increase in the risk of serious infections. As such, the use of plasma exchange in AAV should be limited to patients at risk of a poor kidney outcome as all others are more likely to experience harm than benefit. By estimating the risk of kidney failure and serious infections with and without plasma exchange, healthcare providers can help patients with AAV make informed choices about the use of plasma exchange.

Both imaging and temporal artery biopsy (TAB) are utilized to confirm a suspected diagnosis of giant cell arteritis (GCA). What are the advantages of imaging over TAB?

Spatial transcriptomics enables the study of the mechanisms of disease through gene expression and pathway activity analysis in a spatial context. Originally mainly employed in oncology, the techniques developed use different methods of transcript identification, resolution (single cells vs regions), flexibility of target regions and the type of molecules that can be assessed (RNA and/or protein). Selection of regions of interest requires both knowledge of the underlying histopathological changes and limitations of the methods, like artefacts due to variation in pre-analytics, or the probes used to analyse them. Here we review techniques currently available, their opportunities and limitations and discuss results obtained using Digital Spatial Profiling in pauci-immune focal necrotizing (and crescentic) glomerulonephritis (piFNGN) and giant cells arteritis (GCA). Spatial profiling techniques are powerful tools to investigate defined regions of interest in autoimmune and inflammatory disorders and allow for the identification of genes differentially expressed between different types of lesions and different disease aetiologies. Spatial profiling provides an example of a powerful methodology to investigate disease pathways in tissue at a local level across a spectrum of human diseases and generates hypotheses about molecular mechanisms that can be further investigated in detail. When implemented in the setting of a systems biology approach it may ultimately reach the goal of predicting the course of disease from histopathological slides.

Polyarteritis nodosa (PAN) was first described in 1852 with the first widely recognised description in 1866 by Kussmaul and Meier. Since then our concepts of the condition have evolved, with recognition of the difference between polyarteritis nodosa and microscopic polyangiitis (MPA). Classification criteria for PAN remain unsatisfactory. The ACR criteria from 1990 did not recognise MPA or ANCA, with the result that their sensitivity and specificity are poor. The modern ACR/EULAR criteria as yet do not include PAN as yet. The aetiology is better understood, with recognition that hepatitis B associated PAN is a separate condition, discovery of genetic syndromes including DADA2 and VEXAS which can mimic PAN. Epidemiology suggests that PAN is becoming increasingly rare. Truly idiopathic PAN will gradually become a much rarer condition and may well disappear completely.

Drug development in ANCA-associated vasculitis has aimed to improve on the success of the B cell depleting monoclonal antibody rituximab and exploit better understanding of inflammatory pathways. More potent B cell depletion strategies are being tested as are B cell cytokine inhibitors. The involvement of the complement system in pathogenesis is more complicated than previously thought and extends beyond C5a dysregulation and its inhibition with avacopan, broader complement inhibitors and complement regulatory agonists are potential newer therapies. Other approaches have aimed to directly control neutrophil activation and to try to modulate tissue repair and fibrosis that occurs following vasculitis inflammation.

Polymyalgia rheumatica (PMR) is a common inflammatory disorder affecting individuals over 50. The cornerstone of PMR treatment remains oral glucocorticoids (GCs), with initial doses tailored to the risk of relapse and comorbidities. However, relapses occur in up to 76% of cases, and long-term GC use is associated with significant toxicity, affecting up to 85% of patients. Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), such as methotrexate, offer limited benefits, while recent evidence supports the use of biologics, such as tocilizumab and sarilumab, in reducing GC dependency and achieving remission. Emerging treatments, including JAK inhibitors (tofacitinib) and B-cell depletion (rituximab), show promise but require further validation. The treat-to-target (T2T) strategy is advocated for achieving sustained remission and minimizing adverse effects. New treatment options requiring rheumatological expertise are emerging, highlighting the need for specialized management, early referral, improved imaging use, and standardized definitions of remission and relapse to enhance patient care and outcomes.

Our understanding of ANCA vasculitis has advanced from discovery of putative auto-antibodies to a greater understanding of the myriad alterations of innate and adaptive immunity in this disease. The 21st International Vasculitis Workshop held in Barcelona served again as a forum for distributing and sharing advances in this field. B-cell and T-cell subsets are skewed in ANCA vasculitis patients, favoring a pro-inflammatory phenotype. Autoantigen expression of myeloperoxidase (MPO) and proteinase-3 (PR3) is influenced by alterations in chromatin modifications. Changes in DNA methylation may predict the likelihood of sustained remission in vasculitis patients. As our knowledge of disease pathogenesis and disease persistence have progressed, so too has our therapeutic armamentarium. Treatment options are emerging across a variety of immune targets, including the innate and adaptive immune system. Monoclonal antibodies targeting interleukins are available as are complement inhibitors that target the innate immune system. Addressing innate immune responses may be important to abate acute inflammatory responses at disease onset and limit subsequent damage, especially in patients with glomerulonephritis. With expanding therapeutic options, an important consideration remains as to when to stop therapy. A subset of patients discontinue therapy and remain off treatment without relapse, a state of long-term remission off therapy (LTROT). Future therapeutics could be derived from understanding the underlying immunological phenotype in LTROT and developing targeted therapies for durable remission without global immunosuppression. Management of ANCA vasculitis is moving rapidly towards more targeted, less toxic therapies that will optimistically lead to preservation, and perhaps restoration of health.

This session presented emerging realworld evidence on novel glucocorticoid (GC) sparing therapies for ANCA-associated vasculitis (AAV). It covered the first-in-class oral C5a receptor antagonist avacopan for severe granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), and antiinterleukin-5 therapies in the management of eosinophilic granulomatosis with polyangiitis (EGPA). Avacopan was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of AAV in 2021, following the phase 3 ADVOCAT E trial comparing oral avacopan to an oral GC taper for GPA and MPA. The 2024 KDIGO clinical practice guidelines for AAV now incorporate avacopan as an alternative to GC for remission induction. Phase 3 trials in EGPA have demonstrated superiority of mepolizumab versus placebo (MIRRA, 2017) and non-inferiority of benralizumab versus mepolizumab (MANDARA, 2024) for sustaining remission. Real-world data, as presented in this session, are essential to understand the efficacy and safety of these new therapies in broader AAV patient populations.

In this article, the author explains the relationship between GCA and PMR, based on historical studies, his own experience with a large group of patients and recent publications. Searching for occult vasculitis in patients with pure PMR is recommended and the author explains why PET is well suited for this purpose.

In this plenary session of the Vasculitis Workshop 2024, pioneering translational research on autoimmune vasculitis, particularly ANCA-associated vasculitis (AAV), was presented, highlighting advancements in our understanding of disease mechanisms and promising therapeutic prospects. Advances in elucidating molecular pathways, such as IL-17 and IFN-I, pave the way for specific treatments. Preclinical studies have revealed the gut microbiome's role in the pathogenesis of MPO-AAV and demonstrate the therapeutic potential of dietary interventions. Furthermore, research into the protective role of Tregs has shed light on potential new targets for therapeutic interventions. Innovative approaches, such as CAR-T cell therapy and Deoxy Mab DX-1/DX-3, show significant promise in mitigating AAV pathology. These advancements underscore the transformative potential of translational research. By enhancing our understanding of disease mechanisms, these findings pave the way for the development of personalized and effective therapies, ultimately enhancing patient outcomes.

This mini review explores the association of interstitial lung disease (ILD) with antineutrophil cystoplasmic antibodies (ANCA) and the clinical syndrome of microscopic polyangiitis (MPA). Reports on radiographic and histopathologic findings as well as genetic predispositions are reviewed. Based on this evidence a concept for the pathogenesis of the relationship of ILD, MPO-ANCA and MPA is proposed. Finally, a practical clinical management approach to patients presenting either with ILD and a positive ANCA test result, or to patients with MPA found to have pulmonary abnormalities qualifying as an ILD, is derived from the currently available literature. Treatment of these patients is based on up-to-date guidelines for the management of ILD as well as ANCA-associated vasculitis.

The session on other forms of vasculitis included a masterful review on IgG4-related disease (IgG4-RD) following which two research studies evaluating therapeutic agents and one study on histopathologic findings of IgG4-RD were presented. Peyronel F., et al. discussed the results of a prospective multicentre randomized clinical trial evaluating methotrexate for patients with retroperitoneal fibrosis. Methotrexate, in combination with a tapering regimen of glucocorticoids, was effective in inducing remission and allows use of lower cumulative prednisone doses. Hobbelink J., et al. evaluated the histopathologic scoring system from the ACR/EULAR Classification criteria for IgG4-RD. Their study found that these criteria were able to distinguish patients with confirmed and suspected IgG4-RD. Trivioli G et al. retrospectively evaluated rituximab in adult-onset IgA Vasculitis (IgAV) and crescentic IgA Nephropathy (cIgAN). Rituximab resulted in high rate of renal response in IgAV but remission rates in cIgAN remained lower with poorer renal outcomes compared with IgAV.

The use of plasma exchange (PLEX) as adjunct therapy in the initial management of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis remains to be discussed controversially in light of present evidence. In our Viewpoint we highlight scenarios where we think that physicians might still consider the use of PLEX, such as the most severe presentation forms including diffuse alveolar haemorrhage (DAH) with hypoxaemia and acute glomerulonephritis with significantly impaired kidney function. Recent sub-analyses of the PEXIVAS trial have focused on these patient populations and have provided outcomes of these patients. It became obvious that the mortality rates of those presenting with DAH were non-significantly lower and patients with severe GN show a trend of more pronounced estimated glomerular filtration rate (eGFR) recovery in the first weeks after PLEX. Notably, more patients reach a kidney function recovery as defined as eGFR increase ≥15 ml/min/1.73 m2 from baseline to week 52 when randomised to PLEX. These beneficial outcomes need to be balanced against the increased risk of serious infections and we recommend an individualized decision-making when considering addition of PLEX in the induction therapy.

The plenary session on "End organ damage and repair" at the 21st International Vasculitis Workshop Congress featured two lectures and three studies addressing the pathogenesis, diagnosis, and management of fibrosis in vasculitis. The studies presented at the session demonstrate the importance of cellular interplay in driving inflammation and fibrosis, like the B cell-fibroblast interactions in the aorta of giant cell arteritis patients and the potential fibrotic role of specific infiltrating macrophage subtypes in ANCA-associated glomerulonephritis. Moreover, organ damage, such as the presence of interstitial lung disease in ANCA-associated vasculitis, may impact on long-term outcome, and need a personalized treatment approach.

Modern imaging including ultrasound, MRI and PET have all played a pivotal role in characterizing the distinctive musculotendinous pathology that is now recognized to define PMR. Each of these modalities offers inherent advantages and disadvantages relative to availability, cost and radiation exposure, although MRI and hybrid PET/CT are particularly capable of detecting highly sensitive and specific findings, and thus should be considered reliable tools for PMR diagnosis in everyday clinical practice. By contrast, the utility of imaging for monitoring disease activity and predicting long-term clinical outcomes represents areas of ongoing research interest. This narrative review outlines the invaluable contribution made by imaging to our current understanding of PMR as a distinct disease entity and evaluates the diagnostic performance of available modalities together with their future potential for disease activity assessment and prognostication.

Polyarteritis Nodosa (PAN), is the firstly described vasculitis and can be seen in paediatric and adult age. PAN has a heterozygous clinical picture including cutaneous, constitutional, musculoskeletal, gastrointestinal, and renal involvement. Description and splitting of other vasculitis, makes this medium vessel vasculitis, a very rare disease. Additionally, many subgroups of PAN have been defined and this effort let to move Hepatitis B virus-PAN to Vasculitis with probable aetiology. Anyhow, idiopathic PAN still exists and cohorts from various countries such as France, India, and Japan have been published. Rarity of PAN necessities global collaboration to highlight clinical features and genetics studies. GLOBAL-PAN is an ongoing collaborative project of EUVAS, VCRC and many national cohorts. This review covers the recent epidemiological data of PAN along with demographic and clinical characteristics of cohorts from all-over the world and GLOBAL-PAN.

The breakout session "Imaging in Disease Assessment" featured six abstracts on imaging advancements for vasculitis. Disease extent on cranial MRI and its association with visual complications in giant cell arteritis (GCA) was evaluated, introducing the Propensity for Enhancement for GCA (P EG) score to assess inflammation. Predictors of remission and relapse in chronic periaortitis were analyzed, suggesting the potential for tailored treatment approaches. A novel radiomic model using CT chest scans accurately predicted relapses in ANCA-associated vasculitis. FDG-PET for monitoring GCA in patients on tocilizumab demonstrated limited predictive value. Comparative assessments of Takayasu arteritis using the Takayasu Arteritis Disease Activity Index (TAIDAI) highlighted the need for standardized evaluations. Finally, a protocolized ultrasonography pathway for diagnosing large vessel vasculitis showed promising results, suggesting a combined ultrasound and second test approach, guided by CRP levels, as a gold standard. The session emphasized integrating imaging biomarkers with clinical assessments to improve disease management.

Systemic vasculitis can present with different manifestations, some of which require unique approaches. This session at the 21st International Vasculitis Workshop, examined six studies focused on "Management of Special Situations". In ANCA-associated vasculitis (AAV), two institutions reported on their experience with subglottic stenosis (SGS) from the standpoint of histologic features and management compared to patients with idiopathic SGS. In another study in AAV, morbidity and mortality in a recent patient cohort with the potentially life-threatening manifestation of diffuse alveolar hemorrhage was compared to a historical published cohort from the same institution. In Behçet disease, one study investigated gastrointestinal involvement, particularly the management and outcome of those who patients who required abdominal surgery. Pregnancy in vasculitis was the focus of two studies which examined the reproductive experiences and outcomes of women with diverse forms of vasculitis.

ANCA vasculitis is a systemic autoimmune small-vessel vasculitis characterized by autoantibodies targeting either MPO or PR3. While patients with ANCA vasculitis are successfully treated with broad-spectrum immunosuppression, these treatments often leave patients vulnerable to infections. Research in the field has made positive gains in regards to understanding autoantigen specificity and immune cell subset involvement in disease pathogenesis, relapse and remission. This review examines the state of the research field as it relates to possible new antigen- and cell-specific therapies in the vasculitis field. Potential avenues of therapeutic interest include selective elimination of autoreactive B cells by bispecific antibodies, tolerogenic liposomes or engineered T cells. Additionally, restoration of regulatory T-cell function is an attractive avenue to prolong remission of disease. Collectively, the field is well poised to begin investigating new and emerging cell therapies.

The search for targeted therapies and biomarkers for immune-mediated systemic vasculitis requires detailed understanding of molecular pathogenesis. Whilst candidate approaches have identified new opportunities for drug repurposing, they also miss novel approaches for targeting critical immunological or stromal pathways. On the other hand, bulk transcriptional profiling may fail to capture differences in cellular composition and, depending on the cell source profiled, miss important changes within inflamed vascular tissue. The past decade has seen major advances in both experimental techniques and analytical tools that enable multi-dimensional molecular profiling. Interrogation of the transcriptome and proteome is now possible at a single cell level, or at levels of spatial resolution within tissue that was previously unimaginable. As demonstrated during the presentations in the breakout session of the 21st International Vasculitis Workshop entitled Transcriptomic approaches to the study of systemic vasculitis, these techniques are revealing greater understanding of molecular underpinnings of the systemic vasculitides.