Targeted regulation of neutrophils is an effective approach for treating neutrophil-driven inflammatory diseases, but challenges remain in minimizing off-target effects and extending drug half-life. A DNA-based nanorobot was developed to target neutrophils by using an N-acetyl Pro-Gly-Pro (Ac-PGP) peptide to specifically bind to the C-X-C motif of chemokine receptor 2 (CXCR2) on neutrophil membranes. This robot (a tetrahedral framework nucleic acid modified with Ac-PGP, APT) identified and hitchhiked neutrophils to accumulate at inflammatory sites and prolong its half-lives, whilst also was internalized to influence the neutrophil cell cycle and maturation process to regulate oxidative stress, inflammation, migration, and recruitment in both in vivo and in vitro inflammation experiments. Consequently, the tissue damage caused by sepsis was greatly reduced. This novel neutrophil-based nanorobot highlights the high precision of targeting and regulating neutrophils, and presents a potential strategy for treating multiple neutrophil-driven diseases.

NETosis, the process through which neutrophils release neutrophil extracellular traps (NETs), has emerged as a crucial mechanism in host defense and the pathogenesis of autoimmune responses. During the SARS-CoV-2 pandemic, this process received significant attention due to the central role of neutrophil recruitment and activation in infection control. However, elevated neutrophil levels and dysregulated NET formation have been linked to coagulopathy and endothelial damage, correlating with disease severity and poor prognosis in COVID-19. Moreover, it is known that SARS-CoV-2 can induce persistent low-grade systemic inflammation, known as long COVID, although the underlying causes remain unclear. It has been increasingly acknowledged that excessive NETosis and NET generation contribute to further pathophysiological abnormalities following SARS-CoV-2 infection. This review provides an updated overview of the role of NETosis in autoimmune diseases, but also the relationship between COVID-19 and long COVID with autoimmunity (e.g., latent and overt autoimmunity, molecular mimicry, epitope spreading) and NETosis (e.g., immune responses, NET markers). Finally, we discuss potential therapeutic strategies targeting dysregulated NETosis to mitigate the severe complications of COVID-19 and long COVID.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are systemic autoimmune diseases featuring small blood vessel inflammation and organ damage, including necrotizing crescentic glomerulonephritis (NCGN). Persistent vascular inflammation leads to endothelial and kidney cell necrosis. Ferroptosis is a regulated cell death pathway executed by reactive oxygen species and iron-dependent lipid peroxidation culminating in cell membrane rupture. Here we show that ANCA-activated neutrophils induced endothelial cell (EC) death in vitro that was prevented by ferroptosis inhibition with Ferrostatin-1, Liproxstatin-1 and small inhibiting RNA against the enzyme AcylCoA Synthetase Long Chain Family Member 4 (ACSL4). In contrast, neither necroptosis nor apoptosis inhibition affected EC death. Moreover, both ferroptosis inhibitors alleviated lipid peroxide accumulation in EC. Increased lipid peroxidation was detected in kidney sections of AAV mice by immunohistochemistry. We generated MPO-/- ACSL4flox Tie2-Cre+ mice lacking ACSL4 specifically in EC (ACSL4ΔEC) to study the significance of endothelial ferroptosis in vivo. ACSL4ΔEC chimeric mice, but not control mice (ACSL4WT), were protected from NCGN in an MPO-AAV bone-marrow transplantation model. These data establish that EC ferroptosis contributes to ANCA-induced glomerulonephritis. However, systemic pharmacological ferroptosis inhibition with Ferrostatin-1 or Liproxstatin-1 did not protect from NCGN in a murine AAV model. Ferrostatin-1 treatment both directly activated T-cell proliferation and indirectly myeloid-mediated T-cell proliferation and polarization in vitro. Conceivably, both effects may cancel the beneficial effect of endothelial ferroptosis inhibition. Mechanistically, we describe the importance of EC ferroptosis for the development of AAV. However, the lack of protection with systemic pharmacological ferroptosis inhibition should discourage clinicians from evaluating this treatment strategy in clinical AAV studies.

To evaluate the efficacy and safety of avacopan in patients aged ≥65 years with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in the phase 3 ADVOCATE trial of avacopan vs a prednisone taper, plus either rituximab or cyclophosphamide.

In this descriptive, post hoc analysis, patients receiving avacopan or a prednisone taper were stratified by age. Key efficacy outcomes included the rate of remission at week 26 and sustained remission at week 52.

Of 160 patients aged ≥65, 109 were aged 65-74 and 51 were ≥75. Remission at week 26 was achieved in 71.7% vs 69.4% of patients aged 65-74 and 73.1% vs 72.0% aged ≥75 in the avacopan vs prednisone taper groups, respectively. Sustained remission at week 52 was observed in 65.0% vs 55.1% of patients aged 65-74 and 65.4% vs 56.0% aged ≥75. Relapse rates in the avacopan vs prednisone taper groups were 12.3% vs 18.8% and 3.8% vs 20.8% in the 65-74 and ≥75 subgroups, respectively. Improvements in estimated glomerular filtration rate and health-related quality of life were observed in both treatment groups. Use of avacopan compared with a prednisone taper was associated with a 61% and 49% reduction in mean glucocorticoid dose in the 65-74 and ≥75 subgroups, respectively, and lower glucocorticoid toxicity. The proportions of patients with adverse events were similar between treatment groups within each age subgroup.

These data support the efficacy and safety of an avacopan-based regimen to treat patients with GPA or MPA aged ≥65.

In anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and systemic lupus erythematosus (SLE), glomerulonephritis is a severe kidney complication driven by immune cells, including T cells. However, the mechanisms underlying T cell activation in these contexts remain elusive. Here we report that in patients with AAV and SLE, type I interferon (IFN-I) induces T cell differentiation into interferon-stimulated genes-expressing T (ISG-T) cells, which are characterized by an elevated IFN-I signature, an immature phenotype, and cytotoxicity in inflamed tissue. Mechanistically, IFN-I stimulates the expression of interferon regulatory factor 7 (IRF7) in T cells, which in turn induces granzyme B production. In mice, blocking IFN-I signaling reduces IRF7 and granzyme B expression in T cells, thus ameliorating glomerulonephritis. In parallel, spatial transcriptomic analyses of kidney biopsies from patients with AAV or SLE reveal an elevated ISG signature and the presence of ISG-T cells in close proximity to plasmacytoid dendritic cells, the primary producers of IFN-I. Our results from both patients and animal models thus suggest that IFN-I production in inflamed tissue may drive ISG-T cell differentiation to expand the pool of cytotoxic T cells in autoimmune diseases.

Background/Objectives: Granulomatosis with polyangiitis (GPA) is a necrotising vasculitis characterised by granulomatous inflammation involving small vessels. In addition to specific findings for the affected organ, constitutional symptoms and joint and muscle pain can be observed. The prodromal phase, where symptoms last for months before clinical diagnosis, may suggest infection or malignancy. This may cause a delay in GPA diagnosis. The period from the first symptoms to diagnosis may last from one month to three years. In this study, we aimed to demonstrate that, as the time between the onset of symptoms and diagnosis increases, the disease involvement may become more severe, and the possibility of recurrence may increase, indicating the importance of early diagnosis. Methods: For this cross-sectional retrospective study, data from 40 patients with GPA were evaluated. Demographic, clinical, treatment, and follow-up characteristics of the patients were obtained from their medical records. Results: The mean time between the presentation of the first complaints and GPA diagnosis was 7.40 ± 11.84 (0, 60, 3; mean ± standard deviation [minimum, maximum, and median]) months. The time between the first complaints and diagnosis was longer for patients with a history of recurrence (11.44 ± 16.73 [0, 60, 4.5] vs. 4.71 ± 6.04 [0, 24, 2.5], p value = 0.260). Conclusions: GPA is an inflammatory disease with various clinical presentations. In the management of patients with GPA, awareness of its presentation is important for rheumatologists as well as other clinicians during the initial evaluation, demonstrating the importance of interclinical collaboration.

Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) present heterogeneous neurological symptoms that are often misdiagnosed, contributing to delays in identification and prompt treatment. Few studies in Latin America have described the frequency of neurological involvement in AVV; none have explicitly described the characteristics of nervous system involvement.

This case-control study examined patient records for AVV treated at a university hospital in Colombia between 2005 and 2023. Patients with and without neurological manifestations were compared and a survival analysis was performed.

Forty-eight cases and seventy-nine controls were included. The median age was 58 years, 57.5 % were female. The diagnosis was made in 67.7 % of cases during the hospital stay, and in-hospital mortality was 14 %. Nervous system involvement was more frequent in undifferentiated AAV (100 %), followed by eosinophilic granulomatosis with polyangiitis (75 %), microscopic polyangiitis (33.3 %), and granulomatosis with polyangiitis (25.9 %). The most common neurological manifestations were peripheral neuropathy (50 %), patient-reported symptoms of sensory dysfunction (43.7 %), and cranial neuropathy (39.6 %); headache was frequent among patients with neurological involvement. Patients with neurological manifestations presented a lower median creatinine at admission and a lower proportion of patients with a five-factor score > 2. No differences in one-year all-cause mortality were observed.

This study presents an exhaustive clinical characterization of the neurological profile of patients with AAV from a single center in Latin America. Patients with nervous system involvement showed less severe renal involvement and a lower proportion of 5-year risk of mortality scores; one-year all-cause mortality was similar between groups.

Anti-neutrophil cytoplasmic antibodies directed to myeloperoxidase (MPO-ANCA) are key molecules in the pathogenesis of ANCA-associated vasculitis (AAV), however, the mechanisms of autoantibody production have not been elucidated. We hypothesized that an aberrant PTM occurs in the MPO of MPO-ANCA-positive AAV (MPO-AAV), which induces immune responses to self MPO. To test this, we purified MPO proteins from neutrophils of 8 patients with MPO-AAV and 8 healthy subjects, digested them with trypsin, and comprehensively quantified PTMs of the MPO peptides using the sequential window acquisition of all theoretical fragment ion spectra (SWATH) method of LC-MS. Among the 1034 detected MPO peptides, 38 peptides were increased in the patients with MPO-AAV relative to the healthy subjects, whereas 10 peptides were decreased in the patients (p < 0.05). Interestingly, oxidative modifications were found in 11 of the 38 increased peptides (1.14- to 3.29-fold), but not in the decreased peptides. These included oxidation of Met577, Phe686, Met688 and Met719, dioxidation of Met409, Phe605, Trp679 and Met719, and kynurenylation of Trp255. Conversely, glycosylation was detected in 4 of the 10 decreased peptides (-1.32- to -2.32-fold), but not in the increased peptides. They were O-type glycans at Ser357 and Ser731, and N-type glycans at Asn355 and Asn729. In animal experiments, immunization of mice with in vitro oxidized or unoxidized mouse MPO (mMPO) showed that not only anti-oxidized mMPO antibodies but also anti-unoxidized mMPO antibodies were preferentially produced in the oxidized mMPO-immunized mice relative to the unoxidized mMPO-immunized mice (anti-oxidized mMPO antibodies, 6/8 vs 1/9, p < 0.05; anti-unoxidized mMPO antibodies, 4/8 vs 0/9, p < 0.05). Our results suggest that the increased oxidative modifications of MPO in MPO-AAV may break immune tolerance and trigger the MPO-ANCA production. SIGNIFICANCE: AAV is a systemic and refractory disease that causes life-threatening multi-organ involvement such as necrotizing glomerulonephritis and lung hemorrhage. MPO-ANCA is an autoantibody that plays a key role in the pathogenesis of AAV. Therefore, elucidation of the mechanism of MPO-ANCA production is crucial to overcoming this disease. In this study, we applied a SWATH-MS analysis to the detection of aberrant PTMs, and found increased oxidative modifications of neutrophil MPO in patients with MPO-AAV for the first time. Immunization of in vitro oxidized MPO induced autoantibodies to the intact unoxidized MPO, suggesting that the increased oxidative modifications of MPO may break the immune tolerance in MPO-AAV. This study suggests a novel trigger mechanism for MPO-ANCA production.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (ANCA-vasculitis) is an autoimmune disease characterized by inflammation and necrosis of small or medium vessels. In the past, the role of the complement in the pathogenesis of ANCA-vasculitis has been underestimated, due to the paucity of the complement at sites of injured glomeruli. Following evidence from animal models of the major role of the complement in pathogenesis of ANCA-vasculitis, the complement has again attracted interest. Immunohistology analysis of pauci-immune glomerulonephritis-ANCA glomerulonephritis (ANCA-GN)-reveals the presence of complement products and membrane attack complex, suggesting their involvement in the disease process. Researchers emphasize the complement classical or lectin pathway as a contributor to the development of ANCA-vasculitis. The era of targeted therapies to suspend the complement activation as a therapy for ANCA-vasculitis has arrived, and thus, the comprehension of its role is very important. This review summarizes recent insights on the important role of complement activation in the development of ANCA-vasculitis as well as the emerging therapeutic possibilities that target complement components for the treatment of this condition.

Systemic vasculitis, common forms of which include anti-neutrophil cytoplasmic antibody-associated small-vessel vasculitis, large-vessel vasculitis and Behçet syndrome, are frequently complicated by arterial or venous thrombotic events (AVTEs). Newly identified entities such as DADA2 (deficiency of adenosine deaminase 2) and VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, which are driven by genetic mutations, also exhibit vasculitic features and are associated with a high risk of AVTEs. AVTEs in systemic vasculitis, including monogenic forms of vasculitis, are due to the complex interaction of inflammation and coagulation. New insights into the pathogenetic mechanisms implicate endothelial dysfunction, immune complex deposition and the interplay of pro-inflammatory cytokines with prothrombotic factors, which collectively promote thrombus formation. AVTEs impose a substantial disease burden, complicate diagnosis and negatively affect prognosis by increasing the risk of morbidity and mortality. Early diagnosis and treatment are crucial to prevent lasting damage. Management strategies should target both thrombosis and underlying inflammation. Antithrombotic therapies, including low-dose aspirin, or oral anticoagulants should be used on the basis of individual thrombotic risk assessment. Immunosuppressive therapy is the cornerstone of treatment for arterial and venous thrombosis, particularly in Behçet syndrome, in which vascular inflammation has a crucial role in thrombotic complications.

The relationship between anti-neutrophil cytoplasmic antibodies (ANCA) and inflammatory bowel disease has attracted significant attention due to shared immunopathological mechanisms and clinical associations.

This case report describes a 20-year-old African woman with a history of ulcerative colitis who developed diffuse alveolar haemorrhage in the setting of elevated proteinase 3 (PR3)-ANCA. She was treated for ANCA-associated vasculitis with corticosteroids, plasma exchange, and rituximab, leading to a complete resolution.

The case highlights the association between ulcerative colitis and ANCA-associated vasculitis, particularly with PR3-ANCA, and the importance of recognizing this overlap. Although ANCA are frequently present in inflammatory bowel disease, especially ulcerative colitis, their pathogenic role remains unclear. The incidence of ANCA-associated vasculitis is higher in inflammatory bowel disease patients, with ulcerative colitis often preceding ANCA-associated vasculitis. Despite the common presence of ANCA in inflammatory bowel disease, not all patients progress to ANCA-associated vasculitis. This case underscores the need for careful monitoring in ulcerative colitis patients with elevated PR3-ANCA and the role of ANCA in guiding diagnosis and treatment.

High proteinase 3 (PR3)-anti-neutrophil cytoplasmic antibodies (ANCA) titre impacts the severity and management of ulcerative colitis patients.ANCA-associated vasculitis is more frequent in ulcerative colitis patients and occurs several years after ANCA positivity.Close monitoring of ulcerative colitis patients with PR3-ANCA is essential for early detection of progression to ANCA-associated vasculitis.

We aimed to study the disease course, outcomes, and predictors of outcome in pediatric-onset antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) affecting the kidneys.

Patients eligible for this study had a diagnosis of granulomatosis with polyangiitis (GPA), microscopic polyangiitis, or ANCA-positive pauci-immune glomerulonephritis, were 18 years or younger at diagnosis, had renal disease defined by biopsy or dialysis dependence, and had clinical data at diagnosis and at either 12 or 24 months. Ambispective data from A Registry for Children with Vasculitis/Pediatric Vasculitis Initiative Registry was used. The primary outcome was inactive renal disease (pediatric vasculitis activity score = 0 or 1) at 12 months. Secondary outcomes included rates of improved renal function and damage within 24 months. Renal function, defined by estimated glomerular filtration rate, was categorized into Kidney Disease Improving Global Outcomes (KDIGO) stages at diagnosis and tested as a predictor of outcome using a proportional-odds logistic regression model.

A total of 145 patients were included: 68% were female, and 78% had GPA. At 12 months, 83% of patients achieved inactive renal disease; however, 42% had evidence of permanent renal damage. Compared with patients with normal renal function at diagnosis, patients with moderate to severely reduced renal function, or kidney failure at diagnosis, had an odds ratio of 8.62 (P = 0.002; 95% confidence interval [CI] 2.31-32.1) and 26.3 (P < 0.001; 95% CI 6.32-109), respectively, for being in a non-normal KDIGO category at 12 months.

The majority of patients with pediatric AAV achieve inactive renal disease by 12 months; however, almost half have evidence of damage. Renal function at diagnosis is a strong predictor of renal function at 12 months.

This study evaluated the clinical utility of serum periostin measured at diagnosis in reflecting activity at diagnosis and predicting all-cause mortality during follow-up in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV).

This study included 76 patients with AAV whose serum periostin was measured from sera collected and stored at diagnosis. The correlation of either serum periostin or the Birmingham Vasculitis Activity Score (BVAS) with other variables was evaluated. Cumulative survival rates were compared using Kaplan-Meier survival analysis. The variables at diagnosis were compared between deceased and surviving patients. Hazard ratios were obtained by Cox proportional hazard analysis.

The median age of the 76 patients was 64.0 years and 60.5% were female. The median BVAS and serum periostin were 5.0 and 10.9 ng/mL, respectively. Five of the 76 patients (6.6%) died. Serum periostin was independently correlated with cross-sectional BVAS, the Vasculitis Damage Index (VDI), white blood cell count, and serum albumin. Patients with serum periostin ≥ 15.9 ng/mL at diagnosis had a significantly lower cumulative survival rate than those without. In addition to high VDI, dyslipidaemia frequency, and C-reactive protein, deceased patients showed higher serum periostin than surviving patients. In multivariable Cox analysis, however, only dyslipidaemia rather than serum periostin was identified as an independent predictor of all-cause mortality.

This study is the first to demonstrate that serum periostin at diagnosis could independently reflect cross-sectional BVAS and further partially contribute to all-cause mortality prediction in patients with AAV.

CAR-T cell therapy, a pioneering immune-modulating treatment that was initially designed for hematologic malignancies, is now being considered a potential treatment for autoimmune and rheumatic diseases. This method involves genetically engineering T cells to express chimeric antigen receptors (CARs), allowing them to target specific antigens associated with pathogenic immune cells. The review covers the possibility of CAR-T therapy in the treatment of autoimmune diseases like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc). The therapy's ability to maintain remission by targeting autoreactive B cells in the course of disease has been an important aspect of studies involving SLE. In refractory RA, CAR-T cells also demonstrate a potential therapeutic modality in selectively killing immune cells driving the disease process. For SSc, CAR-T therapy may represent a novel therapeutic approach because it targets the dysregulated activity of B cells as well as the fibrotic processes that drive the disease pathology. Emerging evidence suggests potential applications in conditions such as Sjögren's syndrome and dermatomyositis. While CAR-T therapy promises accuracy, persistence, and the potential for long-term remission, many problems remain, including the risk of cytokine release syndrome, immune toxicity, and treatment affordability. The development of CAR-Tregs and advanced gene-editing techniques may increase the specificity and safety of therapy. In addition, clinical trials and long-term studies should be conducted to establish the efficacy, safety, and economic feasibility of this innovative approach. This review underscores the transformative potential of CAR-T therapy in the management of rheumatic diseases, particularly in refractory cases. Offering targeted immunomodulation with a minimum of systemic immune suppression, CAR-T therapy could redefine therapeutic paradigms and offer hope for improved outcomes in autoimmune diseases.

ANCA-associated vasculitis (AAV) is a group of rare small vessels vasculitis that preferentially affect the kidneys, lungs and upper airways. Although the detailed pathophysiology remains unclear, genetic background has been shown to play a role in sporadic forms of AAV. The discovery of these susceptibility genes (and associated biological pathways) involved in AAV have shaped the current understanding of AAV pathophysiology. In addition to common genetic polymorphisms, specific rare inborn errors of immunity (IEI) have been described with a high frequency of ANCA (antineutrophil cytoplasmic antibodies) positivity and vasculitis features in young individuals (in addition to other manifestations). A systematic literature search revealed that patients with pathogenic variants in COPA, STING1, DNASE1L3, and PIK3CD are at increased risk of developing ANCA and AAV features, including alveolar hemorrhage, interstitial lung disease, pauciimmune glomerulonephritis, and upper airways involvement (septum perforation, saddle-nose deformity, chronic nasal/sinuses ulceration). Some of these IEI may also present with a mixed phenotype and/or auto-antibodies profile associating features of AAV and other autoimmune diseases (in particular systemic lupus erythematosus). Notably, a proportion of reports and series lack serological (ANCA specificity and titers) and/or histopathological data, making challenging to assess the likelihood for ANCA pathogenicity in some patients with IEI (as opposed to unspecific signs of biologic autoimmunity). This point is nonetheless essential to make appropriate therapeutic decisions. In addition, since most of the genes mentioned above are involved in the type 1 interferon signaling, the role of this pathway in AAV etiopathogenesis deserves further investigation. In this review, we will describe these IEI, their overlap with sporadic AAV, and their evocative features. Next, we will discuss how these monogenic conditions might inform our general understanding of AAV pathophysiology. We also propose some directions for future research in order to better define the link between ANCA and IEI. Finally, we will consider how making the diagnosis of an IEI in a patient with AAV features might impact individual management.

Chronic kidney disease (CKD) has become highly prevalent worldwide, with major implications for public health, including increased risk of progression to kidney failure, cardiovascular events, and mortality. Up to a decade ago, renin-angiotensin system inhibitors, that is angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, were the only available pharmacological interventions to slow kidney function loss and limit the associated cardiovascular morbidity and mortality in this context. More recently, landmark trials have demonstrated the ability of novel therapeutics to significantly ameliorate kidney and cardiovascular outcomes in patients with CKD, when added on top of optimized renin-angiotensin system blockade. These include sodium-glucose cotransporter-2 inhibitors in patients with diabetic and nondiabetic kidney disease, as well as the nonsteroidal mineralcorticoid receptor antagonist finerenone and the glucagon-like peptide-1 receptor agonist semaglutide in patients with diabetic kidney disease. We herein review the evolving scenario and the latest evidence for the treatment of CKD, mainly focusing on proteinuric CKD. We started with a presentation of established and more recently approved classes of kidney protective drugs, followed by a discussion of therapeutic interventions under clinical investigation to slow CKD progression. Finally, we underscore the added value of personalized and multidrug interventions, which are becoming increasingly more feasible with the availability of a growing number of kidney protective agents, and are likely to stand as the most powerful tools to safely slow, or even prevent, the progression of proteinuric CKD. SIGNIFICANCE STATEMENT: Chronic kidney disease (CKD) is highly prevalent globally, and is associated with substantial morbidity and mortality. This review provides a comprehensive overview of the currently approved and emerging therapeutic options for the treatment of proteinuric CKD. As novel kidney protective agents have recently become available, the outcomes of patients with CKD could hopefully improve over the few decades ahead.

Spinal hypertrophic pachymeningitis (HP) is an extremely rare disorder characterized by the thickening of the spinal dura mater, which harbors distinct repertoires of immune cells due to the unique partitioning of the arachnoid blood-CSF barrier. The objectives were to identify the pathogenesis and therapeutic strategies for spinal HP.

This retrospective cohort study analyzed the clinical and pathologic profiles of patients with idiopathic/immune-mediated HP including spinal HP.

Among 61 patients with idiopathic/immune-mediated HP, all 6 Japanese patients with spinal HP, with a median observation period of 88.8 months, were myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA)-seropositive. The MPO-ANCA+ spinal HP cohort had the following characteristics: (1) a predominance of older women; (2) all patients were classified as having microscopic polyangiitis based on the 2022 American College of Rheumatology/European League Against Rheumatism criteria; (3) 83% of patients developed subacute/chronic myelopathy due to extramedullary spinal cord compression; (4) 50% of patients had lesion extension to the epidural compartment and vertebral column; (5) 50% of patients presented with chronic sinusitis, otitis media, or mastoiditis; (6) 33% of patients had involvement of the lower airways or kidneys; (7) a higher disease activity of the nervous system was noted based on the Birmingham Vasculitis Activity Score (BVAS), in contrast to MPO-ANCA+ cranial HP; (8) granulomatous inflammation with myofibroblasts, immune cells including granulocytes, and B-cell follicle-like structures were observed in the thickened dura mater; (9) immunotherapies (with or without surgical decompression) were effective in reducing the modified Rankin Scale score and reduced BVAS during the first active insults; (10) combined immunotherapies with glucocorticoids and cyclophosphamide/rituximab helped in reducing relapses in the long term; and (11) surgical decompression, including laminectomy and duraplasty, was necessary for compressive myelopathy. These data suggest that MPO-ANCA+ spinal HP shares common features with MPO-ANCA+ cranial HP (1, 2, 6, 8, 9, and 10), but also has unique clinical features (3, 4, 5, 7, and 11).

Our findings highlight the significant pathogenic role of ANCA in spinal HP. MPO-ANCA+ spinal HP, as an organ-threatening disease, should be positioned as having unique characteristics, whether limited to the CNS or as part of a generalized form in ANCA-associated vasculitis.

Interstitial lung disease (ILD) is common in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with usual interstitial pneumonia (UIP) being the most frequent pattern. The impact of different ILD patterns on clinical outcomes remains unclear.

Retrospective cohort study included patients with AAV (MPA and GPA) and ILD confirmed by chest CT scans between 1997 and 2021. ILD patterns were classified according to 2018 Fleischner Society criteria.

Of 1862 patients in the Mayo AAV Cohort, 143 (7.7 %) had ILD on chest CT. The median age at the time of ILD diagnosis (occurring before AAV diagnosis in 26.6 %) was 69 years (IQR 61-75); 60 % were male, and 75 % were MPO-positive. On chest CT, "typical UIP" pattern was identified in 44 patients (30.8 %), whereas 13 (9.1 %) manifested "probable UIP" pattern, 37 (25.9 %) "indeterminate for UIP" pattern, and 49 (34.3 %) "non-UIP" pattern. Among MPO-ANCA patients, typical UIP pattern was most common (37.4 %), while non-UIP pattern was most common (58.3 %) among PR3-ANCA patients. Patients with typical UIP pattern, when compared to those with non-UIP pattern, were more commonly male (70.5 %), MPO-ANCA (90.0 %), diagnosed before the onset of AAV (40.9 %), and had reduced diffusion capacity on pulmonary function tests. The presence of typical UIP was related with higher survival at 12 months and 10 years in MPO-ANCA patients when compared to other ILD patterns (IRR 8.201 and IRR 2.179).

The typical UIP pattern in AAV-ILD is associated with better survival, particularly in MPO-ANCA patients, suggesting distinct mechanisms for ILD development in MPO vs. PR3-AAV.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases characterized by inflammation and destruction of small blood vessels. AAV could be fatal if left untreated. Prompt diagnosis and treatment are crucial to protect AAV-related organs and tissue. Plasmapheresis, a therapeutic intervention aimed at removing harmful substances from the blood, devotes benefits to AAV treatment. However, the specific immune mechanism underlying its effectiveness remains unclear. In our research, we used single-cell RNA sequencing (scRNA-seq) to study the variation of peripheral blood mononuclear cells (PBMCs) before and after plasmapheresis in AAV patients. From this work, we explored a novel method for monocyte classification. In addition, flow cytometry was used to detect the relationship between the monocyte clusters and AAV activity under the new monocyte clustering method. Our scRNA-seq results revealed significant changes in monocyte clusters following treatment, which could be classified into three clusters (CD14+ monocytes, FCGR1A+ monocytes, and FCGR3A+ monocytes). In addition, our flow cytometry results showed that FCGR3A+ (CD16+) monocytes were positively correlated with AAV activity, whereas FCGR1A+ (CD16-CD64+) monocytes were negatively correlated with AAV activity. This may be related to the different biological effects of CD16 and CD64 on monocytes after interacting with the Fc region of ANCAs. In conclusion, our research sheds light on the immune landscape of AAV before and after plasmapheresis, identifying specific monocyte clusters linked to disease activity. These findings offer insights for novel monitoring methods and therapeutic targets in AAV.

To assess the prevalence and outcomes among regimens of glucocorticoid tapering for microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) in real-world practice.

We retrospectively examined the Japan Collaborative Registry of Antineutrophil Cytoplasmic Antibodies-associated Vasculitis (J-CANVAS) registry, and evaluated the prevalence of glucocorticoid tapering regimens in the PEXIVAS trial. In patients with newly diagnosed MPA and GPA, we compared outcomes among standard and reduced pace regimens. Relapse-free survival rates were compared after propensity score matching.

Of 364 eligible patients, 113 (31.0%) received standard tapering and 251 slower tapering. After matching, 87 pairs no significant difference was observed in relapse-free survival (P = .506). Regarding the reduced regimen, there were so few patients (14/364, 3.8%) that statistical analysis was not performed.

The glucocorticoid tapering for MPA and GPA in Japanese real-world practice was found to be generally slower than the standard regimen revealing a huge evidence-practice gap. Additionally, slower tapering did not improve relapse-free survival and might cause unnecessary glucocorticoid exposure.

Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis primarily affecting the respiratory tract and kidneys, with external genital and urethral lesions (EGUL) being exceedingly rare. We present a case of a middle-aged man with relapsing proteinase 3-antineutrophil antibody-positive GPA who developed isolated granulomatous, ulcerative balanitis, and urethritis. His condition abruptly worsened after a prolonged indolent course, requiring treatment with glucocorticoids and rituximab, leading to successful remission. To better characterize EGUL in GPA, a systematic literature search was performed in PubMed, Scopus, and the NPO Japanese Society of Medical Abstracts databases using keywords related to GPA and EGUL. Cases meeting the American College of Rheumatology or Japanese Ministry of Health, Labor, and Welfare criteria for GPA and the 2012 Chapel Hill Consensus Conference definitions were included for analysis. Our review identified that EGUL often presents as an initial symptom and can be classified by the presence or absence of preceding urethritis. Cases with preceding urethritis had a higher risk of severe complications with extensive penile or urethral involvement. In contrast, penile lesions without preceding urethritis typically presented as characteristic mucosal lesions localized around the glans. In females, GPA-associated urethritis frequently led to periurethral mass formation, vaginal involvement, and significant sequelae. Given the potential for delayed diagnosis and serious complications, clinicians should be vigilant for EGUL in patients with suspected or diagnosed GPA. Future prospective studies with larger cohorts are needed to elucidate the prevalence, clinical spectrum, and optimal management of these rare but significant manifestations of GPA.

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a rare disease that manifests as necrotizing vasculitis involving small vessels without immune complex deposition. Granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA) are included in this disease entity. Diagnosis and differentiation of AAV is challenging because of the diverse and overlapping clinical manifestations and lack of pathognomonic findings. Therefore, AAV classification criteria have been developed to increase the likelihood of diagnosis using multidisciplinary approaches, including clinical, radiologic, laboratory, and pathologic findings. The new American College of Rheumatology and European Alliance of Associations for Rheumatology classification criteria were released in 2022 to classify AAVs using weighted criteria and threshold scores. They are expected to make the classification of GPA, EGPA, and MPA more accurate in the setting of suspected small-vessel vasculitis. The criteria present key thoracic imaging discriminators of GPA as "pulmonary nodules, masses, or cavitation" and MPA as "interstitial fibrosis," whereas, radiologic criteria of EGPA are not present. ANCA positivity and eosinophil count are included as key laboratory discriminators. It is essential for radiologists to familiarize themselves with imaging findings of each AAV and know the key imaging discriminators to aid in the differential diagnosis of AAVs. By reviewing the radiologic findings of thoracic manifestations of each AAV and applying the new criteria in a series of cases, the authors aim to provide a practical and stepwise approach to AAV for radiologists. ©RSNA, 2025 Supplemental material is available for this article.

ANCA-associated vasculitis (AAV) is a rare but serious disease. Traditional case-identification methods using claims data can be time-intensive and may miss important subgroups. We hypothesized that a deep learning model analyzing electronic health records (EHR) can more accurately identify AAV cases.

We examined the Mass General Brigham (MGB) repository of clinical documentation from 12/1/1979 to 5/11/2021, using expert-curated keywords and ICD codes to identify a large cohort of potential AAV cases. Three labeled datasets (I, II, III) were created, each containing note sections. We trained and evaluated a range of machine learning and deep learning algorithms for note-level classification, using metrics like positive predictive value (PPV), sensitivity, F-score, area under the receiver operating characteristic curve (AUROC), and area under the precision and recall curve (AUPRC). The hierarchical attention network (HAN) was further evaluated for its ability to classify AAV cases at the patient-level, compared with rule-based algorithms in 2000 randomly chosen samples.

Datasets I, II, and III comprised 6000, 3008, and 7500 note sections, respectively. HAN achieved the highest AUROC in all three datasets, with scores of 0.983, 0.991, and 0.991. The deep learning approach also had among the highest PPVs across the three datasets (0.941, 0.954, and 0.800, respectively). In a test cohort of 2000 cases, the HAN model achieved a PPV of 0.262 and an estimated sensitivity of 0.975. Compared to the best rule-based algorithm, HAN identified six additional AAV cases, representing 13% of the total.

The deep learning model effectively classifies clinical note sections for AAV diagnosis. Its application to EHR notes can potentially uncover additional cases missed by traditional rule-based methods.

Microscopic polyangiitis (MPA) is a type of necrotizing vasculitis that primarily affects small vessels and belongs to the spectrum of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs). While previous studies have identified potential prognostic biomarkers, further research is needed to validate a reliable marker for risk stratification in clinical practice. Kidney injury molecule-1 (Kim-1), a transmembrane protein expressed on proximal tubular epithelial cells, has been implicated in tubular damage. This study investigated the potential of Kim-1 as a biomarker in MPA.

Kidney biopsy tissues, along with urine and blood samples, were retrospectively analyzed from 52 MPA patients and compared to urine samples from 7 healthy controls. Global disease activity was assessed using the Birmingham vasculitis activity score (BVAS) and vasculitis damage index, while renal disease activity was evaluated using renal BVAS (BVAS-R).

Urinary Kim-1 levels were significantly elevated in MPA patients compared to healthy controls. Urinary Kim-1 was positively correlated with the Mayo Clinic Chronicity Score (MCCS) but not with the ANCA Kidney Risk Score (AKRiS), whereas tubular Kim-1 was associated with AKRiS but not with MCCS, indicating their distinct pathological significance. Higher tubular Kim-1 expression was observed in patients with elevated BVAS-R. Urinary Kim-1 levels correlated with proteinuria and were associated with the Mayo Clinic Chronicity Score (MCCS) and ANCA Kidney Risk Score (AKRiS) but not with glomerular lesion severity. Unlike C-reactive protein (CRP), neither urinary nor tubular Kim-1 predicted MPA recurrence.

Urinary Kim-1 reflects histopathologic findings and renal impairment but does not predict systemic disease activity or recurrence in MPA, demonstrating its potential clinical utility as a biomarker for assessing chronic renal damage.

We aimed to investigate the involvement of the classical/lectin complement pathway in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) by exploring the complement activation fragment C4d in association to AAV activity.

Forty patients with active AAV and twenty population-based controls were included. The study included 27 (67.5%) patients with a diagnosis of GPA and 13 (32.5%) with MPA. Twenty-four patients (60%) were anti-proteinase 3 (PR3)-ANCA positive and 16 (40%) anti-myeloperoxidase (MPO)-ANCA positive. Thirty-three (82.5%) patients had kidney involvement. A follow-up sample obtained after induction therapy (median 6 months) was available for 24 of the patients, of whom 20 were in remission. Plasma C4d was analysed by ELISA detecting an epitope that arises upon complement-mediated cleavage. Plasma complement factor 4 (C4) and the soluble terminal complement complex (sTCC) were analysed by ELISA. The C4d/C4 ratio was calculated. HLA-DRB1-typing and immunohistochemistry for C4d in kidney biopsies were performed.

Patients with active AAV had higher C4d, sTCC levels and C4d/C4 ratio than controls (p < 0.001, p = 0.004, p < 0.001). C4d, sTCC levels and C4d/C4 ratio all decreased from active disease to remission (p = 0.010, p = 0.009, p = 0.011). C4d levels in AAV patients in remission remained higher than population-based controls (p = 0.026). Active anti-PR3-ANCA patients had higher C4d levels and C4d/C4 ratio than anti-MPO-ANCA patients (p = 0.001, p = 0.007). Patients with active AAV and kidney involvement had lower C4d levels than patients without (p = 0.04). C4d levels and C4d/C4 ratio correlated positively with the percentage of normal glomeruli in kidney biopsies. The immunohistochemistry was negative for C4d in kidney biopsies.

The specific C4d assay revealed activity in the classical/lectin complement pathway in AAV, which reflected general disease activity, but was not associated specifically with kidney involvement. C4d levels differed depending on anti-PR3/MPO-ANCA subtypes suggesting differences in complement activation and underlying pathogenetic mechanisms. The findings imply that the classical/lectin complement pathway may play a more significant role in AAV pathogenesis than previously reported and that plasma C4d levels and C4d/C4 ratio may be biomarker candidates for disease activity and treatment outcome monitoring.

Rheumatic diseases encompass a wide range of autoimmune and inflammatory disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriatic arthritis (PsA), and systemic sclerosis (SSc). These conditions often result in chronic pain, disability, and reduced quality of life, with unpredictable disease courses that may lead to joint destruction, organ damage, or systemic complications. Biomarkers, defined as measurable indicators of biological processes or conditions, have the potential to transform clinical practice by improving disease diagnosis, monitoring, prognosis, and treatment decisions. While significant strides have been made in identifying and validating biomarkers in rheumatic diseases, challenges remain in their standardization, clinical utility, and integration into routine practice. This review provides an overview of the current state of biomarkers in rheumatic diseases, their roles in clinical settings, and the emerging advancements in the field.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a multifaceted diseased vasculitis typically associated with myeloperoxidase-perinuclear-anti-neutrophil cytoplasmic antibody (+MPO-P-ANCA). Although rare, the diagnosis should be considered in patients with difficult-to-control or late-onset asthma and extrathoracic disease. We present the case of a 37-year-old male with adult-onset asthma and chronic rhinitis hospitalized with pancreatitis and hypoxemia. Blood investigations demonstrated eosinophilia with elevated lipase, and bronchoscopy demonstrated multiple endobronchial lesions with elevated eosinophils on bronchoalveolar lavage. In addition, labs showed proteinase 3-specific antineutrophil cytoplasmic antibody (PR3-C-ANCA) autoantibodies, and the patient was diagnosed with EGPA. Additional differential diagnoses of parasitic infection, sarcoidosis, chronic eosinophilic pneumonia, and granulomatosis with polyangiitis (GPA) were entertained, but ultimately, the multisystemic involvement, anti-neutrophil cytoplasmic autoantibody (ANCA) positivity, bronchoscopy, and imaging findings clinched the diagnosis. This case highlights the spectrum of possible EGPA presentations and a rare case of PR3-C-ANCA with gastrointestinal manifestations.

The anaphylatoxin C5a and its receptor C5aR (CD88) are complement pathway effectors implicated in renal diseases, including ANCA-associated vasculitis. We investigated the kidney expression of C5aR and a second C5a receptor C5L2 by using immunohistochemistry, in situ hybridization, and spatial gene expression on formalin-fixed, paraffin-embedded human and mouse kidney. C5aR was detected on interstitial macrophages and in multiple tubular regions, including distal and proximal; C5L2 had a similar expression pattern. The 5/6 nephrectomy model of chronic kidney injury exhibited increased C5aR expression by infiltrating cells within the fibrotic regions. C5aR expression was confirmed on human leukocytes and in vitro differentiated macrophages by flow cytometry, and treatment with C5a induced the expression of chemokines and remodeling factors by macrophages, including CCL-3/-4/-7, -20, MMP-1/-3/-8/-12, and F3, and promoted leukocyte survival. C5a activity was C5aR dependent, as demonstrated by reversal with the C5aR inhibitor avacopan. Collectively, these results suggest that myeloid C5aR may induce excessive inflammation in the kidney via immune cell recruitment, extracellular matrix destruction, and remodeling, resulting in fibrotic tissue deposition.

ANCA-associated vasculitis is a rare autoimmune disorder affecting small to medium-sized vessels, often targeting the respiratory tract and kidneys. Testicular involvement is rare and can resemble malignancy, leading to unnecessary surgery. A 36-year-old male presented with painful fingers, oral and nasal ulcers, and knee arthritis. Elevated proteinase 3 (PR3) antibodies confirmed PR3 ANCA-associated vasculitis. During hospitalization, patient developed testicular pain, and an ultrasound raised suspicion of malignancy. An inguinal orchidectomy was performed, revealing inflammation consistent with vasculitis, but no malignancy. Testicular involvement in ANCA vasculitis can mimic cancer, and increased awareness may help prevent unnecessary surgical procedures.

Therapeutic plasma exchange (PLEX) is an adjunctive treatment for patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and kidney involvement. Little is known about the effect of PLEX on early changes in kidney function. This post-hoc analysis of the PEXIVAS trial investigated the effects of PLEX on changes in kidney function within 12 months. PEXIVAS was a randomized controlled trial recruiting 691 patients with ANCA-associated glomerulonephritis, of whom 349 underwent PLEX and 342 received no-PLEX. The primary outcomes of this post hoc study of PEXIVAS were change in estimated glomerular filtration rate (eGFR) from baseline and recovery of kidney function (defined as eGFR increase of 15ml/min/1.73m2 or more). Baseline eGFR was 21.7 ± 20.3 and 20.6 ± 18.7 ml/min/1.73m2 in the PLEX and no-PLEX groups, respectively. Mean improvements in eGFR at weeks two, four, and eight after initiation of therapy were greater for the PLEX vs. the no-PLEX groups. The greatest significant difference in recovery of kidney function in the PLEX compared to the no-PLEX groups was at week four (relative risk (RR): 1.41; 95% confidence interval:1.09-1.82). Increased eGFR or recovery of kidney function at week four were significantly associated with lower risk for end-stage kidney disease at week 52 (RR: 0.96: 0.95-0.97, and RR: 0.29: 0.16-0.52; respectively). Neither changes in eGFR nor recovery of kidney function differed by reduced- compared to standard-dose glucocorticoid group. Overall, our study indicates that PLEX improves early kidney function in patients with ANCA-associated glomerulonephritis.

The complex pathophysiology of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) is reflected in the heterogeneity of the presenting clinical syndromes caused by these diseases but also provides a variety of conceivable molecular and cellular targets that can be therapeutically manipulated. The last decade has seen an expansion of established and potential therapies for treating AAV, some of which target the dysfunctional autoreactive immune response and others aim to ameliorate the downstream consequences of local vascular inflammation and necrosis. The success and widespread adoption of the anti-CD20 monoclonal antibody, rituximab, as an agent to both induce and maintain remission, has heralded a change in the standard-of-care management of AAV, replacing the "old guard" combination of cyclophosphamide and high-dose corticosteroids established in the 1970s. The development and approval of avacopan, a first-in-class small-molecule antagonist to the main receptor for the complement anaphylatoxin C5a, has the potential to reduce the corticosteroid burden experienced by patients with AAV and may also improve outcomes for those with AAV kidney disease. It marks the culmination of almost 20 years of international collaboration, from understanding the pathological role of complement in basic murine models of AAV through to a phase III clinical trial, and emphasises the importance of following promising translational discoveries through to drug development and clinical deployment. This article summarises how recent progress in our understanding of the basic pathophysiology of AAV has resulted in the development of new and effective treatments and, reciprocally, how studying the impact of these treatments in patients has advanced our understanding of dysfunctional immunobiology in disease.