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.

Although previous studies have reported poor outcomes in older-onset (≥ 75 years old) antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) compared with younger-onset AAV, the distinct cause of poor prognosis remains unclear. This study aimed to investigate the clinical features, therapies, and outcomes of older patients with granulomatosis with polyangiitis (GPA) and patients with microscopic polyangiitis (MPA) compared to younger-onset patients.

This two-center retrospective cohort study enrolled 70 newly-onset Japanese patients with AAV (GPA and MPA) from the Fukushima Medical University Hospital and Ohta-Nishinouchi Hospital in Fukushima, Japan, between 2004 and 2019. Clinical records were retrospectively reviewed, and clinical features and outcomes (1-year and 3-year survival by the Kaplan-Meier method) were compared between older and younger GPA/MPA groups, respectively.

Clinical features of the older GPA/MPA group were similar to those of the younger GPA/MPA group; however, the older GPA group showed severe inflammation and the older MPA group had an increased frequency of renal involvement and fever. The 1-year survival in the older MPA group was significantly lower than that in the younger MPA group. Immunosuppressive therapy including cyclophosphamide, rituximab, and other immunosuppressive agents was important to sustain the survival of patients with GPA/MPA.

Older patients with GPA/MPA may have specific clinical features; careful observation is needed during the treatment of older patients with MPA. Immunosuppressive therapy may improve the prognosis of patients with AAV.

Drug-induced autoimmune diseases are increasingly recognized, although mechanistic insight into disease causation is lacking. Hydralazine exposure has been linked to autoimmune diseases, including antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. Our hypothesis posits that hydralazine covalently binds to myeloperoxidase (MPO), triggering the autoimmune response in ANCA vasculitis. In vitro, we observed formation of carbonyl derivatives on amine groups in the presence of acrolein. This facilitated the subsequent binding of hydralazine to heme-containing proteins, including MPO, via a Michael addition. Our studies demonstrated that carbonyl derivatives and hydrazone adducts induced conformational changes in the MPO heavy chain, potentially changing its immunogenicity. We identified hydrazone adducts on circulating MPO in patients with hydralazine-associated ANCA vasculitis. These patients exhibited elevated anti-MPO IgM levels, while anti-MPO IgG levels were comparable between hydralazine-associated and nonhydralazine-associated vasculitis patients. IgM isolated from patients with hydralazine-associated MPO ANCA demonstrated a heightened affinity to hydralazine-modified MPO and activated neutrophil-like HL-60 cells. Hydralazine-modified MPO was pathogenic, as demonstrated by splenocyte transfer in a mouse model of ANCA vasculitis. Our findings unveil a mechanism of drug-induced autoimmunity wherein stepwise chemical modifications of MPO lead to conformational changes and hydrazone adduct formation, producing a neoantigen that generates pathogenic autoantibodies.

Autoinflammation and autoimmunity are almost "opposite" phenomena characterized by chronic activation of the immune system, 'innate' in the first and 'adaptive' in the second, leading to inflammation of several tissues with specific protean effectors of tissue damage. The mechanism of involvement of multiprotein complexes called 'inflammasomes' within autoimmune pictures, differently from autoinflammatory conditions, is yet undeciphered. In this review we provide a comprehensive overview on NLRP3 inflammasome contribution into the pathogenesis of some autoimmune diseases. In response to autoantibodies against nucleic acids or tissue-specific antigens the NLRP3 inflammasome is activated within dendritic cells and macrophages of patients with systemic lupus erythematosus. Crucial is NLRP3 inflammasome to amplify tissue inflammation with interleukin-1 overexpression and matrix metalloproteinase production at the joint level in rheumatoid arthritis. A deregulated NLRP3 inflammasome activation occurs in the serous acini of salivary and lacrimal glands prone to Sjogren's syndrome, but also in the inflammatory process involving endothelial cells, leucocyte recruitment, and platelet plugging of vasculitides. Furthermore, organ-specific autoimmune diseases such as thyroiditis and hepatitis may display hyperactive NLRP3 inflammasomes at the level of resident immune cells within thyroid or liver, respectively. Therefore, it is not unexpected that preclinical studies have shown how specific inflammasome inhibitors may significantly overthrow the severity of different autoimmune diseases and slow down their trend towards an ominous progression. Specific markers of inflammasome activation could also reveal subclinical inflammatory components escaping conventional diagnostic approaches or improve monitoring of autoimmune diseases and personalizing their treatment.

Wunderlich syndrome (WS) is a rare condition characterized by spontaneous renal hemorrhage in the absence of obvious trauma or iatrogenic injury. Given that most WS cases are life-threatening and require prompt intervention, timely identification and resolution are essential. Patients with connective tissue diseases (CTDs) account for a small proportion of reported WS cases; however, owing to the specific pathogenic mechanisms and treatments associated with CTDs, these patients exhibit distinctive pathological traits and clinical features in WS.

We present the identification and treatment process of WS in a patient with systemic lupus erythematosus. This patient suffered from sudden abdominal pain and a drastic decline in hemoglobin level accompanied by confusion of consciousness. After the abdominal computerized tomography scan revealed the presence of a renal hematoma, transcatheter arterial embolization was performed on her. Unexpectedly, three days later, the patient had severe anemia and consciousness disorders again. Highly suspecting renal rebleeding, we performed a repeated angiography for the patient. After confirming the bleeding, embolization was carried out again. The renal bleeding stopped, and the patient's hemoglobin level gradually stabilized. Regrettably, this patient ultimately died due to multiple systemic infections.

WS that occurs in CTDs can evolve into critical and severe conditions. Infection, immune complex deposition, thrombocytopenia, abnormal coagulation function, complement activation, autoantibodies production, and glucocorticoid treatment in patients with CTDs are potentially linked to the development of WS. The treatment strategies for WS should be guided by hemodynamic status.

Here, we report a case of antineutrophil cytoplasmic antibody (ANCA)-associated central nervous system (CNS) vasculitis that mimicked a brain tumor. The patient presented with progressive right upper arm weakness. Brain magnetic resonance imaging (MRI) revealed large tumor-like lesions in the left frontal and parietal lobes, with patchy and irregular enhancement with gadolinium and edema. Based on the clinical course and radiological findings, a brain tumor was suspected, and stereotactic brain biopsy was performed. Brain histopathology revealed necrotic tissue and lymphocyte infiltration around small vessels and blood vessel walls. Although the patient's clinical course and pathological findings suggested primary angiitis of CNS (PACNS), double staining for myeloperoxidase (MPO) and CD31 (a neutrophil marker) revealed infiltration of MPO-positive neutrophils in the blood vessel walls. Therefore, we diagnosed the patient with ANCA-associated CNS vasculitis. Because CNS vasculitis, including PACNS, presents nonspecific clinical findings and can depict brain tumor-like MRI findings, CNS vasculitis should be carefully differentiated from brain tumors. Additionally, double staining for MPO and CD31 might be useful for evaluating the pathogenesis of CNS vasculitis.

Our objective was to review the available literature on cardiac magnetic resonance imaging (cMRI) findings in patients with antineutrophil cytoplasmic antibody-associated vasculitides (AAV), evaluate its diagnostic utility, and assess its potential as a screening tool.

We systematically searched PubMed, Embase, Scopus, and Web of Science from inception to March 29, 2023, following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines. English-language studies involving adult patients diagnosed with AAV-eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA)-using recognized classification criteria were included. Studies had to report specific cMRI parameters in at least three patients. Three independent reviewers conducted study selection, data extraction, and quality assessment.

Of 2,251 studies, 30 met the inclusion criteria, encompassing 1,149 patients with AAV (87% with EGPA, 13% with GPA, and 0.3% with MPA). The mean patient age was 52 ± 5 years, with 50.4% being female. The mean left ventricular ejection fraction (LVEF) was 55.6% ± 11.3%, and 29% of patients had an LVEF less than 50%. Myocardial fibrosis, indicated by late gadolinium enhancement (LGE), was present in 49% of patients, with predominantly subendocardial or endocardial (23%), intramyocardial (14%), and subepicardial (10%) patterns. Patients in remission (26%), when compared to those not in remission (74%), exhibited higher proportions of LGE (55% vs 47%) and glucocorticoid use (77% vs 68%), despite similar rates of abnormal electrocardiograms (44% vs 42%).

This systematic review reveals a high prevalence of myocardial fibrosis detected by cMRI in patients with AAV, even during remission. Significant subclinical cardiac involvement may be missed by conventional diagnostic methods, underscoring the utility of cMRI during routine evaluation.

Surgical mesh, often made from polypropylene, is commonly recommended to enhance hernia repair outcomes in adults. Concerns about polypropylene, as a cause of allergy and/or autoimmune disease prompted this study to evaluate immunological parameters in patients with mesh and healthy controls.

A case-control cohort study was conducted at a university hospital. Electronic patient records of hernia repairs using polypropylene mesh (January 2018-April 2022) were analysed. Blood samples from patients and healthy controls were assessed using various methods, including enzyme-linked immunosorbent assay (ELISA), immunofluorescence, immunoblotting, and flow cytometry.

The database search identified 1544 participants. After applying the exclusion criteria 33 patients remained in the polypropylene mesh group. Patients with mesh had lower median IgG3 levels (p = 0.02) and Rheumatoid factor (RF) IgM (p = 0.018) compared to the control group. Although both IgG3 and RF IgM levels were in the normal reference range. In addition, 5 patients in the mesh group tested positive for serum ANCA levels compared to none in the control group (p = 0.053). No other differences in immunoglobulins, autoantibodies, complement, or immune cell subtypes were observed.

Patients with polypropylene mesh exhibited median IgG3 and RF IgM serum levels that were within the normal reference range but slightly lower compared to the control group. Among patients with polypropylene mesh, five displayed positive serum ANCA levels without autoimmune-related symptoms. Overall, no definitive signs of autoimmunity caused by polypropylene mesh. A larger, prospective study is warranted to further explore potential immune responses to polypropylene mesh.

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.

Eosinophilic granulomatosis with polyangiitis (EGPA) is an immune-mediated, inflammatory, multisystemic disease that is considered a form of ANCA-associated vasculitis and whose association with asthma and blood and tissue eosinophilia differentiate it from other types of vasculitis. Nevertheless, diagnosis of EGPA may be difficult or delayed not only because of the rarity of the disease, but also because other diseases can present with similar manifestations.

We review a series of key areas in EGPA, namely, laboratory and clinical indicators of disease, diagnosis, role of biomarkers, induction and maintenance therapy, and use of traditional and novel drugs. This narrative review was based on a thorough search of PubMed.

Clinicians should be aware of the limitations of available tools for diagnosing EGPA, and more efforts should be made to identify clinical and laboratory red flags, with the purpose of achieving an early diagnosis before irreversible damage occurs. New effective therapies are available, although future research should target an approach that spares glucocorticoids, reduces the risk of flares and organ damage, and maintains long-term remission with minimum adverse effects.

Avacopan, an oral C5a receptor antagonist, demonstrated efficacy as an alternative to glucocorticoid therapy in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in the phase 3 ADVOCATE trial. However, limited real-world data exist on the outcomes and experiences associated with avacopan use for AAV in Japan.

We performed a single-centre retrospective analysis and evaluated 21 patients with newly diagnosed or relapsed AAV who received avacopan. The co-primary outcomes were clinical remission at 6 and 12 months.

Among the 21 patients, 20 (95.2%) achieved clinical remission at 6 months, and 19 (90.4%) sustained remission at 12 months. The median time from initiation of immunosuppressive therapy to the start of avacopan was 12 days (interquartile range, 5-26). Adverse events were reported in 10 patients (47.6%), with elevated liver enzyme levels observed in eight patients (38.1%) as the most frequent complication. Avacopan was discontinued in nine patients (42.9%). Despite early discontinuation, these patients achieved comparable rates of clinical remission at 6 months, sustained remission at 12 months, and experienced a reduction in glucocorticoid doses relative to those who continued avacopan.

A high incidence of adverse events, particularly liver enzyme elevation, and frequent early discontinuations of avacopan were observed. Nevertheless, favourable clinical outcomes and reduced glucocorticoid doses were achieved regardless of avacopan discontinuation. Further studies are warranted to validate the optimal use of avacopan in clinical practice.

Pediatric granulomatosis with polyangiitis (GPA) is associated with several pulmonary manifestations. This study aims to describe these manifestations at time of diagnosis and longitudinally at a tertiary-care pediatric hospital.

We performed a retrospective chart review of patients with GPA treated at our facility between 1 January 2010 through 31 December 2021. We collected baseline demographics, reported symptoms, imaging findings, pulmonary function tests (PFTs), and laboratory data at time of diagnosis. Data were collected using 6-month observation intervals to follow recurrence of respiratory manifestations, testing during recurrence, and resultant treatment modifications.

Of 13 patients treated for GPA during the study period, 12 developed respiratory tract involvement. A total of 87 6-month observation periods were analyzed. At time of diagnosis, 83% (10/12) of subjects reported respiratory symptoms, 92% (11/12) had abnormal chest computed tomography (CT) imaging, and 42% (5/12) had abnormal PFTs. Fewer than half of the patients were seen by pulmonology within 6 months of diagnosis. Eight subjects (75%) had respiratory manifestations during subsequent observation periods. Chest CT or PFTs were obtained in 23/44 (52%) of observations periods with respiratory symptoms, with pulmonary consultation in only 9/44 (20%).

This is the first US study to describe respiratory manifestations in pediatric GPA patients longitudinally, finding they are common and frequently recurrent. Our cohort had almost universally abnormal imaging at diagnosis regardless of respiratory symptoms. Early collaboration with pediatric pulmonology in the care of GPA patients may allow rheumatology teams to efficiently evaluate recurrent symptoms and address concomitant lung disease.

Cyclophosphamide is a widely used immunosuppressant for inducing remission in various immune-mediated conditions. However, its potential for cardiotoxicity is well documented. One of the earliest possible manifestations of this cardiotoxicity following cyclophosphamide infusion is atrial fibrillation (AF), which typically presents within 48 h of the infusion.

The authors present a case of a 58-year-old male with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis who presented to the emergency department with clinical features of acute kidney injury. Following subsequent assessment and evaluation, the patient was managed in the intensive care unit with hemodialysis and intravenous corticosteroids. He was aimed at inducing remission with cyclophosphamide infusion. However, a few hours following induction with cyclophosphamide infusion, the patient developed palpitation, sweating, and tachycardia with a heart rate of 140-180/min. The electrocardiogram showed an irregular QRS complex with an absent p-wave. AF was diagnosed and managed with amiodarone infusion for 24 h followed by oral maintenance dosing. No further episode of AF occurred following cessation of cyclophosphamide and switching to rituximab for the treatment of ANCA-associated vasculitis.

Cyclophosphamide, even at lower dosages, can cause cardiotoxicity in patients with renal impairment due to the delayed elimination of its toxic metabolites. In addition, patients who receive CYP 450 inducers, such as prednisone, may experience the accelerated build-up of its toxic metabolites, thereby raising the risk for cardiotoxicity.

The cardiotoxic manifestation of cyclophosphamide can arise from its use in several immune-mediated conditions. Given its potential for cardiotoxicity, careful cardiac monitoring during and after cyclophosphamide infusion is essential to ensure timely intervention, if needed.

Ongoing therapeutic advances in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) have significantly reduced the risk of death in AAV, but 30%-50% of patients still relapse. Relapse is a major problem in these diseases, leading to increased morbidity and mortality. It is, therefore, necessary to find predictors of relapse at the end of the remission induction and maintenance phases in order to personalize treatment.

Genome-wide association studies (GWASs) have been successful at finding associations between genetic variants and human traits, including the immune-mediated diseases (IMDs). However, the requirement of large sample sizes for discovery poses a challenge for learning about less common diseases, where increasing volunteer numbers might not be feasible. An example of this is myositis (or idiopathic inflammatory myopathies [IIM]s), a group of rare, heterogeneous autoimmune diseases affecting skeletal muscle and other organs, severely impairing life quality. Here, we applied a feature engineering method to borrow information from larger IMD GWASs to find new genetic associations with IIM and its subgroups. Combining this approach with two clustering methods, we found 17 IMDs genetically close to IIM, including some common comorbid conditions, such as systemic sclerosis and Sjögren's syndrome, as well as hypo- and hyperthyroidism. All IIM subtypes were genetically similar within this framework. Next, we colocalized IIM signals that overlapped IMD signals, and found seven potentially novel myositis associations mapped to immune-related genes, including BLK, IRF5/TNPO3, and ITK/HAVCR2, implicating a role for both B and T cells in IIM. This work proposes a new paradigm of genetic discovery in rarer diseases by leveraging information from more common IMD, and can be expanded to other conditions and traits beyond IMD.

Hydralazine has been used for decades for the management of hypertension. However, hydralazine has been associated with various side effects, including autoimmune diseases such as hydralazine-induced antineutrophil cytoplasmic antibody-associated vasculitis (ANCA-vasculitis) and lupus-like syndrome characterized by multiorgan involvement and complex clinical manifestations. We present four cases of hydralazine-induced vasculitis (sometimes referred to as drug-induced lupus or DIL) with different presentations, including diffuse alveolar hemorrhage, hemoptysis, and skin rash. Based on variable manifestations, diagnosis can be difficult, and a high index of suspicion is of paramount importance. The final diagnosis is made by kidney biopsy, and treatment includes discontinuation of the offending agent and frequent immunosuppression. We urge caution with the use of hydralazine and choosing alternative antihypertensives when possible.

Objectives: We applied the 2022 American College of Rheumatology/ European Alliance of Association for Rheumatology (ACR/EULAR) criteria for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) to patients histologically diagnosed with lupus nephritis (LN) to investigate the overall rate of and initial contributing factors to the reclassification of overlap syndrome of LN with AAV (OS-LN-AAV). Methods: We retrospectively reviewed the medical records of 1292 patients with systemic lupus erythematosus (SLE) and included 164 patients with LN in this study. Patient demographics, SLE manifestations, LN classes, and laboratory data, including ANCA levels, were recorded. All-cause mortality and end-stage kidney disease (ESKD) were evaluated as poor outcomes. Results: The median age of the 164 patients was 37.0 years, and 12.2% were men. The overall reclassification rate was 37.8%, of which 34.1% and 3.7% of the patients were reclassified as having OS-LN-microscopic polyangiitis and OS-LN-granulomatosis with polyangiitis (GPA), respectively, but none as having eosinophilic GPA. ANCA positivity and AAV-suggesting lung lesions were major contributors to OS-LN-AAV reclassification. When patients were compared based on OS-LN AAV reclassification, ANCA positivity and myeloperoxidase-ANCA (or P-ANCA) positivity favoured for OS-LN-AAV reclassification, whereas oral ulcers did not. However, OS-LN-AAV reclassification did not affect all-cause mortality or ESKD. Conclusions: This is the first study demonstrating a 37.8% reclassification rate in patients histologically diagnosed with LN using the 2022 ACR/EULAR criteria for AAV. Furthermore, it was also the first to reveal ANCA positivity and AAV-suggesting lung lesions as major contributors to OS-LN-AAV reclassification.

Autoantibody-mediated glomerulonephritis (AGN) arises from dysregulated renal inflammation, with urgent need for improved treatments. IL-17 is implicated in AGN and drives pathology in a kidney-intrinsic manner via renal tubular epithelial cells (RTECs). Nonetheless, downstream signaling mechanisms provoking kidney pathology are poorly understood. A noncanonical RNA binding protein (RBP), Arid5a, was upregulated in human and mouse AGN. Arid5a-/- mice were refractory to AGN, with attenuated myeloid infiltration and impaired expression of IL-17-dependent cytokines and transcription factors (C/EBPβ, C/EBPδ). Transcriptome-wide RIP-Seq revealed that Arid5a inducibly interacts with conventional IL-17 target mRNAs, including CEBPB and CEBPD. Unexpectedly, many Arid5a RNA targets corresponded to translational regulation and RNA processing pathways, including rRNAs. Indeed, global protein synthesis was repressed in Arid5a-deficient cells, and C/EBPs were controlled at the level of protein rather than RNA accumulation. IL-17 prompted Arid5a nuclear export and association with 18S rRNA, a 40S ribosome constituent. Accordingly, IL-17-dependent renal autoimmunity is driven by Arid5a at the level of ribosome interactions and translation.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of rare diseases with a chronic and relapsing course. Recent treatment guidelines offer many therapeutic options depending mainly on the type of diagnosis and disease manifestations. Areas that remain under discussion include whether all patients diagnosed with AAV belong to a homogeneous group with a similar prognosis at baseline or if the type and duration of remission-inducing treatment should depend on factors other than just diagnosis and disease severity. The aim of this review is to present the recent literature on the tools available to use while evaluating the risk of relapse in patients upon presentation as well as potential biomarkers of proceeding flare in patients upon remission.

Despite significant breakthroughs in the understanding of immunological and pathophysiological features for immune-mediated kidney diseases, a proportion of patients exhibit poor responses to current therapies or have been categorized as refractory renal disease. Engineered T cells have emerged as a focal point of interest as a potential treatment strategy for kidney diseases. By genetically modifying T cells and arming them with chimeric antigen receptors (CARs), effectively targeting autoreactive immune cells, such as B cells or antibody-secreting plasma cells, has become feasible. The emergence of CAR T-cell therapy has shown promising potential in directing effector and regulatory T cells (Tregs) to the site of autoimmunity, paving the way for effective migration, proliferation, and execution of suppressive functions. Genetically modified T-cells equipped with artificial receptors have become a novel approach for alleviating autoimmune manifestations and reducing autoinflammatory events in the context of kidney diseases. Here, we review the latest developments in basic, translational, and clinical studies of CAR-based therapies for immune-mediated kidney diseases, highlighting their potential as promising avenues for therapeutic intervention.

Rhinosinusitis in granulomatosis with polyangiitis (GPA) is categorised as a secondary, diffuse and inflammatory chronic rhinosinusitis (CRS). It is one of the conditions that impacts the nasal microbiota. This study aimed to compare the nasal microbiomes of patients with GPA, CRS and NSP. A total of 31 patients were included in the study (18 GPA, 6 CRS and 7 nasal septum perforation (NSP)). In all patients, SNOT 22, a nasal endoscopy (Lund-Kennedy scale) and a brush swab were performed. The metagenomic analysis was carried out based on the hypervariable V3-V4 region of the 16S rRNA gene. At the genus level, statistically significant differences were observed in two comparisons: the GPA/NSP and the GPA/CRS groups. In the GPA/NSP group, the differences were related to four genera (Actinomyces, Streptococcus, Methylobacterium-Methylorubrum, Paracoccus), while in the GPA/CRS group, they were related to six (Kocuria, Rothia, Cutibacterium, Streptococcus, Methylobacterium-Methylorubrum, Tepidimonas). Patients with GPA had lower diversity compared to CRS and NSP patients. There were no statistically significant differences found for the Staphylococcus family and Staphylococcus aureus between the three groups.

Skin lesions are frequently observed in children with rheumatic diseases, particularly in conditions such as IgA vasculitis (IgAV) and Kawasaki disease (KD). In paediatric vasculitis, the presence of skin lesions serves as an early indicator, emphasising the importance of timely diagnosis to prevent complications, such as cardiac or renal involvement. Conversely, autoinflammatory disorders like juvenile systemic lupus erythematosus (SLE) and juvenile dermatomyositis (DM) may manifest with cutaneous manifestations either at the onset of disease or during its progression. Identifying these skin lesions prior to the appearance of systemic symptoms offers an opportunity for early diagnosis and treatment, which has a positive influence on the outcomes. Additionally, it is noteworthy that specific rheumatological conditions, such as acute rheumatic fever (ARF) or oligoarticular or polyarticular forms of juvenile idiopathic arthritis (JIA), may exhibit occasional, but significant skin involvement, which is strongly correlated with an unfavourable prognosis. The assessment of skin is important in the holist approach to assessing patients for potentially systemic/multisystem disorder and helps distinguish discrete conditions.

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are two entities of ANCA-associated vasculitis (AAV). Both diseases are characterised by systemic necrotising small-vessel vasculitis, which can affect any organ. In GPA, extravascular necrotising granulomatous inflammation, usually affecting the respiratory tract, is found in addition. In the majority of cases, the clinical presentation is dominated by a pulmonary-renal syndrome with alveolar haemorrhage and rapidly progressive glomerulonephritis. Other organ involvement is found as well. In GPA, the upper respiratory tract is commonly affected. GPA is associated with anti-neutrophil cytoplasmic autoantibodies (ANCA) with specificity for proteinase 3 (PR3-ANCA) and MPA with specificity for myeloperoxidase (MPO-ANCA). Immunosuppressive therapy depends on disease activity and the severity of organ involvement.

The gut microbiota and short chain fatty acids (SCFA) have been associated with immune regulation and autoimmune diseases. Autoimmune kidney diseases arise from a loss of tolerance to antigens, often with unclear triggers. In this review, we explore the role of the gut microbiome and how disease, diet, and therapy can alter the gut microbiota consortium. Perturbations in the gut microbiota may systemically induce the translocation of microbiota-derived inflammatory molecules such as liposaccharide (LPS) and other toxins by penetrating the gut epithelial barrier. Once in the blood stream, these pro-inflammatory mediators activate immune cells, which release pro-inflammatory molecules, many of which are antigens in autoimmune diseases. The ratio of gut bacteria Bacteroidetes/Firmicutes is associated with worse outcomes in multiple autoimmune kidney diseases including lupus nephritis, MPO-ANCA vasculitis, and Goodpasture's syndrome. Therapies that enhance SCFA-producing bacteria in the gut have powerful therapeutic potential. Dietary fiber is fermented by gut bacteria which in turn release SCFAs that protect the gut barrier, as well as modulating immune responses towards a tolerogenic anti-inflammatory state. Herein, we describe where the current field of research is and the strategies to harness the gut microbiome as potential therapy.

Granulomatosis with polyangiitis (GPA) is characterised by granulomatous inflammation and small-to-medium vessel necrotising vasculitis, mainly affecting respiratory tract and kidneys. Renal involvement presenting as tumour-like lesions poses diagnostic and treatment challenges.

Following the observation of a GPA patient presenting with multiple renal tumour-like lesions, we conducted a systematic literature review on MEDLINE/PubMed, EMBASE, and Cochrane databases. Data gathered from the literature were analysed to summarise the diagnostic approach, management, and outcome of renal GPA-related tumour-like lesions.

a 49-year-old female presented with persistent constitutional symptoms and multiple bilateral renal lesions. Renal biopsy showed chronic interstitial inflammation with necrotising granulomas. Laboratory tests disclosed positive anti-proteinase 3 (PR3) anti-neutrophil cytoplasmic antibody (ANCA) leading to a final diagnosis of GPA. She was effectively treated with high-dose glucocorticoids and rituximab. Literature search yielded 41 articles, concerning 42 GPA patients with renal masses, presenting bilaterally in 23.8% of the cases. Positive PR3-ANCA was observed in 86.5% of the cases. Half of 42 patients showed kidney abnormalities. Treatment with glucocorticoids (83.3%) and immunosuppressive agents (80.9%) resulted in an overall good remission rate and favourable prognosis.

GPA should be considered in the differential diagnoses of kidney tumour-like lesions. The diagnosis is challenging, and histological examination greatly contributes to the diagnostic work-up.

Granulomatosis with polyangiitis (GPA) is a chronic relapsing systemic autoimmune vasculitis. Current treatment of GPA is unsatisfactory, as it relies on strong immunosuppressive regimens, with either CYC or rituximab, which reduce the immunogenicity of several vaccines and are risk factors for a severe form of COVID-19. This emphasizes the need to identify new drug targets and to develop treatment strategies with less harmful side effects. Since CD4+ effector memory T cells (TEM) play a key role in the pathogenesis of GPA, we aimed in this study to modulate CD4+TEM cell activity via Kv1.3 blockade using the specific peptide inhibiter, ShK-186.

Peripheral blood samples from 27 patients with GPA in remission and 16 age- and sex-matched healthy controls (HCs) were pre-incubated in vitro in the presence or absence of ShK-186, followed by stimulation with phorbol myristate acetate, calcium ionophore and brefeldin-A. The effect of ShK-186 on the cytokine production (IFNγ, TNFα, IL-4, IL-17, IL-21) within total and subsets of CD4+ T helper (CD4+TH) cells were assessed using flow cytometry.

ShK-186 reduced the expression level of IFNγ, TNFα, IL-4, IL-17 and IL-21 in CD4+TH cells from patients with GPA in vitro. Further analysis performed on sorted CD4+T cell subsets, revealed that ShK-186 predominantly inhibited the cytokine production of CD4+TEM cells. ShK-186 treatment reduced the production of the pro-inflammatory cytokines to the level seen in CD4+ TH cells from HCs.

Modulation of cellular effector function by ShK-186 may constitute a novel treatment strategy for GPA with high specificity and less harmful side effects.

Major histocompatibility complex (MHC) class II molecules play a crucial role in immunity by presenting peptide antigens to helper T cells. Immune cells are generally tolerant to self-antigens. However, when self-tolerance is broken, immune cells attack normal tissues or cells, leading to the development of autoimmune diseases. Genome-wide association studies have shown that MHC class II is the gene most strongly associated with the risk of most autoimmune diseases. When misfolded self-antigens, called neoself antigens, are associated with MHC class II molecules in the endoplasmic reticulum, they are transported by the MHC class II molecules to the cell surface without being processed into peptides. Moreover, neoself antigens that are complexed with MHC class II molecules of autoimmune disease risk alleles exhibit distinct antigenicities compared to normal self-antigens, making them the primary targets of autoantibodies in various autoimmune diseases. Elucidation of the immunological functions of neoself antigens presented on MHC class II molecules is crucial for understanding the mechanism of autoimmune diseases.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) refers to a group of small vessel inflammatory disorders. Overlapping clinical phenotypes of AAV subgroups continually provoke controversies over their diagnostic and classification criteria.

Using the agglomerative hierarchical clustering method, we classified 210 Korean patients diagnosed with AAV into mutually exclusive clusters according to Birmingham Vasculitis Activity Score items, ANCA specificity, sex, and age. We analyzed the resulting clusters' outcomes to investigate the clinical significance of the classification. We proposed a distance-based algorithm of patient assignment and explored its clinically relevant modification.

In total, 116 patients (55%) had microscopic polyangiitis, 53 (25%) had granulomatosis with polyangiitis, and 42 (20%) had eosinophilic granulomatosis with polyangiitis. Our model grouped the patients into five clusters, namely, "limited proteinase 3 (PR3)-ANCA vasculitis," "generalized PR3-ANCA vasculitis," "ANCA-negative vasculitis," "renal-limited vasculitis," and "myeloperoxidase-ANCA vasculitis." Patients clustered under "generalized PR3-ANCA vasculitis" had a higher relapse rate (hazard ratio [HR] = 2.12, P = 0.067). The incidence of end-stage renal disease was higher in patients belonging to the "renal-limited vasculitis" cluster (HR=1.50, P=0.03), and those in the "ANCA-negative vasculitis" cluster experienced a relatively milder clinical course of AAV (mortality = 0).

Because the clusters were naturally derived from their distinguished phenotypes and have different clinical courses, our clustering method may be a more clinically relevant classification system for AAV, revealing its phenotypic diversity. We also proposed a simple and intuitive distance-based assignment algorithm, which can be easily modified according to specific clinical needs. Key Points • In this study with a single-center AAV cohort, we showed that AAV can be divided into five distinct subclasses with different disease courses based on the clinical and laboratory features of the patients. • Our study revealed ethnic differences in AAV manifestation and suggests that physicians may need to analyze their own AAV patients to assess the disease status of AAV patients. • We proposed a distance-based cluster membership assignment method that can be clinically modified to fit the specific purpose of grouping patients.

To evaluate trends in results of care and management for antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV).

We employed multicenter cohort data collected during 2011-2021, recruiting 43 patients with granulomatosis with polyangiitis (GPA) and 91 with microscopic polyangiitis (MPA). According to the median registration date of September 2015, patients have split into two groups: an early group and a late group (both of them, n = 67). To prevent bias, a propensity score according to numerous baseline characteristics variables was calculated; 50 matching members of each group were statistically extracted. Their treatments and clinical outcomes were examined at 6, 12, and 24 months after initial remission therapy.

Statistics demonstrated that the baseline characteristics were similar. The late group used rituximab (RTX) more often for both remission induction and maintenance therapy, compared with the early group. The mean daily PSL doses of the late group were significantly lower than those of early group at each time point. The late group discontinued PSL 14.0% at 12 months and 23.3% at 24 months. Despite their intensive glucocorticoids (GC) tapering, the remission rates and the relapse rates were significantly fairer in the late group. The Vasculitis Damage Index (VDI) and VDI due to GC at each time point were lower in the late group, and those differences had become wider over time.

Recent developments in AAV treatment have allowed efficient remission and prevention of relapses, which in turn enabled extensive GC tapering causing fewer sequelae.

Recent years have brought progress in understanding the role of the neutrophil, dispelling the dogma of homogeneous cells mainly involved in the prime defence against pathogens, shedding light on their pathogenic role in inflammatory diseases and on the importance of antineutrophil-cytoplasmic antibodies' pathogenic role in ANCA-associated vasculitides vasculitis (AAV). Myeloperoxidase (MPO) and proteinase 3 (PR3) expressed in neutrophil granulocytes are the most common targets for ANCAs and contribute to the formation of MPO-ANCAs and PR3-ANCAs which, released to the bloodstream, become an excellent diagnostic tool for AAV. In this study, we focus on increasing the clinical and experimental evidence that supports the pathogenic role of ANCAs in AAV. Additionally, we discuss the diagnostic utility of ANCAs for disease activity and prognosis in AAV. Understanding the central role of ANCAs in AAV is crucial for advancing our knowledge of these complex disorders and developing targeted therapeutic strategies in the era of personalized medicine.

This study examined whether plasma FXII levels reflect disease activity in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Plasma FXII levels were detected by ELISA in 127 patients with AAV, and their associations with disease activity and plasma myeloperoxidase (MPO)-ANCA titre were examined. Immunofluorescent co-staining of FXII and neutrophils was performed on the renal tissues of patients with AAV. MPO expression in renal biopsy tissues was determined by immunohistochemical staining. The association between plasma FXII levels and histological activity was assessed in 82 patients who underwent kidney biopsy. Plasma FXII levels were considerably increased in patients with clinically active AAV compared to those in clinical remission and healthy individuals. Plasma FXII levels correlated positively with creatinine (r = 0.377), CRP (r = 0.222), urine red blood cell (r = 0.203), serum MPO-ANCA titer (r = 0.353), white blood cell (r = 0.194), percentage of glomeruli with crescents (P = 0.001), capillary breaks (P = 0.001), interstitial inflammation (P < 0.001) and fibrinoid necrosis (p < 0.001) on kidney biopsy. The plasma FXII optimal cut-off value for evaluating AAV activity was 24.5 μg/mL (sensitivity = 0.81, specificity = 0.82, P = 0.0001), which was superior to that achieved using conventional serologic biomarkers. Co-expression of FXII and neutrophils was higher, with increased MPO expression, in renal tissue with pathologically active AAV than that observed in pathologically inactive tissues. In conclusion, elevated plasma FXII levels reflect AAV clinical and histologic activity, and can serve as markers of active AAV.

Due to the suboptimal therapeutic efficacy and potential adverse effects associated with traditional immunosuppressive medications, there has been an increasing emphasis on the development and utilization of immunotherapies. This paper aims to provide clinicians with valuable insights for selecting appropriate therapeutic approaches and contribute to the development of novel immunotherapeutic drugs.

This paper categorizes the immunotherapeutic drugs that are used for the treatment of immune-mediated glomerular diseases into three groups: immunotherapies targeting antigen-presenting cells (anti-CD80), immunotherapies targeting T/B cells (anti-CD20, anti-CD22, BAFF and APRIL inhibitors, CD40-CD40L inhibitors, proteasome inhibitors, Syk inhibitors, and Btk inhibitors), and immunotherapies targeting the complement system (C5 inhibitors, C5a/C5aR inhibitors, C3 inhibitors, MASP2 inhibitors, factor B inhibitors, and factor D inhibitors). The article then provides a comprehensive overview of advances related to these immunotherapeutic drugs in clinical research.

Certain immunotherapeutic drugs, such as rituximab, belimumab, and eculizumab, have exhibited notable efficacy in treating specific immune-mediated glomerular diseases, thereby providing novel therapeutic approaches for patients. Nonetheless, the efficacy of numerous immunotherapeutic drugs remains to be substantiated.

Immune mechanisms play an important role in the pathogenesis of glomerulonephritis (GN), with autoimmunity being the main underlying pathogenetic process of both primary and secondary GN. We present three autoimmune diseases mediated by different autoimmune mechanisms: glomerulonephritis in vasculitis mediated by anti-neutrophil cytoplasmic antibodies (ANCAs), glomerulonephritis mediated by anti-glomerular basement membrane antibodies (anti-GBM antibodies), and immune complex-mediated glomerulonephritis. Some of these diseases represent a common clinical and histopathologic scenario, namely rapidly progressive crescentic glomerulonephritis. This is a severe illness requiring complex therapy, with the main role being played by therapy aimed at targeting immune mechanisms. In the absence of immune therapy, the crescents, the characteristic histopathologic lesions of this common presentation, progress toward fibrosis, which is accompanied by end-stage renal disease (ESRD). The fact that three diseases mediated by different immunopathologic mechanisms have a common clinical and histopathologic picture reveals the complexity of the relationship between immunopathologic mechanisms and their clinical expression. Whereas most glomerular diseases progress by a slow process of sclerosis and fibrosis, the glomerular diseases accompanied by glomerular crescent formation can progress, if untreated, in a couple of months into whole-nephron glomerulosclerosis and fibrosis. The outcome of different immune processes in a common clinical and histopathologic phenotype reveals the complexity of the relationship of the kidney with the immune system. The aim of this review is to present different immune processes that lead to a common clinical and histopathologic phenotype, such as rapidly progressive crescentic glomerulonephritis.

To study circulating myeloperoxidase (MPO)-positive extracellular vesicles (MPO+EVs) exposing citrullinated histone-3 (H3Cit), tissue factor (TF), and plasminogen (Plg) in association to thrombin generation in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV).

We have involved well-characterized patients with AAV together with population-based controls. Flow cytometry was used to assess the levels of MPO+EVs in citrated plasma. MPO+EVs were phenotyped by anti-MPO-antibodies together with anti-CD142 (anti-TF), anti-H3Cit, and anti-Plg antibodies. A modified Calibrated Automated Thrombogram (CAT) assay was utilized to measure thrombin generation in plasma initiated by EVs-enriched pellets. The activity of AAV was evaluated with the Birmingham Vasculitis Activity Score (BVAS).

This study comprised 46 AAV patients, 23 in the active stage of the disease and 23 in remission, as well as 23 age- and sex matched population-based controls. Augmented levels of all investigated MPO+ EVs were found in active AAV patients in comparison to the subgroup of patients in remission and controls. Thrombin generation, measured by endogenous thrombin potential (ETP) and peak of thrombin formation, was higher in plasma when triggered by EVs-enriched pellet from AAV patients. ETP and peak were associated with the levels of MPO+TF+ and MPO+H3Cit+ EVs. Additionally, MPO+TF+ EVs correlated with the disease activity evaluated with BVAS.

Augmented thrombin generation is found in AAV patients regardless of disease activity and is associated with higher exposure of TF and H3Cit on MPO+EVs. This may contribute to the increased risk of thrombosis seen in AAV patients.

We investigated whether soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) reflects cross-sectional activity of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA).

Forty-seven MPA and 32 GPA patients with well-documented clinical records and stored sera were enrolled. sTREM-1 levels were evaluated using Magnetic Luminex® assay, and disease activity was assessed using Birmingham vasculitis activity score (BVAS). Patients were divided into two groups according to the upper and lower halves of BVAS. Receiver operator characteristic (ROC) curve analysis was used to identify cut-off for determining upper half of BVAS. Linear and binary logistic regression was performed to evaluate the association between sTREM-1 and disease activity and status.

The median age of patients was 67.0 years, and 58.2 % were women. The median BVAS and sTREM-1 were 12.0 and 467.1 pg/mL. sTREM-1 was significantly correlated with BVAS along with five-factor score, Short-Form 36-Item Health Surveys, and C-reactive protein. In multivariable linear regression analysis, erythrocyte sedimentation rate (standardised β 0.241), and sTREM-1 (standardised β 0.288) were correlated with BVAS. ROC analysis revealed that the cut-off of sTREM-1 for the upper half of BVAS was 474.1 pg/mL. MPA and GPA patients with sTREM-1 ≥474.1 pg/mL exhibited a significantly higher risk for the upper half of BVAS than those without (relative risk 5.932). Multivariable logistic regression analysis demonstrated sTREM-1 ≥474.1 pg/mL (odds ratio 5.662) was associated with the upper half of BVAS.

sTREM-1 reflects the activity of MPA and GPA, suggesting its role as a potential biomarker for assessing disease severity.

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a rare and severe systemic autoimmune disease characterized by pauci-immune necrotizing inflammation of small blood vessels. AAV involves multiple organ systems throughout the body. Our knowledge of the pathogenesis of AAV has increased considerably in recent years, involving cellular, molecular and genetic factors. Because of the controlled environment with no other confounding factors, animal models are beneficial for studying the mechanistic details of disease development and for providing novel therapeutic targets with fewer toxic side effects. However, the complexity and heterogeneity of AAV make it very difficult to establish a single animal model that can fully represent the entire clinical spectrum found in patients. The aim of this review is to overview the current status of animal models for AAV, outline the pros and cons of methods, and propose potential directions for future research.

Immunoglobulin G (IgG) contains a conserved N-glycan in the fragment crystallizable (Fc), modulating its structure and effector functions. In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) alterations of IgG Fc-glycosylation have been observed to correlate with the disease course. Here, we examined longitudinal changes in N-linked Fc glycans of IgG in an AAV patient cohort and their relationship with disease flares.

Using liquid chromatography coupled with mass spectrometry, we analysed IgG Fc-glycosylation in 410 longitudinal samples from 96 individuals with AAV.

Analysis of the cross-sectional differences as well as longitudinal changes demonstrated that IgGs of relapsing PR3-ANCA patients have higher ΔFc-bisection at diagnosis (P = 0.004) and exhibit a decrease in Fc-sialylation prior to the relapse (P = 0.0004), discriminating them from non-relapsing patients. Most importantly, PR3-ANCA patients who experienced an ANCA rise and relapsed shortly thereafter, exhibit lower IgG Fc-fucosylation levels compared to non-relapsing patients already 9 months before relapse (P = 0.02).

Our data indicate that IgG Fc-bisection correlates with long-term treatment outcome, while lower IgG Fc-fucosylation and sialylation associate with impending relapse. Overall, our study replicated the previously published reduction in total IgG Fc-sialylation at the time of relapse, but showed additionally that its onset precedes relapse. Furthermore, our findings on IgG fucosylation and bisection are entirely new. All these IgG Fc-glycosylation features may have the potential to predict a relapse either independently or in combination with known risk factors, such as a rise in ANCA titre.

Avacopan (TAVNEOS® capsules) is an orally available selective C5a receptor (C5aR) antagonist. It has been approved in Japan since 2021 for the treatment of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), the two major subtypes of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current standard therapy combining glucocorticoids (GC) and immunosuppressants has greatly improved the prognosis of AAV, however, issues such as side effects associated with GC use remain to be resolved. Avacopan suppresses priming of neutrophils induced by the complement component C5a, a process deeply involved in the pathogenesis of AAV. In pre-clinical studies, avacopan inhibited chemotaxis and priming of neutrophils induced by C5a-C5aR signaling. It also significantly suppressed nephritis and renal damage in an ANCA-induced glomerulonephritis mouse model. In the global phase 3 study "ADVOCATE", avacopan achieved both primary endpoints being 1) non-inferior to prednisone in inducing remission at week 26 and 2) superior in sustained remission at week 52 for MPA and GPA patients. Additionally, with avacopan, GC toxicity score was significantly lower and fewer adverse events possibly related to GC were observed. Furthermore, avacopan increased estimated glomerular filtration rate (eGFR) more than prednisone indicating improved renal function. Thus, the novel mechanism of avacopan targeting the complement system is a promising new therapeutic option for AAV with fewer GC-related side effects and better improvement of renal function.

Avacopan is a novel C5a receptor antagonist recently approved for the treatment of microscopic polyangiitis and granulomatosis with polyangiitis. To our knowledge, thrombocytopenia induced by avacopan has not been reported. We report a case of a 78-year-old man with microscopic polyangiitis who developed rapidly progressive glomerulonephritis (RPGN) and vasculitis neuropathy. After developing RPGN, he was treated with prednisolone, which was ineffective. As the dosage of corticosteroids was decreased, he developed impaired dorsiflexion of the left ankle, tingling and numbness in his feet, consistent with vasculitis neuropathy. After a 3-day administration of methylprednisolone, we started avacopan and prednisolone 20 mg/d to reduce the corticosteroid dosage. One week after starting avacopan, platelet counts began to decrease, eventually leading to the cessation of the drug. The possibility of thrombotic microangiopathy and heparin-induced thrombocytopenia was considered unlikely given the clinical course and laboratory studies. After 3 weeks of avacopan cessation, platelet counts began to increase, suggesting avacopan as the most probable cause of thrombocytopenia. Our case highlights the importance of postmarketing surveillance of avacopan to identify its adverse events that were not reported in clinical trials to ensure its safe use. Clinicians should carefully monitor platelet counts when using avacopan.

Granulomatous polyangiitis (GPA) is a rare systemic autoimmune vasculitis disease that is highly correlated with anti-neutrophil cytoplasmic antibodies (ANCAs). It was formerly called as "Wegener's granulomatosis." The clinical manifestations are diverse, mainly involving the upper respiratory tract, lungs, and kidneys, and this disease can involve the brain parenchyma as an isolated solid mass. Only one case has been reported thus far. To provide further information on this rare case, we report a case of GPA involving the fourth ventricle and review the relevant literature. A 32-year-old Chinese female developed fever, cough, and shortness of breath for 20 days. An 80 mm × 80 mm skin ulcer was seen on the right lower limb. CT showed multiple large patches of increased density in both lungs. The patient's serological ANCA was positive. Later, the patient developed dizziness and headache. Magnetic resonance imaging of the head showed a mass of approximately 21 mm × 24 mm in the fourth ventricle. The patient had a craniotomy for mass resection, and macroscopically, the mass was gray-red and measured 25 mm × 20 mm × 20 mm, was soft, had local hemorrhage and necrosis, and had no capsule. The main microscopic features included necrotizing granulomatous vasculitis, the patient's immunohistochemistry was positive for CD68 and negative for glial fibrillary acidic protein, and the acid-fast staining and hexaamine silver staining were negative. Combined with the clinical history, serology, and imaging, the pathological diagnosis was GPA in the fourth ventricle. The patient was switched to rituximab combined with steroid therapy because she did not tolerate cyclophosphamide. After 5 months of follow-up, the patient's lung lesions and skin ulcers had completely improved, but the brain lesions had further progressed. When a patient has multiple system diseases, abnormal clinical manifestations, and positive serological ANCAs, a diagnosis of GPA should be carefully considered, and biopsies of easy-to-access sites should be performed. If the patient's histopathological manifestations include vasculitis, granuloma, and necrosis, a diagnosis of GPA is more likely. If a patient subsequently develops an intraventricular mass, the clinicians should consider a diagnosis of GPA, which can rarely involve the cerebral ventricle to avoid an unnecessary biopsy or surgical treatment of intracranial lesions. When a patient is intolerant to the traditional treatment drug cyclophosphamide and needs to be switched to rituximab, the treatment effect of intracerebral lesions is not ideal; therefore, the treatment of lesions involving GPA in the ventricle is worthy of further exploration.