顕微鏡的多発血管炎

Avacopan, a selective complement C5a receptor antagonist, is utilized to manage microscopic polyangiitis (MPA). Recently, attention has grown regarding severe liver injury, particularly vanishing bile duct syndrome (VBDS), as a potential adverse event during avacopan therapy. However, its clinicopathological features and underlying mechanisms remain poorly understood. Herein, we report a case of non-suppurative destructive cholangitis (NSDC), considered a pre-conditional state of VBDS, after avacopan therapy for MPA. A 55-year-old obese female with myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated crescentic glomerulonephritis achieved remission via steroid pulse therapy, oral prednisolone (PSL), and rituximab. Seven weeks before admission, avacopan and ursodeoxycholic acid (UDCA) were initiated. Despite stable renal function, MPO-ANCA seroconversion to negative, and successful PSL tapering, she presented with acute liver injury. Laboratory tests revealed marked elevations in transaminases and biliary enzymes (aspartate aminotransferase (AST): 313 U/L, alanine aminotransferase (ALT): 488 U/L, gamma-glutamyl transferase (γ-GTP): 364 U/L) with normal direct bilirubin (D-bil). Avacopan was discontinued, and PSL was increased. A liver biopsy showed lymphocytic (non-suppurative) destructive cholangitis with a florid duct lesion and frequent spotty necrosis in lobuli, without central necrosis. Immunohistochemical staining revealed focal decreased CK19 immunointensity in the bile ducts and predominant infiltration of CD4-positive T cells and CD68-positive macrophages around interlobular bile ducts. Although D-bil transiently peaked at 4.0 mg/dL on day 7, intensive treatment with high-dose UDCA and intravenous glycyrrhizin restored D-bil to the normal range by day 34, with significant transaminase improvement. Pathological findings revealed biliary epithelial damage with predominant T-cell and macrophage infiltration, distinct from typical drug-induced liver injury. The onset during PSL tapering and responsiveness to temporary PSL intensification strongly support a cell-mediated immune mechanism driving VBDS. To the best of our knowledge, this is the first report describing a comprehensive immunohistochemical evaluation of the periportal microenvironment in avacopan-induced biliary injury. This case highlights that severe cholangitis can occur regardless of baseline risk profiles or disease activity, underscoring the need for vigilant, long-term monitoring of liver enzymes and bilirubin levels during avacopan therapy.

Granulomatosis with polyangiitis (GPA) is a rare necrotizing vasculitis of small- to medium-sized vessels characterized by granulomatous inflammation, most commonly involving the upper respiratory tract, lungs, and kidneys. Early manifestations are frequently non-specific and may resemble chronic allergic or infectious rhinosinusitis, delaying recognition until destructive sinonasal, pulmonary, renal, neurologic, or cutaneous involvement emerges. Cutaneous vasculitis and cavitary pulmonary nodules further complicate the diagnostic process by raising concern for infection or malignancy. We report a 69-year-old woman with years of refractory nasal congestion and recurrent epistaxis who developed progressive sinonasal obstruction, septal perforation, palpable purpura, peripheral sensory symptoms, renal urinary abnormalities, and bilateral cavitary pulmonary nodules. Laboratory evaluation demonstrated PR3-ANCA/c-ANCA positivity, elevated inflammatory markers, anemia of inflammation, mild renal dysfunction, and urinalysis with proteinuria and microscopic hematuria. Computed tomography demonstrated destructive sinonasal disease and bilateral cavitary pulmonary nodules. Nasal biopsy showed necrotizing granulomatous inflammation with small to medium vessel vasculitis, confirming GPA. High-dose systemic glucocorticoids and rituximab-based induction therapy were initiated with Pneumocystis jirovecii pneumonia prophylaxis and multidisciplinary rheumatology, otolaryngology, pulmonology, and nephrology follow-up. This case is not presented as a unique manifestation of GPA but as an educational reminder that chronic rhinosinusitis becomes a diagnostic trap when accompanied by epistaxis, septal destruction, pulmonary cavitation, purpura, neuropathic symptoms, or urinary abnormalities. Earlier recognition of this pattern may prevent irreversible organ damage.

Avacopan is an oral C5a receptor antagonist approved for severe active granulomatosis with polyangiitis and microscopic polyangiitis. However, its real-world safety profile, particularly hepatobiliary safety signals, remains incompletely characterized. We analyzed avacopan-related adverse event reports from FAERS, JADER, and EudraVigilance. Disproportionality analyses were performed using reporting odds ratio and Bayesian Confidence Propagation Neural Network. Subgroup, sensitivity analysis, time-to-onset, Bradford Hill, network pharmacology, molecular docking, machine learning, and SHAP analyses were used to characterize safety signals, explore potential mechanisms, and identify factors associated with hepatobiliary disorder reporting. In FAERS, 5,293 avacopan-related individual case safety reports comprising 11,901 adverse event terms were identified. Positive signals were detected for infections, gastrointestinal disorders, and hepatobiliary disorders. Liver-related events, including drug-induced liver injury, jaundice, cholestasis, and vanishing bile duct syndrome, were consistently observed across FAERS, JADER, and EudraVigilance. In FAERS, most adverse events occurred early after treatment initiation. A Bradford Hill-informed contextual appraisal provided additional context for the observed DILI reporting signal; however, it did not permit causal inference. Network pharmacology identified 83 overlapping targets, with enrichment mainly involving xenobiotic response, oxidative stress, lipid metabolism, and PI3K-Akt signaling. Molecular docking supported favorable interactions between avacopan and key targets. Among machine learning models, NeuralNet showed the best validation performance for report-level classification, and SHAP analysis identified country as the dominant contributor to model predictions, suggesting substantial influence of regional reporting patterns. This real-world study expands the safety profile of avacopan and highlights hepatobiliary disorders as important signals requiring clinical attention. These findings support strengthened post-marketing surveillance and careful liver monitoring during avacopan therapy.

This review describes vasculitis syndromes that can be diagnosed by kidney biopsy. Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) typically follow a rapidly progressive course, often leading to end-stage renal failure within a few months, with crescentic glomerulonephritis being the predominant finding on a kidney biopsy. However, some types primarily present with fever and elevated C-reactive protein levels, while the kidney function is preserved; in such cases, a kidney biopsy shows arteriolitis. Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by eosinophil infiltration and small-artery arteritis, and the renal prognosis is often favorable. Anti-glomerular basement membrane (GBM) glomerulonephritis is a hyperacute form of progressive glomerulonephritis that leads to end-stage renal failure within a few weeks, with most glomeruli exhibiting synchronous necrotizing glomerulitis. Among immune complex-mediated small-vessel vasculitides, many cases of IgA vasculitis correspond to IgA nephropathy; however, cases accompanied by endocapillary hypercellularity have also been observed.

OBJECTIVES: To compare rates and characteristics of hospital episodes in which ANCA-associated vasculitis (AAV) was recorded as the primary discharge diagnosis across eight jurisdictions, including subtype distribution, demographic patterns, temporal trends, and in-hospital mortality. METHODS: We conducted a multinational ecological cross-sectional study using national hospital discharge databases from eight jurisdictions (Spain, Australia, Germany, England, Wales, Chile, Mexico, and the USA) between 2016 and 2022. AAV episodes were identified using ICD-10 primary diagnosis codes for granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Crude and age-adjusted hospitalisation rates, hospitalisation rate ratios and in-hospital mortality were analysed. Temporal trends were primarily assessed using Pearson-scaled Poisson models, with negative binomial models as sensitivity analyses. RESULTS: Among 758,257,987 hospital episodes, 116,039 were AAV (0.015%). GPA was the most frequent subtype (63.6%), followed by MPA (25.6%) and EGPA (10.9%). Crude AAV hospitalisation rates ranging from 0.04/100,000 in Mexico to 9.61/100,000 in Germany; age-adjusted rates were similar. Mortality data from Spain, Mexico, and the USA showed the highest AAV in-hospital mortality proportion in the USA (6.75%). In Pearson-scaled Poisson analyses, AAV hospitalisation rates increased in Spain (HRR 1.12, 95% CI 1.09-1.15; p < 0.001) and Australia (1.08, 1.06-1.10; p < 0.001), and decreased in Wales (0.86, 0.80-0.93; p < 0.001) and Chile (0.92, 0.86-0.98; p = 0.012). These trends persisted after exclusion of 2020 but were not statistically significant in negative binomial models. CONCLUSIONS: AAV hospital burden varied substantially across jurisdictions in rates, subtype distribution, and outcomes, warranting cautious interpretation in light of differences in population structure and health system capture.