The diagnostic delay in AAV varies by disease subtype and clinical presentation. EGPA shows the numerically longest time to diagnosis, while renal involvement seems to facilitate earlier diagnosis. Enhanced awareness among non is essential to reduce diagnostic delay and prevent organ damage, although outcome measures were not assessed in our study. Key Points • Diagnostic delay in ANCA-associated vasculitis varies between disease subtypes, organ involvement, and consulted specialties. • EGPA shows the numerically longest diagnostic delay, whereas renal involvement seems to facilitate earlier diagnosis. • Earlier recognition of AAV across specialties may reduce diagnostic delay and prevent organ damage.
Objective This study aims to characterize pathogenic somatic mutations in patients with autoinflammatory or autoimmune diseases lacking disease‐causing germline mutations, explore their contribution to disease pathogenesis and progression, and evaluate their implications for diagnosis and targeted therapy. Methods We performed a systematic analysis of somatic mutations in a selected panel of 185 immune‐related genes in 2,912 patients with autoinflammatory or autoimmune diseases, recruited from 41 medical centers across China, who were previously negative for germline mutations based on whole‐exome sequencing. Results We identified both previously reported and novel somatic mutations in genes such as UBA1 , KRAS , and NLRP3 . Pathogenic somatic mutations in TNFAIP3 were discovered first in patients with autoinflammatory diseases. The pathogenic somatic mutation detection rate was 1.35% in adults and 0.97% in children, emphasizing the importance of genetic diagnosis and novel gene discovery for somatic mutations. In addition, somatic mutations in Ras‐related genes were identified in seven patients, and 39 clonal hematopoiesis–associated mutations were identified in 36 adult patients. Moreover, myeloid cells harboring somatic mutations expanded during disease flare and reduced during remission. Disregarding the dynamic elevation of the variant allele fraction during disease progression led to therapeutic failure. Conclusion This study delineated the genetic landscape of pathogenic somatic mutations underlying autoinflammatory and autoimmune diseases, offering valuable insights for genetic diagnosis and targeted therapies.
Autoimmune rheumatic diseases (ARDs) are a diverse group of chronic disorders characterized by immune dysregulation and multi-organ inflammation. B cell receptor (BCR) signaling emerges as a shared, yet heterogeneously regulated, pathogenic axis across these diseases. This dysregulation drives B cell activation, autoantibody production, and ultimately tissue damage. Recent research highlights its involvement in both common and disease-specific mechanisms, which helps explain the wide variation in clinical features and therapeutic responses across ARDs. This review summarizes current evidence establishing BCR signaling as a central regulatory and therapeutic target in rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, IgG4-related disease, and ANCA-associated vasculitis. It integrates mechanistic insights with recent clinical trial data on BCR signaling-targeted therapies, discussing factors that may contribute to variability in therapeutic responses and treatment limitations. Finally, we outline current challenges and future directions for precision medicine in ARDs, with a focus on biomarker-guided strategies and innovative combination therapies to improve patient outcomes.
A newsletter destaca que a normalização da IgG total no primeiro ano de tratamento é um preditor de recaída superior à IgG4 na Doença Relacionada à IgG4. Discute também que pacientes com vasculite anti-MPO apresentam maior risco cardiovascular e menor tempo para eventos adversos do que os anti-PR3. Por fim, aborda como a fragilidade impacta a tolerância aos corticoides na polimialgia reumática e o papel dos iSGLT2 na redução da necessidade de alopurinol.
ANCA-associated vasculitis (AAV) is a rare multisystem autoimmune disease in which diagnostic delay remains common and contributes to organ damage. This study aimed to develop a multispecialty, consensus-based set of clinical, laboratory, and imaging red flags to facilitate early recognition across medical disciplines. A structured consensus process inspired by modified Delphi methodology and the RAND/UCLA Appropriateness Method was conducted. A multispecialty panel including rheumatologists, nephrologists, and specialists in internal medicine, otolaryngology, pulmonology, ophthalmology, and neurology evaluated a comprehensive list of AAV manifestations. All items were scored on a 0-10 relevance scale through inter-specialty voting. Following five intra-specialty Scientific Discussion Sessions to interpret scores and refine items, a second-round evaluation was performed, and a final meeting validated the definitive checklist. Organ-specific manifestations without a better explanation involving the upper airways, kidneys, nervous system, lungs, and eyes were consistently rated as the most relevant red flags for early AAV recognition. High relevance was attributed to refractory ENT (Ear, Nose and Throat) disease, active urinary sediment, otherwise unexplained central or peripheral neurological deficits in young individuals, inflammatory ocular involvement, and pulmonary hemorrhagic features. Systemic symptoms showed lower relevance scores and were considered supportive rather than specific indicators. In parallel, a unified panel of first-level laboratory and instrumental investigations was defined to facilitate early multisystem assessment when AAV is suspected. This multispecialty consensus-based checklist provides a pragmatic tool to support early suspicion of AAV in routine clinical practice and may help reduce diagnostic delay.
Antineutrophil cytoplasmic autoantibody-associated vasculitides can be classified by clinical phenotype or antineutrophil cytoplasmic autoantibody specificity, with overlapping yet distinct characteristics. Transcriptomic analyses of kidney biopsies from 2 French antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) cohorts revealed a pronounced type I interferon signature in microscopic polyangiitis (microscopic polyangiitis/myeloperoxidase-AAV) compared with granulomatosis with polyangiitis (granulomatosis with polyangiitis/proteinase 3-AAV). Among biopsies with high interferon scores, 66% were myeloperoxidase-AAV and 28% proteinase 3-AAV. The interferon score was associated with decreased kidney survival. These findings highlight AAV patient heterogeneity and support targeted treatment approaches.
The aim of this study was to investigate the relationship between antineutrophil cytoplasmic antibodies (ANCA) specificity and the risk of major adverse cardiovascular events (MACE) in patients with ANCA-associated vasculitis (AAV). We conducted a retrospective study using the ANCA-associated vasculitis Toulouse cohort. The incidence of MACE, defined as myocardial infarction (MI) and/or stroke and/or all-cause death, was compared among patients according to their ANCA specificity. We also applied Cox regression models adjusted for traditional cardiovascular risk factors, age and sex to assess the risk of MI, stroke and MACE. A total of 402 patients were included, of whom 166 (41%) had antiproteinase 3 (anti-PR3) ANCA and 236 (59%) had antimyeloperoxidase (anti-MPO) ANCA. We identified 78 MACE during the follow-up period, including 15 MIs, 12 strokes and 62 deaths. The incidence rate of MACE in the ANCA+anti-PR3+ group was 21.4 per 1000 patient-years compared with 33.1 per 1000 patient-years in the ANCA+anti-MPO+ group (p=0.036). The time elapsed between the diagnosis of AAV and MACE occurrence was significantly shorter in the ANCA+anti-MPO+ group. The Cox regression model found that patients with anti-MPO ANCA tend to present more MACE, but the association was not statistically significant (HR 1.62; 95% CI 0.98 to 2.66; p=0.06). An association was found between the presence of anti-PR3 ANCA and a lower risk of strokes (HR 0.61; 95% CI 0.37 to 0.99; p=0.049) and none with the risk of MI. Patients with anti-MPO ANCA appear to be at a higher risk of a composite MACE-all-cause mortality outcome than patients with anti-PR3 ANCA.
Abstract Objectives Rituximab (RTX) is a standard maintenance therapy for ANCA-associated vasculitis. Its efficacy in Japan remains unclear, where microscopic polyangiitis (MPA) predominates and clinical characteristics differ from Western-dominated RCT populations. Methods Japanese patients with MPA or granulomatosis with polyangiitis (GPA) enrolled in a nationwide registry were included. Exposure was RTX use during maintenance therapy. The primary endpoint was major relapse-free survival at 104 weeks. The secondary endpoint was any relapse-free survival (major or minor) at 104 weeks. Baseline differences were adjusted using inverse probability of treatment weighting (IPTW) based on key demographic and disease-related covariates. Results A total of 389 patients were analyzed, with 85 in the RTX group. The RTX group included a higher proportion of GPA cases (37/85 vs. 74/304), resulting in baseline imbalance. After IPTW, no major relapses were observed in the RTX group, whereas the major relapse-free survival at 104 weeks was 94.8% in the non-RTX group. The RTX group showed significantly higher any relapse-free survival at 104 weeks (95.4% vs. 83.3%; HR for any relapse, 0.27; 95% CI, 0.09–0.74; p = 0.02). Conclusions Our findings suggest that RTX may be an effective option for remission maintenance in Japanese patients with MPA or GPA.
To assess the performance of the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria for eosinophilic granulomatosis with polyangiitis (EGPA) in a multicenter cohort in Eastern China and compare it against the 1990 ACR and 2017 mepolizumab in relapsing or refractory EGPA (MIRRA) criteria. EGPA patients diagnosed between January 2018 and March 2025 were included in the study, and the diagnosis by "an expert panel" was used as the gold standard. The sensitivity, specificity, positive/negative predictive value (PPV, NPV), accuracy and receiver operating characteristic (ROC) curves of three sets of classification criteria (1990 ACR, 2017 MIRRA and 2022 ACR/EULAR) were evaluated. A total of 96 EGPA patients and 163 controls including 91 cases of other types of vasculitis and 72 cases of eosinophilic disorders were enrolled. 2022 ACR/EULAR classification criteria had the highest sensitivity of 87.5% and accuracy of 94.2% compared with 1990 ACR and 2017 MIRRA criteria. However, the specificity (98.2%) was slightly lower than that of the 1990 ACR and 2017 MIRRA criteria in the entire control. Thirty-five patients (36.5%) fulfilled all three criteria. The most sensitive item was eosinophilia (eosinophil ratio > 10% or count ≥ 1 × 109/L), with a sensitivity of 90.6%, followed by eosinophil ratio > 10% (89.6%) and eosinophil count ≥ 1 × 109/L (82.3%). The most specific item was vascular wall eosinophils (98.6%). The 2022 ACR/EULAR classification criteria demonstrated significant improvement in sensitivity and accuracy while maintaining a relatively high level of specificity. It is noticing that these criteria should not be used for the diagnosis of EGPA. Key Points • 2022 ACR/EULAR EGPA classification criteria were validated in a cohort of China. • 2022 ACR/EULAR criteria had higher sensitivity and accuracy compared to 1990 ACR criteria and 2017
Abstract Objectives To examine contemporary trends in mortality due to granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) in Europe. Methods We utilised publicly available data from Eurostat on deaths recorded with GPA or MPA as the underlying cause of death for the period 2011–2021. Crude and standardised mortality rates (SMRs) were calculated for each country and linear regression used to determine changes in mortality rates over time. Crude mortality rate was also stratified by age and sex. To investigate the association between geography and mortality rate, the SMR for each country was displayed on a choropleth map and plotted against the country’s latitude. Results Our analysis of 29 European countries showed a stable mortality rate due to GPA and MPA between 2011–2021, but rising age at death median age-band 70–74 at the start and 75–79 at the end of the study period. There were differences between countries with the highest mortality rate in Denmark (SMR 31.03 per 10 million) and the lowest in Romania (SMR 0.77 per 10 million). Mortality rates were higher in adults aged over 80 years and there were more deaths in men compared with women. A latitudinal gradient in SMR was seen in GPA but not MPA, with the highest mortality rates in Scandinavia. Conclusion Despite major advances in disease management, our results show that deaths due to GPA and MPA were stable over the last decade, indicating an ongoing need to improve the treatment of these diseases.
Background Interstitial Lung Disease (ILD) can occur in association with ANCA‐associated Vasculitis (AAV‐ILD) or as an isolated entity with positive ANCA (ANCA‐ILD). However, data on the epidemiology and outcomes of these conditions remain limited. Methods A European multicentre retrospective study encompassed patients with AAV‐ILD or ANCA‐ILD. Baseline and subsequent chest CT studies were centrally reviewed. Primary outcomes included forced vital capacity (FVC) decline, respiratory failure, and mortality. Results 162 patients (MPO‐ANCA 85%); 123 (76%) had AAV‐ILD and 39 (24%) ANCA‐ILD. At baseline, Usual Interstitial Pneumonia (UIP) was the most frequent radiologic pattern (57%), while half had a radiological fibrosis grade >10%. Kidney involvement was present in 73%, most commonly Berden focal class. UIP and Non‐specific interstitial pneumonia (NSIP) patterns showed greater annual FVC decline than other patterns (UIP: −1.99%, NSIP: −3.76%, [p=0.35] others: +0.36%). An adjusted mixed‐effects model indicated that rituximab was associated with mean FVC % improvement at 12 months (+6.02%; p=0.07). Radiologic progression occurred in ~50%, mainly in younger patients with higher fibrosis severity grade. Respiratory failure (19%) was associated with fibrosis severity (grade 4: HR 4.7; p=0.029) and baseline FVC% (HR 0.95; p=0.002). Over a median 4.2‐year follow‐up, 48% died. Age (HR 1.08; p=0.04) and baseline FVC% (HR 0.97; p=0.05) were independent predictors of mortality. Conclusion At baseline, higher fibrosis severity, UIP, and lower FVC% were associated with worse outcomes. Immunosuppressives, such as rituximab, may help preserve lung function. The need for early identification and individualized treatment in ILD associated with AAV or ANCA is underscored.
Antineutrophil cytoplasmic antibodies (ANCA) are a key biomarker for ANCA-associated vasculitis (AAV), particularly microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). Although indirect immunofluorescence (IIF) has traditionally been the reference technique, its diagnostic value in contemporary real-world practice remains uncertain. The aim of this study was to evaluate the diagnostic performance of IIF ANCA testing in routine clinical practice. We conducted a retrospective study of all patients with an ANCA request at a tertiary hospital over a four-year period. All IIF-positive sera were subsequently tested for anti-PR3 and anti-MPO antibodies by chemiluminescent immunoassay (CLIA). Clinical data, test indication and final diagnoses were retrieved from electronic medical records. We included 5,157 patients and IIF was positive in 653 (12.7%): perinuclear ANCA (P-ANCA) in 17.9%, cytoplasmic ANCA (C-ANCA) in 13.3% and atypical ANCA (A-ANCA) in 68.8%. CLIA was negative in 97.3% of A-ANCA. AAV was diagnosed in 47 patients, and 42 (89.4%) had positive IIF. For GPA and MPA, IIF showed a sensitivity of 93% and specificity of 88%, with a very high negative predictive value (NPV) (99.9%) but low positive predictive value (PPV) (6.1%). Specificity improved to 96.8% when restricted to typical patterns (C-ANCA or P-ANCA) and to 99.6% when combined with positive CLIA results >20 IU/ml. Almost all AAV cases were diagnosed in patients with high pre-test probability (such as renal disease, lung infiltrates, or peripheral neuropathies) and interstitial lung disease was the most frequent non-AAV diagnosis in IIF-positive patients. ANCA IIF retains good diagnostic efficiency and a very high NPV for GPA and MPA, but has low PPV, particularly when tested for nonspecific symptoms.
Ocular manifestations frequently occur in ANCA-associated vasculitides (AAV). Orbital inflammatory disease (OID) is a subset with limited management guidelines. This systematic review evaluated interventions for AAV-OID. We searched Embase, MEDLINE, Web of Science, ClinicalTrials.gov, and Cochrane Central without language or date restrictions for clinical trials, case-control studies, observational studies, and case series (≥5 patients) of adults treated for AAV-OID. Included studies reported therapy type and clinical response after ≥1 month. The primary outcome was clinical response, defined as any improvement in signs or symptoms, up to and including remission. Secondary outcomes included remission, relapse, sustained remission (>6 months), and serious adverse events. Two reviewers independently screened records and appraised studies using the Newcastle-Ottawa Scale (NOS). A qualitative synthesis and meta-analysis of proportions were performed using a random effects model. Of 1001 studies screened, 18 met inclusion criteria (277 patients; 14 retrospective cohorts, 4 case series). Most (17/18) had NOS scores ≥5. Thirteen studies included rituximab (RTX), 10 cyclophosphamide, 7 RTX + another immunosuppressant (IS), 11 conventional IS, and 7 surgical therapies. Most studies involved refractory/relapsing cases. In 4 RTX monotherapy series, 95% (95 %CI 89-100%, p < 0.001) had a clinical response and 84% (95%CI 72-95%, p < 0.001) achieved remission at 6 months. Our results suggest high remission rates of OID with RTX but highlight the need for high-quality prospective studies examining treatments for AAV-OID.
Objective The objective of the study was to determine risk factors for relapse of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) after reinduction of remission with rituximab and discontinuation of maintenance therapy. Methods This is a post hoc analysis of the RITAZAREM clinical trial. Patients aged 15 years or older with AAV and a positive test for anti–proteinase‐3 or anti‐myeloperoxidase‐ANCA who achieved remission after reinduction with rituximab and glucocorticoids were randomized at month 4 to receive continued rituximab or azathioprine for a maintenance period up to 24 months, followed by observation until relapse or up to 48 months. Generalized estimating equations logistic regression identified baseline and time‐varying risk factors for relapse by the next visit for the two study phases: maintenance (months 4–24) and off‐treatment (months 24–48). Results Among 170 patients (median [interquartile range] age 59 [48–68] years, disease duration 5 [2–10] years), 99 relapses occurred (46 during maintenance). During maintenance, musculoskeletal involvement (odds ratio [OR]: 2.8, 95% confidence interval [CI]: 1.1–7.2; P = 0.03) and higher patient global assessment (OR: 1.1, 95% CI: 1.0–1.2; P = 0.04) were associated with relapse. During the off‐treatment phase, presence of CD19 + B cells (OR: 2.5, 95% CI: 1.2–5.1; P = 0.01) and reappearance of ANCA (OR: 3.2, 95% CI: 1.3–7.7; P = 0.01) were each associated with higher relapse risk. Multivariable analysis identified markers of inflammation (changes in platelets, white blood cells, and IgA) associated with relapse. Conclusion Risk factors for relapse in AAV vary by treatment phase. Monitoring markers of inflammation and immune reconstitution may identify patients at risk for relapse, particularly after treatment withdrawal.
Immunoglobulin G4-related disease (IgG4-RD) is a rare, multisystemic fibro-inflammatory condition affecting various organs, including kidneys, lungs, nasal cavity, pancreas, salivary glands, and orbit. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAVs) is a multi-systemic inflammatory vascular disease encompassing eosinophilic granulomatosis with polyangiitis (EGPA), microscopic polyangiitis (MPA), and granulomatosis with polyangiitis (GPA). It often overlaps with the organs or tissues affected by IgG4-RD. Clinically, some individuals with IgG4-RD are ANCA-positive, while some with AAV exhibit elevated IgG4 levels or IgG4-positive plasma cell infiltration, making these conditions difficult to distinguish. Reports have documented cases of overlap syndromes involving IgG4-RD and AAV, highlighting shared pathogenic mechanisms that may include macrophages, B cells, CD4+T cells, and inflammatory cytokines. However, the pathophysiological mechanism underlying these overlap syndromes remains unclear. This review examines potential pathophysiological links between IgG4-RD and AAVs (GPA/MPA) overlap syndromes.
Systemic sclerosis (SSc) is an autoimmune disease characterized by autoantibody production, fibrosis, and vasculopathy. The coexistence of ANCA-associated vasculitides (AAV) in SSc is rare and poorly characterized, with limited data on the impact of treatments, particularly high-dose glucocorticoids (GCs), on both conditions. This study aimed to describe the clinical phenotype, management, and outcomes of patients with overlapping SSc and AAV. We conducted a multicenter retrospective study in 18 French centers, including patients who met the 2013 ACR/EULAR criteria for SSc and the 2022 ACR/EULAR criteria for AAV. Clinical, biologic, and radiologic data were collected. We included 30 patients (median age 51.5 years, 83% female). SSc preceded AAV in all cases; 27% had diffuse cutaneous SSc, while 73% had limited cutaneous SSc. Anti-Scl70 antibodies were detected in 50%, and interstitial lung disease (ILD) was present in 80%, predominantly with a fibrosing non-specific interstitial pneumonia pattern (54%). AAV was microscopic polyangiitis in 90%, with MPO-ANCA positivity in 93%. Renal involvement was common (76%), with a median serum creatinine of 170 μmol/l (IQR 120-361) and proteinuria of 2 g/g (IQR 0.9-2.3). All patients received GCs in combination with cyclophosphamide (50%) or rituximab (47%). No cases of scleroderma renal crisis were observed. SSc manifestations, including ILD and skin involvement, remained stable during follow-up. AAV, predominantly microscopic polyangiitis with MPO-ANCA, can occur in SSc, particularly in patients with fibrosing ILD and anti-Scl70. Standard vasculitis treatments appear to be effective and do not worsen outcomes in SSc.
Rapid progressive glomerulonephritis (RPGN) is a severe complication of microscopic polyangiitis (MPA), leading to end-stage renal disease (ESRD). However, biomarkers for assessing the disease severity have not been elucidated in MPA-RPGN. The aim in this exploratory hypothesis-generating study was to identify serum biomarkers associated with renal disease severity and prognosis in patients with MPA. This study enrolled 73 patients with MPA. We measured 16 serum biomarker profiles, and compared them between patients with MPA with RPGN and those without RPGN. We identified biomarkers with higher levels in MPA with RPGN and evaluated their associations with progression to ESRD. Five kidney biopsy specimens were examined by haematoxylin and eosin staining and immunostaining to evaluate the biomarker expressions. Of the 73 patients, 30 patients (41.1%) had RPGN on admission. Initial serum M-CSF levels and TNF-a levels were significantly higher in patients with MPA with RPGN than those without RPGN. Among them, serum M-CSF levels significantly correlated with glomerular and renal tubular damage markers. The 5-year ESRD-progression rate was significantly higher in patients with initial serum M-CSF ≥ 416.95 pg/ml than in patients with serum M-CSF < 416.95 pg/ml (P = 0.0002). Immunohistochemical staining showed enhanced M-CSF expression in glomerular capillary endothelial cells and tubular epithelial cells in cases with severe glomerular and tubular damage. CD163-positive macrophages showed high infiltration into the periglomerular and peritubular areas in the sclerotic group. The serum M-CSF level may serve as a biomarker that reflects RPGN severity and predicts progression to ESRD in patients with MPA. M-CSF-inducing CD163 + macrophages might contribute to the pathogenesis of RPGN in MPA. The online version contains supplementary material available at 10.1186/s13075-025-03718-1.
Inflammatory ratios derived from routine complete blood counts, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), have been proposed as activity markers in ANCA-associated vasculitis (AAV), but their interpretation is limited by heterogeneous sampling and treatment-related confounding. We conducted a single-center cross-sectional study including adult patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Patients were sampled during active disease (new-onset prior to induction or relapse prior to escalation) or during stringent glucocorticoid-free remission (BVASv3 = 0). Healthy controls (HCs) were included for secondary comparisons. Ratios were compared across groups and correlated with BVASv3 and c-reactive protein (CRP). Between-group differences (active vs. remission; remission vs. healthy controls) were additionally quantified using age- and sex-adjusted log-linear models (log-transformed outcomes), reported as ratios of geometric means. Discriminative performance for active disease versus remission was assessed using unadjusted ROC analyses and age- and sex-adjusted logistic regression models. Sensitivity analyses stratified remission by maintenance immunosuppression at sampling. The study included 99 AAV patients (28 active, 71 remission) and 258 HCs. NLR, PLR, and MLR were significantly higher in active disease than in remission (all p ≤ 0.004), and remained significantly higher after age/sex adjustment in log-linear models (geometric mean ratios [Active/Remission]: NLR 1.97, PLR 1.64, MLR 1.40). NLR and PLR correlated moderately with BVASv3 (ρ = 0.506 and 0.478, respectively; both p < 0.001) and CRP. Discriminative performance was strongest for NLR and PLR: in age- and sex-adjusted models, AUC increased from 0.664 (age/sex only) to 0.832 after adding NLR and 0.827 after adding PLR (whereas the AUC after adding MLR was 0.724). During glucocorticoid-free remission, ratios remained higher than in HCs (geometric mean ratios: NLR 1.55 [1.39-1.74], PLR 1.18 [1.08-1.29], MLR 1.40 [1.27-1.55]; all p < 0.001). Treatment
Severe infections contribute to morbidity and mortality in microscopic polyangiitis (MPA). This study aims to investigate the clinical characteristics and identify risk factors for early severe infections in newly diagnosed patients with MPA. This retrospective cohort study included patients newly diagnosed with MPA followed up for at least 6 months at two tertiary care centres between January 2013 and December 2023. Clinical data, including demographics, laboratory findings, treatment regimens, and infection details, were collected. Multivariable logistic regression analysis was used to identify risk factors for severe infections within 6 months after the diagnosis in patients with new-onset MPA. A total of 374 patients with MPA were included, and 25.9% (97/374) experienced severe infections. Compared to the non-infection group, the infection group had a significantly higher daily average dosage of prednisone for remission induction, a higher proportion of patients with a history of chronic lung disease, and a higher proportion receiving rituximab (RTX) therapy (p<0.05). In multivariable logistic regression analysis, a history of chronic lung disease, higher daily average dosage of prednisone therapy and RTX therapy for remission induction were associated with an increased risk of severe infections, whereby higher baseline serum IgM levels were associated with a decreased risk. The most common site of infection was the lung (75.23%), and bacteria (43.1%) was the most prevalent pathogen. MPA is associated with a high risk of severe infections, especially in patients treated with higher dosage glucocorticoid and with a history of chronic lung disease.
To assess the 2022 American College of Rheumatology (ACR)/EULAR classification criteria for antineutrophil cytoplasmic antibody-associated vasculitis (AAV) in children with chronic small-to-medium vessel vasculitis. A cohort of 574 patients, identified by physician's diagnosis (MD-diagnosis) in A Registry of Childhood Vasculitis, was classified by computation of registry data as having granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), or eosinophilic GPA after applying (1) ACR/EULAR AAV criteria and (2) pediatric-adapted European Medicines Agency (Ped-EMA) classification algorithm (incorporating Ankara GPA criteria). Venn diagrams compared the resulting GPA and MPA cohorts with MD-diagnosis. Sensitivity and specificity of criteria for GPA were evaluated against MD-diagnosis. Fisher exact test evaluated differences in the frequencies of individual clinical features in GPA versus MPA. Comparing ACR/EULAR criteria against the Ped-EMA algorithm for classifying AAV, more patients were classified as GPA or MPA (n = 396 vs 360, respectively), fewer had GPA (n = 261 vs 288, respectively), more had MPA (n = 135 vs 72, respectively), and fewer GPA cases coclassified as MPA (12% vs 28%, respectively); there were more differences between GPA and MPA in Pediatric Vasculitis Activity Score-defined clinical features (n = 14 vs 10, respectively). When classifying GPA by ACR/EULAR or Ankara criteria, sensitivity (74.5% vs 72.1%, respectively) was comparable, and specificity for ACR/EULAR criteria (93.9% vs 79.9%, respectively) was improved. The 2022 ACR/EULAR classification criteria for AAV perform at least as well as previous pediatric criteria and provide categorical MPA criteria where none existed previously; the criteria for GPA and MPA now specifically differentiate each other, with more differences between them in the frequencies of clinical features. Our findings support the preferential use of ACR/EULAR over Ankara criteria for GPA in pediatrics.
Avacopan (AVAC), an oral selective C5a receptor inhibitor, has been approved for treatment in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Outside randomized controlled studies, real-world data are scarce. The aim of this study was to provide further insight into the clinical experience of AVAC. We analysed data from 16 patients with severe AAV included in an AVAC compassionate use programme. Disease activity was estimated with the Birmingham Vasculitis Activity Score (BVAS). Fatigue was assessed using the Multidimensional Assessment of Fatigue (MAF). Thirteen patients (81%) were diagnosed with granulomatosis with polyangiitis (GPA) and three (19%) with microscopic polyangiitis. The mean age at AVAC initiation was 51 (range 16-74) years. The median [interquartile range (IQR)] BVAS score was 10 (3.25-13.25) at baseline and 0 (0-0) at 6 months (p < 0.0001). All but one reached clinical remission. Prednisolone was tapered from a median (IQR) dose of 25 (20-60) to 2.5 (0-5) mg/day at 6 months (p = 0.0001). Eight patients discontinued prednisolone [median time 2.5 month1 week to 10 months)]. The median (IQR) estimated glomerular filtration rate in patients with renal AAV (n = 10) increased from 50 (13-75) to 58 (15.5-88) mL/min/1.73 m2 at 6 months (p = 0.055). One patient progressed to end-stage kidney disease, while another was able to discontinue haemodialysis. Serious adverse events were seen in five of the 16 patients (31.3%). The MAF score decreased, with a mean difference of 6.65 (p = 0.05) at 6 months. The use of AVAC in a case series with mainly GPA patients led to rapid clinical improvement, reduction of corticosteroid doses, and improvement in fatigue. The findings demonstrate beneficial effects of AVAC as add-on therapy in severe AAV.
To investigate the clinical characteristics of muscle-dominant ANCA-associated vasculitis (muscle-dominant AAV) in a consecutive single-center cohort. We retrospectively analyzed consecutive patients newly diagnosed with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) at a single center. Cases with muscle-dominant AAV were defined as those with muscle involvement due to AAV in the absence of other organ manifestations, including glomerulonephritis, cutaneous vasculitis, vasculitic neuropathy, or alveolar hemorrhage. We compared the muscle-dominant AAV group with all remaining AAV patients, who served as the comparison group. Among 72 consecutive patients newly diagnosed with MPA or GPA, 8 (11%) were classified as having muscle-dominant AAV. All patients with muscle-dominant AAV (100%) were MPO-ANCA-positive. In all patients with muscle-dominant AAV, serum creatine kinase levels remained within the normal range despite MRI-confirmed muscle inflammation. Compared with the comparison group, the muscle-dominant AAV group had significantly higher rheumatoid factor (RF) levels. ROC analysis identified an exploratory RF cutoff value of 47.55 U/mL (AUC = 0.79). The prevalence of interstitial lung disease (ILD) tended to be more frequent in the muscle-dominant AAV group than in the comparison group (75 vs. 37.5%, p = 0.060). Muscle-dominant AAV was characterized by MPO-ANCA positivity, elevated RF levels, normal CK levels, and MRI-confirmed muscle involvement. ILD was often observed but did not reach statistical significance. These findings suggest a possible clinical pattern within AAV, which we tentatively refer to as the hypothesized IMARM pattern (ILD, MPO-ANCA, RF, myopathy).
Despite previous reports on the risk factors for relapse in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), none have evaluated the relationship between serum syndecan-1 levels and AAV relapse. Therefore, this study aimed to investigate the association between serum syndecan-1 levels at AAV diagnosis and subsequent relapses in patients with AAV, hypothesizing that higher levels would be associated with increased risk of relapse. This single-center, medical record-based cohort study included 60 consecutive patients with microscopic polyangiitis or granulomatosis with polyangiitis treated at Aichi Medical University Hospital in Japan in 2018-2022. The relationship between serum syndecan-1 levels at diagnosis and subsequent first relapse was assessed using multivariable Cox proportional hazards models after adjusting for age, sex, estimated glomerular filtration rate, antineutrophil cytoplasmic antibody (ANCA) titers, Birmingham Vasculitis Activity Score, and AAV classification. The cumulative probability of relapse was calculated using the Kaplan-Meier method and log-rank test. Statistical significance was set at p<0.05. During a median follow-up period of 48 (range, 24 to 64) months, 20 (33.3%) patients experienced at least one relapse. Patients with high-serum syndecan-1 levels (adjusted hazard ratio=19.0, 95% CI: 1.17-307.8) were associated with an increased risk of relapse compared with those with low serum syndecan-1 levels. Among patients with ANCA-associated vasculitis, high-serum syndecan-1 levels at diagnosis were associated with an increased risk of relapse.
Serious infections in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) represent a contributor to morbidity and mortality. Patients are susceptible to both typical and opportunistic infections due to immunocompromise resulting from immunosuppressive treatments and disease activity. Over the past decade, studies predominantly in retrospective cohorts have outlined the incidence and nature of serious infections, including organ involvement and pathogens, as well as various risk factors for serious infections. This review summarises the recent literature on serious infections and discusses risk factors for these infections; we have categorised them into baseline characteristics, laboratory values, end-organ damage, and immunosuppressive treatments. It discusses emerging data on the role of reduced glucocorticoid regimens and trimethoprim-sulfamethoxazole prophylaxis in preventing serious infections. Finally, implications on clinical practice and important avenues for future research are discussed.
We investigated the diagnostic and prognostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for interstitial lung disease (ILD) in patients with microscopic polyangiitis (MPA). In this single-centre observational study, 61 patients with MPA who underwent high-resolution computed tomography (HRCT) and 18F-FDG PET/CT were included. ILD diagnosis was based on HRCT. 18F-FDG uptake in the lung parenchyma was assessed as a binary variable (present/absent). Diagnostic performance was evaluated by sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The prognostic value was determined by Δ (1-year-baseline; positive=improvement) in forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) using multivariable linear regression models. 18F-FDG uptake showed high specificity and PPV (both 1.00) but limited sensitivity (0.63) and NPV (0.26) for ILD detection. Patients with 18F-FDG uptake demonstrated significantly greater Δ in FVC (β=8.26 [2.87-13.64], p=0.004) and DLCO (β=7.38 [0.06-14.69], p=0.048) compared with those without uptake. The prognostic value of 18F-FDG uptake was greater than that of the ILD pattern determined by HRCT (usual interstitial pneumonia [UIP] vs. non-UIP). While non-UIP patterns were associated with favourable Δ in FVC (β=8.02 [0.66-15.38], p=0.034), they were not associated with significant changes in DLCO (β=0.66 [-8.83-10.16], p=0.885). 18F-FDG PET/CT demonstrated high specificity but limited sensitivity for detecting ILD in MPA, limiting its use as a screening tool. However, given its prognostic value, 18F-FDG PET/CT could be considered as a complementary imaging modality may aid prognostic stratification in MPA-associated ILD.