Background The expanding use of biologic and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs) has substantially improved outcomes in autoimmune diseases but is accompanied by complex safety concerns. Risk management plans (RMPs) have been introduced to mitigate treatment-related risks; however, real-world adherence to these strategies and their broader clinical impact remain incompletely characterized. Methods We conducted a retrospective observational cohort study of adult patients with autoimmune diseases who received bDMARDs, tsDMARDs, or biosimilars at a tertiary medical center in southern Taiwan between October 2014 and December 2023. Patients were classified into RMP and non-RMP groups based on completion of predefined pre-treatment safety assessments within 6 months prior to therapy initiation, including pulmonary and tuberculosis evaluation, viral hepatitis screening, and documentation of cardiovascular and malignancy risk factors. Clinical outcomes included Pneumocystis jirovecii pneumonia (PJP), major adverse cardiovascular events (MACE), treatment-related respiratory adverse events, and all-cause mortality. Multivariable logistic regression and time-to-event analyses were performed to evaluate associations between RMP implementation and clinical outcomes. Results Among 1,078 patients included, only 348 (32.3%) fulfilled the predefined RMP criteria prior to treatment initiation. Compared with the RMP group, patients without RMP exhibited significantly higher incidences of PJP (11.9% vs. 2.3%), MACE (8.5% vs. 2.6%), treatment-related respiratory adverse events (50.4% vs. 42.8%), and all-cause mortality (7.3% vs. 1.7%) (all p < 0.05). After multivariable adjustment, RMP implementation remained independently associated with lower risks of PJP (adjusted odds ratio [aOR] 0.18, 95% CI 0.15–0.84), MACE (aOR 0.30, 95% CI 0.13–0.71), and all-cause mortality (aOR 0.21, 95% CI 0.07–0.61). Subgroup and time-to-event analyses demonstrated that anti-CD20 therapy was associated with the highest risk of early-onset PJP, MACE, and mortality, with most events occurring within the first three
Advances in high-throughput sequencing and genotype-first approaches have revealed a growing number of monogenic autoimmune and autoinflammatory conditions that present in late adolescence or adulthood and sometimes mimic more common rheumatologic diseases. These disorders arise from both germline and somatic mutations and span a broad spectrum of immune dysregulation, including autoinflammation, autoimmunity, immunodeficiency, allergic disease, and hematological disorders. Importantly, many affected individuals do not exhibit classical Mendelian inheritance or early-onset disease, instead presenting with incomplete penetrance, variable expressivity, or atypical phenotypes that fulfill established classification criteria for diseases such as systemic lupus erythematosus and vasculitides. In this review, we highlight recently described monogenic immune disorders with relevance to adult rheumatology practice, including germline inborn errors of immunity and somatic mutation-driven conditions. We discuss emerging mechanisms that link innate and adaptive immune dysregulation, clinical features that should prompt genetic evaluation, and practical considerations for genetic testing in adult patients. Finally, we examine current challenges and future opportunities in integrating molecular diagnostics into rheumatology care, emphasizing the potential for genetic diagnoses to refine disease classification and inform targeted, mechanism-based therapeutic approaches.
OBJECTIVE: The Plasma Exchange and Glucocorticoids in Severe Antineutrophil Cytoplasmic Antibody-Associated Vasculitis (PEXIVAS) trial evaluated plasma exchange (PLEX) and glucocorticoid dose in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study reanalyzed the PEXIVAS trial using Bayesian methods to focus on patients with diffuse alveolar hemorrhage (DAH). METHODS: In the PEXIVAS trial, adults with AAV and kidney injury and/or DAH were randomized to receive PLEX or no PLEX and reduced- or standard-dose glucocorticoids. This study evaluated 1-year survival and severe infection among participants with DAH, no DAH, and severe DAH (oxygen saturation ≤ 85% on room air or mechanical ventilation) across multiple priors. The secondary outcome was severe infection (leading to hospitalization, intravenous antibiotics, or death). This study calculated mean hazard ratios (HRs) for survival and odds ratios (ORs) for infection, 95% credible intervals (CrIs), and probabilities of survival benefit (HR 1). RESULTS: Among 704 participants (191 with DAH and 61 with severe DAH), using noninformative priors, the probability of improved survival was 93% for participants with DAH receiving PLEX (HR 0.52; 95% CrI 0.21-1.26) and 67% for those without DAH (HR 0.86; 95% CrI 0.43-1.71). Participants receiving reduced-dose glucocorticoids had a 98% probability of improved survival without DAH (HR 0.46; 95% CrI 0.22-0.95) but a 12% probability with severe DAH (HR 2.02; 95% CrI 0.64-6.35). Plasma exchange increased the odds of severe infection (OR 1.25; 95% CrI 0.92-1.70; 92% probability of OR > 1), whereas reduced-dose glucocorticoids decreased the odds of infection (OR 0.85; 95% CrI 0.63-1.15; 85% probability of OR < 1). Results were consistent across priors. CONCLUSION: Patients with AAV and DAH may benefit from PLEX. Reduced-dose glucocorticoids improve survival for individuals without DAH but may be harmful in
Objective Steroid‐induced osteonecrosis of the femoral head (SONFH) is a refractory skeletal disorder influenced by genetic and environmental factors. However, conclusive pathogenic genetic evidence remains elusive due to the limited exploration of rare damaging variants. In this study, we aimed to identify rare variants associated with SONFH. Methods We conducted whole‐exome sequencing (WES) in a SONFH case‐control study comprising 174 systemic lupus erythematosus (SLE) patients on steroids. Followed by comparing the cases with an ethnically matched healthy population and validation in an additional SONFH cohort of 246 patients without SLE. Rare damaging variants were identified via genetic burden analysis and confirmed by Sanger sequencing and pedigree studies. The functional assessments of the erythrocytes on target variants were performed. Results We identified 10 heterozygous ANK1 and EPB41 rare variants in 9 (10.8%) of 83 SONFH patients compared with 0 (0%) of the 91 non‐SONFH controls.The burden effect of them remained robust after adjusted analysis (aOR [Firth's logistic regression adjusted odds ratio] ANK1 11.3; aOR EPB41 32.3; both p<0.05). The variants were detected in 10 (4.1%) of the validated SONFH cohort with 246 non‐SLE conditions. Functional analyses revealed that the variants result in membrane dysfunctions in the patients’ erythrocytes, characterized by reduced ANK1 expression, abnormal morphology, and increased hypotonic hemolysis. Conclusion These findings suggest that the rare variants in ANK1 and EPB41 are novel SONFH disease risk factors which compromise erythrocyte membrane integrity, exacerbating microcirculatory damage in the presence of glucocorticoid as a second hit.
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.
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare and heterogeneous immune-mediated disorder in which eosinophilic inflammation, vasculitis, and airway disease coexist in highly variable combinations. In clinical practice, diagnosis remains challenging because no single biomarker reliably captures disease complexity, and therapeutic decisions must still be based on careful integration of clinical, laboratory, imaging, and histopathological findings. In recent years, EGPA management has evolved from a largely glucocorticoid-based approach toward a more phenotype-oriented strategy that distinguishes eosinophilic and vasculitic manifestations and incorporates targeted biologic therapies. This Perspective discusses current challenges and emerging opportunities in EGPA diagnosis and treatment, with emphasis on early recognition, multidisciplinary assessment, glucocorticoid-sparing strategies, and individualized long-term follow-up. Specific recommendations are provided on diagnostic orientation, phenotype-driven therapeutic selection, and the practical use of conventional immunosuppressants and anti-IL-5/IL-5R biologics according to disease severity and organ involvement. In addition, we propose a new treatment algorithm intended to support real-world decision-making and to facilitate a more consistent and structured approach to care. By combining expert recommendations with a forward-looking perspective on evolving therapeutic strategies, this article aims to contribute to safer, more effective, and more personalized management of patients with EGPA.
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.
Immune-mediated cochleovestibular dysfunction has gained recognition as an important yet frequently overlooked entity in recent decades. These disorders-ranging from isolated inner-ear syndromes to cochleovestibular manifestations of systemic autoimmune diseases-exhibit humoral or cellular immune attacks on inner-ear structures, commonly accompanied by microvascular injury and inflammatory cascades. Despite increasing awareness, the precise pathophysiological mechanisms remain incompletely understood for most conditions, and diagnostic and therapeutic approaches vary considerably. This narrative review summarizes current evidence on immune-mediated cochleovestibular disorders, dividing them into two main categories (1): primary Isolated disorders (delayed endolymphatic hydrops, bilateral vestibulopathy, and Ménière's disease with established or suspected autoimmune features) (2) cochleovestibular manifestations of rheumatologic diseases (systemic lupus erythematosus, multiple sclerosis, autoimmune thyroid disease, Behçet's disease, Vogt-Koyanagi-Harada disease, psoriasis, Cogan's syndrome, Susac syndrome, Sarcoidosis, Rheumatoid arthritis, Necrotizing vasculitides with polyangiitis and Giant cell arteritis). We examine their clinical features, proposed immune and microvascular mechanisms, diagnostic evaluation, and current management strategies, with particular emphasis on immunomodulatory and immunosuppressive therapies. Systemic corticosteroids at high doses are the primary treatment for most of these disorders, though the ideal duration, tapering protocols, and indications for steroid-sparing medications differ significantly across various syndromes. Evidence supporting many adjunctive therapies is limited or conflicting, underscoring the need for higher-quality clinical trials. Early recognition and prompt immunomodulatory treatment can often reverse or stabilize symptoms in immune-mediated cochleovestibular dysfunction. This review offers a clinically oriented synthesis of current evidence, elucidating the complex immunological underpinnings and the corresponding therapeutic landscape of these disorders. By integrating otologic and rheumatologic perspectives, we aim to heighten awareness, promote earlier diagnosis, and inform more effective treatment of patients presenting with vertigo, hearing loss, or imbalance suggestive of immune-mediated inner-ear pathology.
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.
IgG4-RD is a rare but increasingly recognized systemic condition characterized by complex clinical manifestations and multi-organ involvement, often leading to misdiagnosis or delayed diagnosis. This study aims to elucidate the clinical features of IgG4-RD and evaluate the diagnostic and therapeutic utility of key laboratory indicators. We conducted a retrospective analysis of IgG4-RD patients, comparing laboratory profiles across different organ involvement patterns. The diagnostic and therapeutic value of serum IgG4 levels in IgG4-RD was evaluated, with comparative analyses of serum IgG4 levels extended to non-IgG4-RD patients. Distinct patterns of laboratory markers were observed across affected organs, with elevated IgG and ESR levels consistently noted. The optimal diagnostic cutoff for serum IgG4 in IgG4-RD was 1.94 g/L, while a cutoff of 9.05 g/L effectively identified multi-organ involvement. Following 6 months of standardized treatment, serum IgG4 levels in IgG4-RD patients decreased significantly. Notably, ANCA-associated vasculitis patients exhibited markedly elevated serum IgG4 levels, which remained unchanged post-treatment. The integration of serum IgG4 with other laboratory markers enhances diagnostic precision for IgG4-RD. Elevated serum IgG4 levels are associated with multi-organ involvement, underscoring their utility in assessing disease extent. Serum IgG4 is indispensable for monitoring therapeutic response. Given the overlapping clinical features between ANCA-associated vasculitis and IgG4-RD, accurate differentiation is essential for optimal clinical management. Key Points • IgG4-RD predominantly affects middle-aged and elderly males, yet its occurrence in younger individuals and less commonly involved organs (e.g., brain and heart) warrants attention. • Affected organs demonstrate distinct laboratory marker profiles, providing valuable insights for clinical diagnosis and therapeutic strategies. • Serum IgG4 levels are instrumental in diagnosing, assessing disease progression, and monitoring treatment response, though their interpretation should be integrated with other clinical indicators. • In ANCA-associated vasculitis, serum IgG4
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a leading cause of rapidly progressive glomerulonephritis and a major contributor to end-stage kidney disease (ESKD). Prognostic tools remain limited, particularly in Latin American populations. We historically analyzed 164 adults with biopsy-proven pauci-immune necrotizing and/or crescentic glomerulonephritis consistent with AAV, diagnosed between 2011 and 2024 at a tertiary referral center in Colombia. Clinical and histopathologic variables obtained near the kidney biopsy (≤30 d) were analyzed using Cox proportional hazards models. The primary outcome was ESKD, defined as initiation of chronic dialysis or sustained estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m². Independent predictors were used to derive the ANCLA (ANCA in Latin America) Risk Score. Model performance was evaluated using the area under the ROC curve (AUC), Harrell C-index, and Kaplan-Meier analysis. During a median follow-up of 12.9 months, 63 patients (38.4%) progressed to ESKD. Independent predictors included younger age, lower eGFR, higher 24-hour proteinuria, and a lower percentage of normal glomeruli. The ANCLA model demonstrated strong discrimination (AUC: 0.82, 95% CI: 0.79-0.85; C-index 0.72). Risk quartiles showed distinct kidney survival, with 2-year survival of ~95% in the lowest group versus <20% in the highest (log-rank p < 0.001). In comparative exploratory analyses, ANCLA outperformed the Berden classification and the Renal Risk Score within our cohort. The ANCLA Risk Score integrates routine clinical and histopathologic data into a simple, accurate tool for predicting kidney outcomes in AAV, including ANCA-negative cases (17.1%). Its strong performance in a Latin American cohort supports its potential for early risk stratification and clinical decision-making. External and multicenter validation are warranted.
Most studies on renal outcomes in ANCA-associated vasculitis (AAV) focus on GN; however, the prognosis of patients without clinically apparent kidney involvement is understudied. We aimed to characterize kidney prognosis in this overlooked subgroup. Estimated glomerular filtration rate (eGFR) trajectories by kidney Birmingham Vasculitis Activity Score (BVAS; 0 vs ≥1) were analysed. The primary outcome was incident chronic kidney disease (CKD) in the kidney BVAS = 0 group, defined as at least two eGFR values <60 ml/min/1.73 m2 obtained at least 90 days apart, accompanied by a decline ≥30% from baseline. The cohort included 129 patients with kidney BVAS = 0 and 228 with kidney BVAS ≥ 1. After remission induction, eGFR improved in kidney BVAS ≥ 1 but declined in kidney BVAS = 0; this worsening trajectory in the kidney BVAS = 0 group was observed regardless of treatment intensity. Over 3 years, incident CKD occurred in 30 patients in kidney BVAS = 0 (cumulative incidence 30.7%, 95% CI 21.6-42.6%). In Cox models, older age and higher baseline-to-1-month time-weighted average CRP (TWA-CRP) were associated with incident CKD. Baseline-to-1-month TWA-CRP predicted incident CKD (age-adjusted HR 1.21; 95% CI 1.06-1.39; P < 0.01), and TWA-CRP from 1 to 6 months ≥0.5 mg/dl at the 6-month landmark identified higher risk (HR 2.61; 95% CI 1.01-6.78; P = 0.049). In AAV without clinically apparent kidney involvement, TWA-CRP, as a surrogate of sustained systemic inflammation, was associated with incident CKD. Even with unremarkable urinalysis, eGFR monitoring is warranted.
To update the existing European Alliance of Associations for Rheumatology (EULAR) points to consider (PtC) for use of antirheumatic drugs in reproduction, pregnancy, and lactation, including additional drugs and adverse outcomes as well as paternal drug safety. According to the EULAR standardised operating procedures, an international task force (TF) defined the questions for a systematic literature review, followed by formulation of the updated statements. A predefined voting process was applied to each overarching principle and statement. Level of evidence and strength of recommendation were assigned, and participants finally provided their level of agreement for each item. The TF proposes 5 overarching principles and 12 recommendations for the use of antirheumatic drugs before and during pregnancy, through lactation, and in male patients. The current evidence indicates that synthetic disease-modifying antirheumatic drugs (DMARDs) compatible with pregnancy include antimalarials, azathioprine, colchicine, cyclosporine, sulfasalazine, and tacrolimus. Regarding nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, a more restrictive approach to their use during pregnancy is recommended. Based on an individualised risk-benefit assessment, all tumour necrosis factor inhibitor (TNFi) biologic DMARDs (bDMARDs) can be used throughout pregnancy, and non-TNFi bDMARDs may be used if needed. In relation to lactation, compatible drugs include antimalarials, azathioprine, colchicine, cyclosporine, glucocorticoids, intravenous immunoglobulin (IVIG), NSAIDs, sulfasalazine, and tacrolimus. All bDMARDs are considered compatible with breastfeeding. Concerning the use of drugs in men, compatible options include antimalarials, azathioprine, colchicine, cyclosporine, IVIG, leflunomide, methotrexate, mycophenolate, NSAIDs, glucocorticoids, sildenafil, sulfasalazine, tacrolimus, and bDMARDs. The updated recommendations provide consensus guidance and will help to improve the quality of care of patients during the phases of reproduction, pregnancy, and lactation.
This study aimed to summarise and update evidence to inform the 2024 update of the European Alliance of Associations for Rheumatology recommendations for the use of antirheumatic drugs in reproduction, pregnancy, and lactation. A systematic literature review (SLR) was performed, including keywords on reproduction, adverse pregnancy outcomes (APOs), and lactation. Two appraised SLRs were the basis for the SLR on drug safety in men. If sufficient data were available, a meta-analysis was performed on maternal drug exposure and the risk of APOs. Of 6680 screened articles, 255 were included in the final analysis. In pregnancy, most evidence was available for biologic disease-modifying antirheumatic drugs (bDMARDs). Meta-analyses with adjusted risk estimates did not reveal APOs or serious infant infections to be associated with tumour necrosis factor inhibitor (TNFi) use. Data on non-TNFi bDMARDs did not raise concerns. In bDMARD-exposed infants, no serious adverse effects to rotavirus live vaccination were reported. Safety of Bacille Calmette-Guérin vaccination in TNFi-exposed infants could be a concern in the first 6 months of life. Regarding oral glucocorticoids, the SLR and meta-analysis using adjusted risk estimates found a dose-dependent association with an increased risk of preterm birth. Nonsteroidal anti-inflammatory drug use could reversibly reduce fecundability. Concerning lactation, available data on various bDMARDs was reassuring. In male patients, available evidence on methotrexate and most other drugs did not reveal adverse effects on sperm quality or birth outcomes. Cyclophosphamide remains the only drug that causes a dose-dependent irreversible infertility. This SLR provides up-to-date evidence to guide the 2024 update of the European Alliance of Associations for Rheumatology recommendations for the use of antirheumatic drugs in reproduction, pregnancy, and lactation.
To investigate respiratory syncytial virus (RSV) vaccine uptake, associations, and breakthrough infection among patients with systemic autoimmune rheumatic diseases (SARDs). We performed a retrospective cohort study investigating RSV vaccination among patients with SARDs at Mass General Brigham (Boston, Massachusetts, USA). We identified all patients with SARDs who were aged ≥ 60 years and thus eligible to receive the RSV vaccine between May 2023 and February 2025. We used multivariable logistic regression to identify factors associated with RSV vaccination. Among the vaccinated, we described documented cases of laboratory-confirmed breakthrough RSV infection. Among 10,587 patients with SARDs (median age 71.7 years, 72.4% female) eligible for RSV vaccination, 1075 (10.2%) received RSV vaccination. Factors associated with higher odds of RSV vaccination included higher median census-tract household income and comorbidities, such as cancer and interstitial lung disease. Associations with lower odds of RSV vaccination included Black race, lack of previous influenza or COVID-19 vaccinations, and glucocorticoid use. RSV vaccination was not associated with specific SARD types or disease-modifying antirheumatic drugs (DMARDs), including CD20 inhibitors. Among the 1075 who were vaccinated, there were 9 (0.8%) documented cases of RSV breakthrough infection (2 hospitalizations and no deaths).  CONCLUSION: Only 10.2% of eligible patients with SARDs received RSV vaccination. Glucocorticoid users were less likely to receive RSV vaccination, whereas specific SARD types and DMARDs were not associated. Although some predictors of vaccine uptake were observed in this dataset, there are many unmeasured factors that may play a role in vaccine uptake. There were few documented breakthrough infections and no deaths. Future studies are needed to optimize RSV vaccine use and establish safety and efficacy in this vulnerable population.
Systemic Lupus Erythematosus (SLE) presents a significant diagnostic challenge for clinicians due to its diverse clinical manifestations and overlap with other autoimmune conditions. Large Language Models (LLMs) are currently regarded as having the potential to assist clinicians in expediting decision-making. This study aimed to evaluate the performance of four LLMs in differentiating SLE from clinically mimicking conditions. A retrospective diagnostic accuracy study was conducted involving 100 patients at a rheumatology center: 50 patients with confirmed SLE and 50 non-SLE patients with conditions including rheumatoid arthritis, systemic sclerosis, axial spondyloarthritis, psoriatic arthritis, myositis, ANCA-associated vasculitis, mixed connective tissue disease, undifferentiated connective tissue disease, and fibromyalgia. Four LLMs were evaluated: Deepseek, ChatGPT 4.0, Claude Sonnet 4, and Gemini. The 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) classification criteria were applied. Diagnostic accuracy, positive predictive value (PPV), negative predictive value (NPV), and Area Under the Receiver Operating Characteristic Curve (AUC) were calculated. IBM SPSS Statistics version 25 was used for all analyses. Gemini achieved the highest performance score, with an accuracy of 96% (95% CI: 91.2-100.0%), sensitivity of 94% (95% CI: 89.3-98.7%), specificity of 98% (95% CI: 93.1-100.0%), and an AUC of 0.960. ChatGPT 4.0 and Claude Sonnet 4 exhibited comparable accuracy. Deepseek recorded the lowest performance score. Gemini demonstrated significant potential to assist clinicians in differentiating SLE from mimicking conditions. Nevertheless, prospective validation in real-world clinical settings is required before these tools can be reliably integrated into clinical practice.
The presence of immunoglobulin A (IgA) autoantibodies has been described in many autoimmune diseases, and some of its characteristics, such as IgA dimerization, are considered a sign of a mucosal origin. However, limited information is available about the (patho)physiological conditions leading to the development of monomeric vs dimeric (autoreactive) IgA in humans. Therefore, we investigated IgA dimerization in rheumatic autoimmune diseases with a possible mucosal origin, as well as after vaccination. Plasma of patients with rheumatic disease (rheumatoid arthritis [RA], systemic sclerosis [SSc], anti-neutrophil cytoplasmic antibody associated vasculitis [AAV], systemic lupus erythematosus [SLE]), SARS-CoV-2 vaccinated healthy individuals, and healthy controls was used for size exclusion chromatography (SEC). Enzyme-linked immunosorbent assays were performed on SEC fractions to determine the size of IgA. Results were confirmed using western blot and tandem mass spectrometry. The proportion of dimeric IgA was increased for autoantibodies compared to total IgA. This was most evident in RA, AAV, and SLE (dimeric autoreactive IgA ≈ 60%-80% vs total IgA ≈ 20%, SLE ≈ 60% total IgA), but not in SSc. Intramuscular vaccination against SARS-CoV-2 also led to an increased proportion of dimeric anti-spike IgA shortly after vaccination, irrespective of previous mucosal exposure. These findings indicate that dimeric (autoreactive) IgA responses are associated with newly emerging antigen-specific immune activation, where production temporarily shifts to dimeric IgA. Mucosal triggering is not necessarily always involved in these IgA immune responses. These findings provide key insights into the circumstances for IgA dimerization and suggest that dimeric IgA could serve as a marker for immunological disease activity in autoimmunity.
Autoimmune rheumatic diseases (ARDs) often affect women during their reproductive years, and early studies of pregnancy in these patients reported high rates of adverse outcomes. Continuation or initiation of safe and effective medications in the preconception period is beneficial for maintaining or achieving disease quiescence throughout pregnancy thereby improving both maternal and pregnancy outcomes. The European Alliance of Associations for Rheumatology, the American College of Rheumatology, and the British Society for Rheumatology have published recommendations and guidelines regarding management of ARDs during pregnancy. The American College of Obstetricians and Gynecologists and the American Gastroenterological Association have also provided guidance statements with relevant recommendations. This review provides an overview of available recommendations for medication use in ARD pregnancy, with discussion of safety considerations for maternal and fetal well-being. Medications considered compatible with pregnancy include hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine, tacrolimus, and TNF inhibitors. Methotrexate, mycophenolate, leflunomide, and cyclophosphamide should be avoided before and during pregnancy. Other medications, most of them newer, are largely discouraged for use in pregnancy due to inadequate data or concerns for neonatal immunosuppression, including non-TNF biologics and small molecule therapies. Further investigation is needed regarding effects of non-TNF biologics, biosimilars, and small molecules in pregnancy. Important efforts for the future will include improved methodologies to gather critical safety data, with consideration of inclusion of pregnant women in clinical trials, a complex and controversial issue. Long-term information on outcomes in offspring of treated women is lacking for many of these medications.
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.
Real-world practice patterns of eosinophilic granulomatosis with polyangiitis (EGPA) remain poorly defined. This study aimed to describe current diagnostic and therapeutic approaches across experienced European centres, identifying areas of convergence and variability to inform future standardization of care. We distributed a 44-item online survey covering diagnostic evaluation, treatment strategies, patient-reported outcome measures (PROMs) and the role of patient advocacy groups. The survey was reviewed by an expert panel and disseminated within the European EGPA Study Group. Responses were collected anonymously between April and August 2025 for statistical analysis. Fifty-four experts from six countries participated, most with long-standing experience and substantial EGPA caseloads. Multidisciplinary care and screening for cardiac and renal involvement were widely adopted; histological confirmation was reported in fewer than 25% of cases. Treatment strategies varied considerably: over half of respondents initiated anti-IL-5 therapy at diagnosis, and the combination of glucocorticoids, rituximab and mepolizumab was the preferred induction regimen in severe disease. CS tapering protocols differed, with most clinicians targeting withdrawal within 12 months. PROMs and disease-specific questionnaires were used inconsistently, despite broad recognition of their value. Advocacy groups were viewed as crucial, particularly for patient education and referral. This first multinational survey reveals substantial heterogeneity in real-world diagnostic and therapeutic practice, reflecting gaps in validated criteria, standardized activity measures and treatment algorithms. These findings highlight the need for coordinated prospective research and harmonized evidence-based guidance to optimize outcomes for patients with EGPA.
To determine the incidence, predictors and impact of pneumonia among hospitalized patients with ANCA-associated vasculitis (AAV). A nationwide retrospective analysis of Spanish hospital discharges (2016-2023) identified all AAV admissions and coexisting pneumonia using ICD-10 codes. Outcomes included pneumonia incidence, intensive care unit (ICU) utilization, length of stay, temporal trends, in-hospital mortality and case fatality rate (CFR). Illness severity was classified using the severity of illness (SOI) and risk of mortality (ROM) indices. Multivariable logistic regression was used to identify independent predictors of in-hospital mortality. Among 12 378 AAV hospitalizations, 1280 (10.3%) had pneumonia. Pneumonia was associated with higher ICU admission rates (13.5% vs 6.5%), longer stays (median 22 vs 17 days), and greater in-hospital mortality (14.9% vs 4.4%) than those without pneumonia (all P < 0.001). In-hospital AAV mortality increased significantly over time (incidence rate ratio [IRR], 1.13 per year; P < 0.001). Viral pneumonia cases in AAV surged during the COVID-19 pandemic (2021-2022), declined by 2023, and showed a significant overall increase across the study period (IRR, 1.46; 95% CI: 1.38, 1.54; P < 0.001). In-hospital CFR rose sharply with extreme SOI (27.1% vs 18.7%; P < 0.001). Pneumonia was an independent predictor of death (odds ratio 1.97; 95% CI: 1.63, 2.37; P < 0.001), and a higher ROM was strongly associated with mortality risk. Around 1 in 10 hospitalizations with AAV develop pneumonia, which is associated with higher odds of in-hospital death and greater ICU utilization. Pneumonia is strongly associated with worse outcomes in AAV, supporting the need for proactive infection prevention and early treatment in AAV.
This study describes data from bronchoscopies performed at the diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA) in Chinese patients. We conducted a retrospective study between May 2005 to May 2023 in patients with EGPA who underwent bronchoscopy at the initial diagnosis of the disease. Clinical manifestations and bronchoscopic findings were analysed. 109 patients with EGPA were included, 59 males (54.1%). The most common clinical manifestations were asthma in 104 patients (95.4%), rhinosinusitis in 101 patients (92.7%), and peripheral neuropathy in 70 patients (64.2%). Eosinophilia (>1.0×109/L) was present in 87 patients (79.8%). ANCA positivity was found in 18 patients (16.5%). The most common chest imaging findings were ground-glass opacities in 61 patients (56.0%), bronchial wall thickening and bronchiectasis in 53 patients (48.5%), and consolidation in 52 patients (47.7%). All 109 patients underwent bronchoscopy at diagnosis of the disease. The most common bronchoscopic findings were mucosal oedema and inflammatory changes in 95 patients (87.2%), with specific changes being less common, including tracheobronchial stenosis in 12 patients (11.0%), mucosal nodules and masses in 10 patients (9.2%), and bleeding in 1 patient (0.9%). Transbronchial biopsy (TBB) was performed in 93 patients, with 76 (81.7%) showing pathological support for EGPA, including eosinophilic infiltration in 72 patients (77.4%), vasculitis in 23 patients (24.7%), and granulomas in 7 patients (7.5%). 2 patients underwent transbronchial needle aspiration biopsies of mediastinal lymph nodes, and pathology revealed eosinophilic infiltration and granulomas in both cases. Bronchoalveolar lavage (BAL) was performed in 89 patients, with 67 (75.3%) showing eosinophilia (>1%), and the median percentage of eosinophils was 9 (1, 33%). Bronchoscopy plays a crucial role in patients with EGPA by detecting endobronchial lesions, providing definitive pathological evidence, and identifying eosinophilic infiltration or
This study aimed to validate the German version of the ANCA-associated vasculitis patient-reported outcome (AAV-PRO) measure by evaluating its psychometric properties. Our study was a prospective cohort study of German speaking AAV patients, recruited in the rheumatology outpatient clinics at the University Hospital Düsseldorf. The questionnaire includes 29 items across six domains, each rated from 0 to 4 points. Participants completed the AAV-PRO (German) at three time points. They also completed the EuroQol-5D-5L (EQ-5D-5L) and self-reported their vasculitis status. The Birmingham Vasculitis Activity Score version 3 (BVASv3) and Vasculitis Damage Index (VDI) were completed by the treating physicians. 70 AAV patients (48.5% female) participated. Overall, fatigue was the most prevalent symptom. Female AAV patients reported higher symptom burden across all domains and had a higher total score (Z=-2.55, p=0.011). The AAV-PRO (German) demonstrated good internal consistency in the domains "social and emotional impact", "concerns about the future" and "physical function" (Cronbach's alpha≥0.83). The domain "systemic symptoms severity" demonstrates acceptable to good consistency. The other domains demonstrated insufficient consistency. All domains showed high test-retest reliability (Pearson r≥0.8). BVASv3 and VDI showed limited correlations with the AAV-PRO (German) domains. Construct validity was supported by moderate to strong correlations with the EQ-5D-5L in five domains. Patients with self-reported active disease had statistically significantly higher mean scores than those with self-reported inactive disease in three domains. Our study supports the use of the AAV-PRO (German). However, two domains need to be interpreted carefully.
The pathogenic roles of the complement system in many human diseases have become increasingly understood, in large part through the results of informative clinical trials. In addition, based on biomarker studies in patients and results of murine models, there are an increasing number of indications under consideration for the use of therapeutics targeting different components of the pathway. Here, lessons learned from several of these studies are reviewed, with an emphasis on diseases of clinical and research interest to rheumatologists. Publications focused on the complement-related pathogenesis and clinical trials of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and rheumatoid arthritis (RA), in addition to studies relevant to other diseases, are summarised. Following translational studies demonstrating activation in affected tissues and blood from patients, the potential pathogenic roles of complement in AAV and RA were studied in murine models. These studies suggested in both diseases that complement alternative pathway generation of C5a is a primary driver of target organ damage. In AAV, clinical trials using a novel small molecular oral C5a anaphylatoxin receptor (C5aR1) antagonist revealed a substantial corticosteroid-sparing effect and initial evidence of clinical benefit. With regard to RA, although there is strong support through biomarker and murine model studies, intervention with C5 and C5aR1 inhibitors revealed only modest benefit, and additional work is necessary to determine if different targets or timing of intervention is necessary. Beyond AAV and RA, a substantial number of additional diseases cared for by rheumatologists exhibit evidence of complement activation in a potentially pathogenic manner. Inappropriate activation of the complement pathway mediates tissue inflammation and damage in many human diseases, including key ones cared for by rheumatologists.
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.
To evaluate the risk of severe infection and examine the secular change in infection counts among patients with newly diagnosed antineutrophil cytoplasmic antibody-associated vasculitides (AAV). We conducted an age- and sex-matched cohort study of all patients with incident AAV, using administrative health data from British Columbia (1997-2022). We used multivariate Cox proportional hazard models to compare the time to the first severe infection after AAV onset. To examine long-term risk patterns of repeated severe infections, we used a zero-inflated Poisson mixed model. Among 1626 AAV patients and 16,260 matched controls, AAV patients had a higher adjusted hazard ratio for first severe infection (HR = 2.83; 95% CI = 2.41-3.33). The trajectory analysis revealed that AAV patients at the time of disease onset had higher odds of being at risk of severe infection (OR = 9.87). The odds of being at risk of severe infection remained unchanged for AAV patients over time. The rate of severe infection counts for the AAV patients at risk was greater (RR = 2.86) at the disease onset, reduced annually by 23% (RR = 0.77) for the first 2 years, but increased annually by 7% thereafter (RR = 1.07). AAV was associated with an increased risk of severe infections, affecting one in three patients. While this increased risk decreased over time, AAV patients who were still at risk exhibited an increasing rate of recurrent infections beyond 2 years post-diagnosis. This highlights the urgent need for targeted strategies in these vulnerable AAV patients. Key Points • No incident cohort study with a large sample size has examined the association between AAV and the risk of severe infection after accounting for potential confounders. • One in three patients with newly diagnosed AAV developed severe infection (2.8-fold when compared to non-AAV). AAV patients