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.

OBJECTIVE:Lupus nephritis (LN) is characterized by a variable disease course, necessitating continuous monitoring. There is an urgent need to identify noninvasive biomarkers. By reviewing and critically assessing the quality of existing studies on LN biomarkers correlating with histopathology, we here explore the challenges in promoting their use in clinical practice and identify promising candidates for future validation. METHODS:A systematic literature search was conducted, including studies on adult patients with biopsy-proven LN published between 2012 and 2024. The search focused on studies demonstrating correlations between biomarkers and histologic findings, particularly the National Institutes of Health activity and chronicity indices, the International Society of Nephrology/Renal Pathology Society histologic classes, and specific active and chronic lesions. The quality of selected articles was assessed by a multidisciplinary panel of experts using a standardized scoring system. RESULTS:Ninety-three articles investigating the potential utility of >100 biomarkers were selected. In quality assessment, 68% of the articles were weak or very weak (score <5, scale 2-9). From the remaining articles (adequate or robust) we identified five biomarkers with a potential for implementation in clinical practice: transforming growth factor β1, pentraxin-3, (soluble) CD163, CD11b, and interleukin-16. CONCLUSION:The methodologic heterogeneity across studies and the overall moderate score of the quality of the articles represent obstacles to the implementation of new biomarkers into clinical practice. The LN working group advocates further research on selected biomarkers that demonstrated good capacity to reflect specific histopathologic features outperforming traditional tests. At present, the choice of biomarkers that perform to these standards is very limited.

IgA vasculitis (IgAV) is an autoimmune disease that affects the small vessels of the skin, joints, gastrointestinal (GI) tract, and kidneys. In the long term, IgAV associated with nephritis (IgAV-N) can progress to kidney failure. Evidence-based clinical studies of IgAV-N are few, leading to huge variations in treatment approaches and suboptimal outcomes. The wealth of emerging efficacious treatments for IgA nephrology brings new opportunities to this disease. The aim of this report is to describe the proceedings of a multiprofessional collaborative workshop convened to identify the barriers to developing high quality evidence for patients with IgAV-N. A multiprofessional group consisting of 53 attendees from 13 countries met. The meeting was represented by a variety of professional backgrounds, including lay attendees, with different levels of expertise (32% professors and 19% midcareer doctors). Using predefined aims, key themes were extracted, and an action plan developed. Consensus was obtained that there is sufficient similarity between adults and children in terms of the organs involved, pathophysiology, histological features, and likely response to treatment. Important differences included the greater spontaneous improvement in children and worse kidney outcomes in some populations. It was agreed that patients at greatest risk of kidney failure should be the primary focus of initial clinical trials. Important considerations included the following: diagnostic classification for adult onset IgAV, observational data, evidence of scientific similarity to IgA nephropathy (IgAN), an age-inclusive approach to trial design, systemic disease secondary end points, and the inclusion of patient-reported outcomes. This manuscript communicates an expert-informed pathway to high-quality evidence for IgAV-N.

OBJECTIVE:Older patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are underrepresented in clinical trials, and long-term outcome data in this group are limited. We evaluated treatment approaches and outcomes among hospitalized older patients with AAV. METHODS:We retrospectively collected clinical and laboratory data on all hospitalized patients aged 75 years or older who commenced remission induction with cyclophosphamide- or rituximab-based regimens for severe AAV between 2014 and 2021. RESULTS:Eighty-four patients were included (median age 79, range 75-93), with a median follow-up of 21 months (interquartile range 12-44). Choice of induction regimen was influenced by age and frailty: the rituximab-cyclophosphamide combination was more commonly used in younger patients within the cohort, while low-dose rituximab was favoured for the oldest and most frail, including those requiring residential or nursing home care. The distribution of regimens was as follows: rituximab-cyclophosphamide combination (11.9%), cyclophosphamide (26.2%), standard-dose rituximab (39.6%) and low-dose rituximab (22.3%). Serious infection requiring hospital readmission occurred in 27% of patients within the first year, with rates of 37.5%, 23.8%, 25.8% and 31.6% across the respective treatment groups. One-year mortality was 20% overall (by treatment group: 10%, 23%, 14% and 26%). Increasing age was associated with higher mortality (hazard ratio [HR] 4.15; 95% CI: 1.62, 10.6), but not with serious infection (HR 1.18; 95% CI: 0.47, 2.93). CONCLUSION:Considering the enrichment for hospitalized patients with severe disease and advanced age, a mortality rate of 20% at 1 year that is comparable to less severe and younger cohorts suggests tailoring remission induction strategy according to a holistic assessment of frailty and disease activity may partially mitigate the higher risk of infection and mortality with advancing age.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of rare, autoimmunologic diseases that can manifest as a vital organ- and / or life‑threatening disorder. They are classified as small‑vessel vasculitis. Inflammatory infiltrations cause destruction and necrosis of the vessel wall, as well as occlusion of the vessel lumen; thus, organs supplied by these vessels become ischemic and damaged. According to the 2012 Revised International Chapel Hill Consensus Conference Nomenclature, AAV comprises 3 distinct diseases, but this review focuses on granulomatosis with polyangiitis and microscopic polyangiitis. Quick diagnosis and prompt initiation of intensive immunosuppressive therapy are crucial to prevent an unfavorable outcome in patients with AAV. Recent years have brought development in therapeutic strategies, new immunosuppressive agents, and future perspectives. Our review starts with the description of current diagnostic and long‑term follow‑up strategies, including the role of ANCA, immunoglobulin G, and CD19/CD20 cell monitoring, as well as remission assessment. The following sections present possible induction and maintenance therapies, including cyclophosphamide, rituximab, glucocorticoids, avacopan, and therapeutic plasma exchange, based on current recommendations ofthe European Alliance of Associations for Rheumatology, Kidney Disease: Improving Global Outcomes, and British Society of Rheumatology, as well as results of recent randomized controlled trials and real‑world data. These therapies are particularly relevant for specific clinical conditions, such as rapidly progressive glomerulonephritis and / or pulmonary hemorrhage. We describe in detail a new, promising molecule, avacopan, which acts by blocking the C5a receptor on neutrophils and other cell types. Avacopan is currently approved by the Food and Drug Administration and the European Medicines Agency but rigorous liver function monitoring-specifically the activity of alanine aminotransferase and aspartate aminotransferase and bilirubin level-before and during the treatment course is required to ensure the safe delivery of this steroid-sparing therapy. Recently, in April 2026 the Food and Drug Administration proposed to withdraw approval for avacopan due to, among others, a lack of substantial evidence of effectiveness for the drug.

Abstract Background Glomerulonephritis (GN) accounts for 20%–25% of the causes of chronic and end-stage kidney disease. The evolving treatment landscape with new targeted immunosuppressants has highlighted the unmet need for equity of access to specialist GN services. Regional networks and multidisciplinary team meetings (MDTs) provide access to clinical expertise, high-cost drugs (HCDs) and clinical trials, facilitating collaborative decision-making and optimal use of therapeutics to improve patient outcomes. Launched in May 2023 in the East of England (EoE), the Eastern Network Kidney Inflammatory Disease MDT (ENKID) provides a regional MDT framework designed to improve access to specialist expertise and HCDs- areas identified as lacking for 59% of nephrologists in a 2024 UK GN service survey. Methods ENKID is led by the specialist vasculitis, lupus and primary GN service in Cambridge. A database build allows secure standardised data collection including referral indications and treatment decisions during fortnightly virtual regional MDTs. Results Over 24 months, 229 discussions were conducted for 198 patients in 43 ENKID MDTs, averaging 15 attendees from 6 centres per meeting. Patients were referred for both clinical complexity and HCD use in 46% (n = 106), solely HCD access in 42% (n = 96) and for clinical complexity alone in 12% (n = 27). Clinical trial eligibility was an additional reason in 9% (n = 20). Diagnoses discussed were ANCA-associated vasculitis (33%, n = 65), membranous nephropathy (18%, n = 35), IgA nephropathy (19%, n = 38), lupus nephritis (15%, n = 29), minimal change disease/focal segmental glomerulosclerosis (7%, n = 14), rarer diseases (5%, n = 10) and diagnostic uncertainty (3%, n = 7). Including rituximab, a HCD was endorsed in 71% and alternative treatment recommended in 29% of referrals for HCD discussions. A wide geographical distribution of referrals was observed and facilitated widespread access to HCDs. Conclusions The ENKID regional MDT addresses the increasing demand for specialist advice for patients with complex and rare kidney diseases. High attendance and case load underscore the need for this service, aligning with the UK government’s mandate for rare autoimmune disease. Integration of this MDT within the EoE NHS England renal network structure, providing governance, education and HCD access, serves as an exemplar for improving GN patient care and accessibility of UK services. Clinical trial number Not applicable.

OBJECTIVE:Eosinophilic granulomatosis with polyangiitis (EGPA) is a small vessel vasculitis characterized by eosinophilia, asthma, and ear, nose, and throat (ENT) involvement. Although glucocorticoids (GCs) are effective in controlling symptoms, relapses and GC dependence are common. The aim of this study was to develop predictive models for vasculitis relapse and GC-dependent asthma and/or ENT symptoms. METHODS:This multicenter European retrospective cohort study included patients with EGPA fulfilling the 2022 American College of Rheumatology/EULAR criteria. Using Fine-Gray and logistic regression, we developed two multivariable prediction models, one for vasculitis relapse and another for GC-dependent asthma and/or ENT symptoms at 2 Internal validation was performed using bootstrapping. RESULTS:A total of 809 patients were observed for a median of 72 months (interquartile range 37-115). Vasculitis relapse occurred in 228 patients with a 12-year cumulative incidence of 41.2% (95% confidence interval 36.3-46.8). GC-dependent asthma and/or ENT symptoms were observed in 66.4% at two years. Predictors of vasculitis relapse included age (nonlinear), GC-dependent asthma before EGPA diagnosis (hazard ratio [HR] 1.57), arthralgia (HR 1.27), myocarditis (HR 1.74), peripheral neuropathy (HR 1.39), myeloperoxidase-antineutrophil cytoplasmic antibody (HR 1.56), and baseline eosinophil count (nonlinear). Predictors of GC-dependent asthma and/or ENT symptoms included older age (odds ratio [OR] 0.98 per year), GC-dependent asthma at diagnosis (OR 1.50), chronic sinusitis (OR 1.78), and baseline eosinophil count (OR 0.70 per 109/L). CONCLUSION:Using a large cohort with EGPA, we developed predictive models for vasculitis relapse and GC-dependent asthma and/or ENT symptoms. These tools may help guide treatment decisions. Prospective external validation in the current therapeutic era is warranted.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are systemic small-vessel necrotizing vasculitides, including microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Genetic factors, particularly human leukocyte antigen (HLA) variants, contribute to disease susceptibility and define distinct myeloperoxidase (MPO) and proteinase-3 (PR3) associated phenotypes. This review summarizes current understanding of organ-specific manifestations, therapeutic advances, and prognostic determinants of AAV, with particular relevance for nephrologists. Kidney involvement is common, particularly in MPA, whereas GPA and EGPA more frequently present with extrarenal manifestations. Pulmonary involvement is also frequent, ranging from alveolar haemorrhage and interstitial lung disease (ILD) in MPA to granulomatous nodules and airway disease in GPA, while asthma dominates in EGPA. Other frequent manifestations include ear, nose and throat (ENT), peripheral nervous system, cutaneous, and constitutional manifestations, with ENT activity and non-haemorrhagic respiratory manifestations correlating with relapse risk. Current treatment emphasizes rituximab or cyclophosphamide with reduced-dose glucocorticoids for induction, avacopan for glucocorticoid-sparing strategies, and rituximab for maintenance. Avacopan has shown benefits beyond renal outcomes. Furthermore, anti-interleukin-5 therapies have recently been approved for the treatment of EGPA. Contrarily, ILD remains a therapeutic challenge, with limited evidence for antifibrotic agents. AAV patients are at high risk of infections, thromboembolism, and malignancy, influenced by both disease activity and treatment exposure. Mortality remains high, driven mainly by infections, with kidney and lung involvement serving as major prognostic determinants. For nephrologists, early recognition of extrarenal manifestations, vigilance for relapse beyond the kidney, and multidisciplinary collaboration are crucial for optimizing long-term outcomes.

OBJECTIVES:It is unclear whether clinicians agree which manifestations of ANCA-associated vasculitides (AAV) is associated with necrotizing granulomas or if their presence affects clinical decision-making. METHODS:We surveyed physicians experienced in caring for individuals with AAV, querying: experience with AAV; beliefs concerning how granulomas affect the diagnosis, treatments and outcomes of AAV; beliefs concerning the frequency with which granulomas are found in 36 manifestations of AAV; and degree to which granulomas change choice of induction therapy for specific manifestations of AAV. We analysed responses using descriptive statistics and multivariable linear regression. RESULTS:We received 142 responses from 35 countries. Responses had a median Likert response ≥5 on a seven-point scale (equal to 'partially agree') that granulomatous manifestations respond differently to therapy, increase risk of relapse and increase organ damage. Four of 36 manifestations were believed to be caused by granulomas in a median of ≥75% of cases (on a scale of 0 = never to 100 = always caused by granuloma), 19 in a median of ≤25% of cases, and 13 in intermediate medians. The perceived degree to which granulomas caused manifestations was not associated with changes in therapy to induce remission in severe AAV (P-values 0.26-0.93 across scenarios). CONCLUSIONS:Physicians experienced in vasculitis generally agree on which manifestations of AAV are and are not caused by granulomas and that granulomatous inflammation alters the natural history and treatment of AAV. However, the presence of granulomatous manifestations did not alter treatment choices to induce remission in severe AAV.

BackgroundRituximab is effective for induction and maintenance of remission in relapsing ANCA-associated vasculitis (AAV), but some patients do not achieve complete remission or experience relapse despite treatment. We aimed to describe the frequency, characteristics, and outcomes of patients with suboptimal response to rituximab within the RITAZAREM trial.MethodsPost hoc descriptive analysis, including patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) treated with rituximab for induction (N = 188) and those receiving rituximab maintenance (N = 85). Three scenarios of suboptimal response were examined: (i) failure to achieve protocol-defined remission at month 4 (n = 6); (ii) incomplete remission at month 4, defined as BVAS/WG = 1 (n = 10); and (iii) relapse during rituximab maintenance (n = 13). Data were summarized descriptively. Time to relapse from month 4 in patients with BVAS/WG = 1 versus BVAS/WG = 0 was explored using Kaplan–Meier analysis.ResultsSix of 188 patients (3%) did not achieve protocol-defined remission by month 4, 10 (5%) had residual low-grade disease activity (BVAS/WG = 1), and 13 of 85 patients (15%) receiving rituximab maintenance relapsed within 24 months during maintenance treatment. All patients with BVAS/WG = 1 at month 4 had a history of PR3-ANCA positivity and ear/nose/throat (ENT) baseline manifestations. Relapse occurred more frequently in this subgroup than in patients with BVAS/WG = 0, and time-to-relapse analysis showed shorter relapse-free survival, although interpretation is limited by the small sample size. Most first relapses were minor, and some patients subsequently experienced additional relapses, including major relapses.ConclusionIn this exploratory and hypothesis-generating analysis, a small subset of patients with relapsing AAV showed suboptimal outcomes with rituximab. Residual disease activity at month 4, particularly in patients with PR3-ANCA positivity and ENT involvement, may represent a clinical subgroup associated with an increased frequency of earlier relapse, although this observation requires confirmation.

Abstract Background/Aims Patients with severe, refractory SLE (srSLE) have few treatment options and represent a population with an unmet need. CD19 CAR Ts have potential for deep depletion of the B-cell lineage, including plasmablasts. Obecabtagene autoleucel (obe-cel) is an autologous CD19-directed CAR T with a fast off-rate binding domain designed to reduce immunotoxicity, approved in adult relapsed/refractory B-cell acute lymphoblastic leukaemia. We report initial safety and preliminary efficacy results from the single-arm, open-label, dose-finding, Phase I CARLYSLE study (NCT06333483). Methods Eligible patients (12-65 years old) had SLE per the 2019 EULAR/ACR criteria, a ≥ 8-point SLEDAI-2K score at screening with ≥1 major SLE-related organ involvement, and were refractory to multiple prior standard-of-care medications. Following lymphodepletion with fludarabine (3 × 25 mg/m2) and cyclophosphamide (1 × 1,000 mg/m2), obe-cel was administered as a single starting flat dose of 50 × 106 (±20%) CAR T-cells. Primary endpoints: incidence of dose limiting toxicities (DLTs) within 28 days of infusion; frequency of adverse events. Secondary endpoints included: SLEDAI-2K; PGA; pharmacokinetics (PK); autoantibody and biomarker levels over time. Results As of 17 March 2025, seven patients were enrolled and six infused with obe-cel, with up to 8 months of follow-up. At baseline, all infused patients had active srSLE (SLEDAI-2K range: 15-28), class III or IV lupus nephritis; four also had class V. Four patients had elevated serum creatinine and an estimated glomerular filtration rate of < 60 mL/min/1.73m2; six patients had elevated urinary protein-creatinine ratio. Patients were refractory to B-cell therapies and immunosuppressants (median: 5 prior medicines; range: 5-6). No DLTs or immune effector cell-associated neurotoxicity syndrome (ICANS) occurred. Three patients experienced Grade 1 cytokine release syndrome (CRS) with no Grade ≥2 CRS. Transient/manageable hypertension occurred in five patients and all patients had transient Grade ≥3 neutropenia. Infections were manageable; none were life-threatening. Four patients with ≥3 months follow-up showed ≥10-point SLEDAI-2K reduction and complete resolution of non-renal symptoms within 3 months. Steroids were tapered to ≤ 10mg/day post obe-cel infusion; no other SLE medications were administered. Three of six patients achieved complete renal response (CRR) at last follow-up, one at Month 1 (M1) and two at M3. Complement C3 normalized and anti-double-stranded DNA antibody decreased in all six patients by M1 compared with baseline levels. PK data indicated robust CAR T-cell expansion; peak expansion was reached at a median of 10 days. Three patients had ongoing CAR T-cell persistence at last follow-up. Conclusion Initial findings from the ongoing CARLYSLE study of obe-cel in srSLE show a manageable safety profile, with no DLTs, ICANS or Grade ≥2 CRS. All patients showed SLEDAI-2K score reduction and clinical benefit, including three patients with CRR. Despite the short follow-up and small cohort, initial findings are promising; further research is warranted. Updated data will be presented at the conference. Disclosure M. Leandro: Consultancies; Roche Basel, UCB, GSK. Grants/research support; Roche Basel. Other; PI for Clinical Trials on B-cell targeting therapies: Roche Basel, Autolus Therapeutics, BMS, Artiva, Fate Therapeutics. R. Pepper: Honoraria; Stada Arzneimittel symposium. Other; Advisor/review panel member: Vifor, Roche, Autolus Therapeutics. B. Parker: Honoraria; Otsuka. Grants/research support; LUPUS UK. Other; Advisor/Review Panel Member for Autolus Therapeutics, Conference attendance - UCB. E. Tholouli: Consultancies; Autolus Therapeutics, Bristol Myers Squibb/Celgene, Janssen, Kite/Gilead, Vertex. Honoraria; Amgen, Astellas, Jazz Pharmaceuticals, Kite/Gilead Sciences, Sobi, Pfizer, Takeda, Vertex. Other; Manchester Royal Infirmary. D. Jayne: None. B. Uttenthal: Consultancies; Sartorius, Swarm Oncology, Analog Devices. Honoraria; Kite. Other; Sponsorship to attend conferences: Kyverna, Advisor/review panel member: Kite/Gilead and Kyverna. J. Cortés-Hernández: Honoraria; AstraZeneca, GSK, Novartis. Grants/research support; Novartis. Other; Advisor/review panel member for Novartis; Bristol Myers Squibb. P. Barba: Grants/research support; Allogene, Amgen, Bristol Myers Squibb, InCyte, Gilead Sciences, Jazz Pharmaceuticals, Miltenyi Biomedicine, Nektar, Novartis, Pfizer, Pierre Fabre. J. Román Ivorra: None. Y. Hu: Shareholder/stock ownership; Autolus Therapeutics. Other; Employee - Autolus Therapeutics. W. Brugger: Shareholder/stock ownership; Autolus Therapeutics. Other; Employee - Autolus Therapeutics. S. Basilico: Shareholder/stock ownership; Autolus Therapeutics. Other; Employee - Autolus Therapeutics. D. Germano: Shareholder/stock ownership; Autolus Therapeutics. Other; Employee - Autolus Therapeutics. C. Roddie: Consultancies; Autolus Therapeutics, Bristol Myers Squibb, Gilead, J+J, Miltenyi Biomedicine. Honoraria; Autolus Therapeutics, Bristol Myers Squibb, Gilead, Autolus Therapeutics (Speaking or Teaching), Bristol Myers Squibb (Speaking or Teaching), Gilead (Speaking or Teaching).

Background:Established treatments for granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) include the use of immunosuppressive agents for remission induction followed by maintenance therapy. However, patients continue to experience disease progression, organ damage, and adverse events related to current therapies. Avacopan, an oral selective C5a receptor antagonist, was approved by the European Commission in January 2022 for the treatment of adult patients with severe, active GPA or MPA in combination with rituximab (RTX) or cyclophosphamide (CYC). In the pivotal phase 3 ADVOCATE (Avacopan Development in Vasculitis to Obtain Corticosteroid Elimination and Therapeutic Efficacy) study, avacopan was noninferior to prednisone taper in achieving remission at week 26 and superior in sustaining remission at week 52; furthermore, a greater improvement in estimated glomerular filtration rate with avacopan was also observed at week 52. The AvacoStar study will generate data on the benefit and risk and safety profile of avacopan in patients in a real-world context, including in those where treatment may potentially continue beyond 1 year. Objective:The primary objective of AvacoStar is to evaluate the incidence of defined medical events of special interest in patients with antineutrophil cytoplasmic antibody-associated vasculitis commencing avacopan. These include liver injury, cardiac safety, serious infections, and malignancy. Methods:AvacoStar is a noninterventional, multinational, prospective postauthorization safety study. It will enroll up to 500 patients in Germany and the United Kingdom in 2 groups of approximately 250 participants each: those treated with avacopan (plus a standard of care at local investigators' discretion; usually an RTX- or CYC-based regimen) and a second cohort treated with a CYC- or RTX-based induction regimen without avacopan. Avacopan and the standard of care will be prescribed in the usual manner in accordance with the corresponding summary of product characteristics under the sole decision of the investigator. The treatment decision will fall within current established practice. Eligible participants will be aged ≥18 years with severe, active GPA or MPA as determined by the investigator at the time of commencing avacopan or non-avacopan standard-of-care induction therapy. Patients will be followed for up to 7 years. Results:This study has been enrolling patients since September 11, 2023. The final report is expected in the second half of 2031; interim reports are planned every 24 months after the first patient first visit. Conclusions:The AvacoStar study will be the largest European prospective real-world evidence comparative study conducted to date that evaluates the long-term safety of avacopan in severe, active GPA or MPA. This study is expected to yield important insights on the use of avacopan in severe, active GPA or MPA in a real-world setting.

Abstract Background The phase 3 ADVOCATE trial evaluated the efficacy and safety of avacopan in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Concerns raised regarding the 2019 primary endpoint adjudication process prompted a blinded, independent readjudication of all participants’ primary outcomes, the results of which are described here. Methods Patients with GPA or MPA were randomized 1:1 to receive oral avacopan 30 mg twice daily or oral prednisone on a scheduled taper, each in combination with rituximab- or cyclophosphamide-based standard of care. In 2026, the Duke Clinical Research Institute Clinical Events Classification group conducted an independent, blinded committee readjudicated the Birmingham Vasculitis Activity Score (BVAS), relapse, and remission from weeks 26 through 52 using procedures aligned with the original adjudication charter. The primary endpoints were remission at week 26 and sustained remission at week 52. As per the original analysis plan, noninferiority and superiority were declared if the lower bounds of the 95% confidence interval (CI) for the difference in the primary outcome rates between avacopan and a prednisone taper were greater than −20.0 and 0.0 percentage points, respectively. Results Among 330 participants in the intent-to-treat population, remission at week 26 was achieved by 68.1% (113/166) and 67.1% (110/164) of participants in the avacopan and prednisone taper groups, respectively, in the 2026 readjudication (adjusted difference: 2.2%; 95% CI, −7.5, 11.9), compared with 72.3% (120/166) and 70.1% (115/164) in the 2019 primary outcome adjudication (adjusted difference: 3.4%; 95% CI, −6.0, 12.8). Sustained remission at week 52 was achieved by 61.4% (102/166) and 52.4% (86/164) of participants, respectively, in the 2026 readjudication (adjusted difference: 9.8%; 95% CI, −0.3, 19.9), compared with 65.7% (109/166) and 54.9% (90/164) in the 2019 readjudication (adjusted difference: 12.5%; 95% CI, 2.6, 22.3). Concordance between the 2019 and 2026 adjudications was 95.2% for remission and 93.6% for sustained remission. Conclusion The re-analysis of ADVOCATE based on the 2026 readjudication further supports the efficacy of avacopan for GPA/MPA. Non-inferiority of avacopan versus a prednisone taper was confirmed at weeks 26 and 52 despite a median 81% reduction in glucocorticoid exposure observed in the avacopan versus prednisone taper groups. While a consistent numerical difference favoring avacopan at week 52 was observed in the 2019 and 2026 analyses, this difference did not reach statistical superiority.

Background:Kidney biopsy is the gold standard for lupus nephritis (LN) diagnosis, with the 2018 International Society of Nephrology (ISN)/Renal Pathology Society (RPS) histopathological classification widely used for prognosis and treatment decisions. A survey assessing the use of the 2018 ISN/RPS classification in daily practice was recently conducted on behalf of the RPS. Methods:An online survey was sent to active RPS members after a webinar that introduced RPS members to the topic. The survey contained multiple choice and open-ended questions and remained open 30 days for completion. Results were analysed anonymously. Results:Of 562 RPS members, 185 (32.9%) replied to the questionnaire; 180 (97.8%) were pathologists and 120 of these (64.8%) indicated they encounter >20 biopsies with LN per year. The 2018 ISN/RPS classification and the modified National Institutes of Health activity/chronicity indices are used by 92.4% and 88.1% of respondents, respectively. Respondents rated the utility of both systems with a median score of 8 (interquartile range 7-9) on a 1-10 scale. Suggested improvements to the current classification system include greater standardization and simplicity, clearer definitions for grey-zone entities and the introduction of guidelines for new parameters and biomarkers. Conclusions:This study shows that the 2018 ISN/RPS LN classification is widely used in everyday practice by pathologists. Our results highlight the need for ongoing refinement to facilitate targeted treatment decisions, particularly considering evolving phenotypes and therapeutic advancements in LN.

IgA vasculitis (IgAV) is an immune complex-mediated small-vessel vasculitis that typically affects the skin, gastrointestinal tract, kidneys and joints. Childhood-onset IgAV is a common disease and usually follows a self-limiting course, whereas adult-onset IgAV is considerably less frequent and is associated with a poorer prognosis. The diagnosis, assessment and management of adult-onset IgAV remain challenging owing to the absence of validated diagnostic criteria for adults and lack of IgAV-specific standardized disease activity scores. Short-term outcomes are mainly determined by gastrointestinal complications, whereas kidney involvement and the risk of progression to chronic kidney disease are the major determinants of long-term prognosis. The treatment of adult-onset IgAV is limited by the paucity of high-quality clinical trials and standardized therapeutic approaches. Here, we present evidence-based, multidisciplinary guidelines for the diagnosis and management of adult-onset IgAV that reflect advances in understanding of pathogenesis, differential diagnoses and treatment over the past two decades. Developed by a panel of leading European experts on the basis of systematic literature review and expert opinion, these guidelines comprise 14 recommendation statements and overarching principles that provide a structured and pragmatic clinical framework for the diagnosis, treatment and follow-up of adult-onset IgAV.

In patients with systemic lupus erythematosus (SLE), increased type I interferon signaling is associated with increased disease activity across organs, including in the kidney, which can cause lupus nephritis (LN). Anifrolumab, which abrogates type I interferon signaling, is an approved treatment for moderate to severe SLE. In a phase 2 trial in patients with LN (TULIP-LN; NCT02547922), promising clinical benefit was observed with an intensified regimen (IR) of intravenous anifrolumab (3× 900 mg Q4W, 300 mg thereafter) compared with the approved SLE dose (basic regimen [BR], 300 mg Q4W). Anifrolumab clearance was greater with higher levels of proteinuria; however, the quantitative relationship between proteinuria and anifrolumab exposure was not fully characterized. Here, we describe a mathematical model of time-varying anifrolumab pharmacokinetics, 24-hour urine protein-creatinine ratio (UPCR24), and investigational product discontinuation in patients with LN. The model evaluated both TULIP-LN anifrolumab dosing regimens (IR and BR) and revealed a temporal association between clearance and proteinuria in patients with LN, with each mg/mg UPCR reduction resulting in a 21% decrease in linear anifrolumab clearance. Our model indicated that an intensified regimen including 6 initial anifrolumab 900 mg doses provided adequate exposure and rapid UPCR24 reduction. Higher anifrolumab exposure and reduced UPCR24 were each associated with decreased risk of treatment discontinuation. These model results guided the selection of an optimized, longer intensified anifrolumab dosing regimen (6× 900 mg Q4W, 300 mg thereafter) for the ongoing phase 3 IRIS trial (NCT05138133).

OBJECTIVE:Interstitial lung disease (ILD) can occur in association with antineutrophil cytoplasmic antibody (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 multicenter retrospective study encompassed patients with AAV-ILD or ANCA-ILD. Baseline and subsequent chest computed tomography studies were centrally reviewed. Primary outcomes included forced vital capacity % (FVC%) decline, respiratory failure, and mortality. RESULTS:Of 162 patients (myeloperoxidase [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%), whereas half had a radiologic fibrosis grade >10%. Kidney involvement was present in 73%, most commonly Berden focal class. UIP and nonspecific 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 a higher fibrosis severity grade. Respiratory failure (19%) was associated with fibrosis severity (grade 4 hazard ratio [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.

ObjectiveThis study aimed to characterize the occurrence of hypogammaglobulinaemia (HG) in rituximab (RTX)-treated patients with ANCA-associated vasculitis (AAV) in a population-based Swedish cohort.MethodsPatients with incident AAV (1997–2019) in southern Sweden who received RTX for induction or maintenance therapy were included in this study. Medical records were reviewed to assess the incidence of HG (defined as total IgG < 6.7 g/L; mild 5–6.7, moderate 3–4.9, severe <3), as well as demographics, serology, and treatment history. Incidence rates and predictors of HG were analyzed. Follow-up was extended from the first RTX administration to the onset of HG, death, or the end of the study period (March 2023).ResultsEighty-four patients [51% female; granulomatosis with polyangiitis (GPA), n = 57; microscopic polyangiitis (MPA), n = 25; eosinophilic granulomatosis with polyangiitis (EGPA), n = 2] received RTX and were followed for a total of 236 person-years (py). HG occurred in 38 patients (45%), yielding an incidence rate of 16.1 (95%CI 11–21.2) per 100 py. A sensitivity analysis excluding 14 patients with preexisting HG identified 24 incident HG cases, corresponding to an incidence rate of 17.6 (95%CI 10.6–24.7) per 100 py. Among those who developed HG, the condition was mild in 26 (68%) patients, moderate in 10 (26%), and severe in two patients (5%). Baseline IgG levels were significantly lower in patients who subsequently developed HG, whereas age, clinical characteristics, and other laboratory findings did not differ between groups. Severe infections occurred in 23 patients (35%); five of these infections occurred after the onset of HG, and three occurred before HG onset. The median time to HG development was 3.5 (IQR 0.7–6) months. A lower baseline IgG level was identified as an independent predictor of HG (HR 0.85 per 1 g/L increase; 95%CI 0.76–0.95).ConclusionHG is a common complication in RTX-treated patients with AAV; however, in this cohort, it was not associated with an increased risk of severe infections. A low baseline IgG level was an independent predictor of subsequent HG development, underscoring the importance of close IgG monitoring both before and during RTX therapy.

Advances in the understanding of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis have influenced both treatment strategies and approaches to disease monitoring. While conventional therapies remain the foundation of care, introducing targeted biologics, complement pathway inhibitors, and emerging cellular treatments have broadened therapeutic options to minimise adverse effects, reduce glucocorticoid requirements, and enhance disease control. Nevertheless, many patients still face frequent relapses, progressive tissue damage, and chronic impairments in quality of life. Existing definitions of remission underestimate ongoing disease activity and impact, and interpretation of residual symptoms can be challenging, especially in the absence of overt inflammation. There is a growing interest in personalised management to address these limitations, using biomarkers to better predict relapse risk, differentiate between active disease and residual damage, and guide treatment intensity. Effective long-term care now requires suppression of disease activity and careful management of treatment-related complications, comorbidity risks, and patient-experienced outcomes. Optimising care in ANCA-associated vasculitis will depend on integrating therapeutic innovation with a sustained focus on outcomes that matter most to patients, including durable remission, functional recovery, and improved day-to-day well-being.