OBJECTIVE:The objective of the study was to determine risk factors for relapse of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) after reinduction of remission with rituximab and discontinuation of maintenance therapy. METHODS:This is a post hoc analysis of the RITAZAREM clinical trial. Patients aged 15 years or older with AAV and a positive test for anti-proteinase-3 or anti-myeloperoxidase-ANCA who achieved remission after reinduction with rituximab and glucocorticoids were randomized at month 4 to receive continued rituximab or azathioprine for a maintenance period up to 24 months, followed by observation until relapse or up to 48 months. Generalized estimating equations logistic regression identified baseline and time-varying risk factors for relapse by the next visit for the two study phases: maintenance (months 4-24) and off-treatment (months 24-48). RESULTS:Among 170 patients (median [interquartile range] age 59 [48-68] years, disease duration 5 [2-10] years), 99 relapses occurred (46 during maintenance). During maintenance, musculoskeletal involvement (odds ratio [OR]: 2.8, 95% confidence interval [CI]: 1.1-7.2; P = 0.03) and higher patient global assessment (OR: 1.1, 95% CI: 1.0-1.2; P = 0.04) were associated with relapse. During the off-treatment phase, presence of CD19+ B cells (OR: 2.5, 95% CI: 1.2-5.1; P = 0.01) and reappearance of ANCA (OR: 3.2, 95% CI: 1.3-7.7; P = 0.01) were each associated with higher relapse risk. Multivariable analysis identified markers of inflammation (changes in platelets, white blood cells, and IgA) associated with relapse. CONCLUSION:Risk factors for relapse in AAV vary by treatment phase. Monitoring markers of inflammation and immune reconstitution may identify patients at risk for relapse, particularly after treatment withdrawal.

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.

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.

Despite introduction of vaccination against SARS CoV-2, there remains a need for pre-exposure prophylaxis in patients that mount suboptimal vaccine responses. Sotrovimab is a recombinant human monoclonal antibody directed against the spike protein of SARS-CoV-2. The COMET-ICE study demonstrated that 500mg intravenous (IV) sotrovimab significantly reduced all-cause hospitalization or death in high-risk non-hospitalised patients with mild/moderate COVID-19 infection.Table 2:Number and severity of COVID-19 infections at week 12 (primary efficacy endpoint)*cumulative cases of COVID-19 infection, so includes cases reported in row(s) above.# cases reported before and after 15 December 2023 equate to the total number of symptomatic COVID-19 infections at week 12. PROTECT-V is a platform trial evaluting prophylactic interventions against SARS-CoV2 infection in vulnerable adult patients at high risk of COVID-19 infection and its complications, including dialysis patients, transplant recipients, those with autoimmune diseases, underlying immunodeficiency or haematological/oncological diagnoses. Sotrovimab was the second agent added to the platform. Participants were randomized 1:1 to one dose of IV sotrovimab 2000mg or matched placebo. The primary endpoint was confirmed symptomatic COVID-19 infection at week 12.Table 3:Safety and Tolerability of 2000mg intravenous Sotrovimab 619 (314 placebo, 305 sotrovimab) patients in the UK were randomized between August 2022 and May 2024. 588 (297 placebo, 291 sotrovimab) received investigational medicinal product infusion. Overall, median age was 64.4 years and 50.5% were female (see Table 1: Baseline characteristics). At week 12, 21 symptomatic COVID-19 infections were observed in the placebo group and 17 in the sotrovimab group with a risk ratio of 0.80 (95% CI 0.42– 1.53) adjusting for age and disease group. 4/38 (10.5%) patients were hospitalised (3 placebo, 1 sotrovimab). In view of the 250-fold reduction in EC50 with sotrovimab on pseudovirus testing for JN.1, a pre-specified efficacy analysis according to exposure period was performed (Table 2). Headache, dizziness and skin symptoms were the most common adverse events reported within 24 hours of infusion (Table 3). Although safe and well tolerated, 2000mg sotrovimab did not demonstrate benefit over placebo for the prevention of symptomatic SARS-CoV2 infection at 12 weeks. There was potential signal of benefit for sotrovimab before the emergence of the JN.1 variant in late 2023 that rapidly became the dominant circulating variant in the UK at that time. Michael Chen-Xu, MBChB, MRCP, MPH, GlaxoSmithKline: Grant/Research Support Davinder Dosanjh, n/a, Astrazeneca: Employee Jennifer Han, MD, GlaxoSmithKline: Employee Thomas F. Hiemstra, n/a, GlaxoSmithKline: Stocks/Bonds (Public Company)|Novartis: Employee|Novartis: Stocks/Bonds (Public Company) Alex G. Richter, n/a, CSL Behring: Honoraria Rona M. Smith, MD MRCP, AstraZeneca: Advisor/Consultant|AstraZeneca: Honoraria|GlaxoSmithKline: Grant/Research Support|Vifor Pharma: Honoraria

OBJECTIVE:Ear, nose, and throat (ENT) manifestations are common in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). There is an unmet need for drugs to target these manifestations. Granuloma formation is characteristic of proteinase 3 (PR3)-AAV. In a zebrafish model, niclosamide inhibits PR3-induced granuloma formation. We hypothesized that intranasal niclosamide would reduce AAV-associated ENT symptoms. METHODS:PROTECT-V was a randomized, double-blind, placebo-controlled platform trial evaluating pre-exposure prophylaxis agents against COVID-19 infection. This subanalysis includes patients from a single center with AAV, enrolled into the intranasal niclosamide arm. Clinical data were retrospectively collected for nine months before, during, and nine months after treatment. Researchers were blinded to treatment allocation. RESULTS:Of 32 (14 niclosamide; 18 placebo) patients, 11 (34%) were female; the median age was 69 (interquartile range [IQR] 59-75) years. Median prior AAV disease duration was 5.4 (IQR 1.9-13.1) years; 19 (59%) had active disease in the year before treatment. Median treatment exposure was 200 (IQR 109-251) days. During treatment, ENT symptoms were identified in 1 of 14 (7%) of the niclosamide group compared with 7 of 18 (39%) of the placebo group (P = 0.04). No significant difference between groups was found in the nine months before or after treatment. Among PR3-ANCA-positive patients, 0 of 10 in the niclosamide group compared to 5 of 9 (56%) in the placebo group had ENT symptoms during treatment. CONCLUSION:These data are a signal of potential clinical effect on ENT manifestations in AAV. They support a role for the IL-6 and STAT3 pathway in AAV; intranasal niclosamide or other drug candidates in this pathway warrant further evaluation.

Immune suppression poses a challenge to vaccine immunogenicity. We show that serum antibody neutralization against SARS-CoV-2 Omicron descendants was largely absent post-doses 1 and 2 in individuals with vasculitis treated with rituximab. Detectable and increasing neutralizing titers were observed post-doses 3 and 4, except for XBB. Rituximab in vasculitis exacerbates neutralization deficits over standard immunosuppressive therapy, although impairment resolves over time since dosing. We observed discordance between detectable IgG binding and neutralizing activity specifically in the context of rituximab use, with high proportions of individuals showing reasonable IgG titer but no neutralization. ADCC response was more frequently detectable compared to neutralization in the context of rituximab, indicating that a notable proportion of binding antibodies are non-neutralizing. Therefore, use of rituximab is associated with severe impairment in neutralization against Omicron descendants despite repeated vaccinations, with better preservation of non-neutralizing antibody activity.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) consists of a group of small-vessel vasculitides that often present with organ-threatening or life-threatening manifestations. Current immunosuppressive treatments have improved survival and rates of remission, but are not curative, have frequent toxicities, and do not effectively prevent relapse. Clinical trials have established the role of rituximab, an anti-CD20 B cell-depleting monoclonal antibody, in both the remission-induction and maintenance phases of the disease and demonstrated that glucocorticoid doses can be substantially reduced from historical dosing levels without affecting treatment efficacy. Therapies that have the potential to be more effective and safer have become available or are under investigation. Avacopan, an oral C5a receptor antagonist, was approved as an adjunctive treatment for AAV and use of this drug in combination with rituximab or cyclophosphamide and markedly reduced glucocorticoid dosing demonstrated superior efficacy and potentially greater kidney recovery than prior standard of care. Other agents under study for treatment of AAV include next-generation anti-CD20 monoclonal antibodies, anti-CD19 chimeric antigen receptor T cells, novel complement inhibitors and agents that can target fibrosis. Alongside traditional randomized controlled trials with clinical endpoints, experimental medicine studies are focusing on mechanistic endpoints and disease biomarkers. This Review discusses current treatments and the advances in the management of AAV. This Review discusses the advances and challenges of managing antineutrophil cytoplasmic antibody-associated vasculitis. The authors discuss current treatment options, emerging therapies and unmet needs in the management of this disease.

The complex pathophysiology of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) is reflected in the heterogeneity of the presenting clinical syndromes caused by these diseases but also provides a variety of conceivable molecular and cellular targets that can be therapeutically manipulated. The last decade has seen an expansion of established and potential therapies for treating AAV, some of which target the dysfunctional autoreactive immune response and others aim to ameliorate the downstream consequences of local vascular inflammation and necrosis. The success and widespread adoption of the anti-CD20 monoclonal antibody, rituximab, as an agent to both induce and maintain remission, has heralded a change in the standard-of-care management of AAV, replacing the “old guard” combination of cyclophosphamide and high-dose corticosteroids established in the 1970s. The development and approval of avacopan, a first-in-class small-molecule antagonist to the main receptor for the complement anaphylatoxin C5a, has the potential to reduce the corticosteroid burden experienced by patients with AAV and may also improve outcomes for those with AAV kidney disease. It marks the culmination of almost 20 years of international collaboration, from understanding the pathological role of complement in basic murine models of AAV through to a phase III clinical trial, and emphasises the importance of following promising translational discoveries through to drug development and clinical deployment. This article summarises how recent progress in our understanding of the basic pathophysiology of AAV has resulted in the development of new and effective treatments and, reciprocally, how studying the impact of these treatments in patients has advanced our understanding of dysfunctional immunobiology in disease.

To determine risk factors for relapse of ANCA‐associated vasculitis (AAV) after re‐induction of remission with rituximab and discontinuation of maintenance therapy. This is a post‐hoc analysis of the RITAZAREM clinical trial. Patients 15 years or older with AAV and a positive test for anti‐proteinase‐3 (PR3‐) or anti‐myeloperoxidase (MPO)‐ANCA who achieved remission after re‐induction with rituximab and glucocorticoids were randomized at month 4 to receive continued rituximab or azathioprine for a maintenance period up to 24 months, followed by observation until relapse or up to 48 months. Generalized estimating equations logistic regression identified baseline and time‐varying risk factors for relapse by the next visit for the two study phases: maintenance (months 4‐24) and off‐treatment (months 24‐48). Among 170 patients (median (IQR) age 59 (48‐68) years, disease duration 5 (2‐10) years), 99 relapses occurred (46 during maintenance). During maintenance, musculoskeletal involvement (odds ratio (OR) [95% confidence interval (CI)]: 2.8 [1.1, 7.2], p=0.03) and higher patient global assessment (OR [95% CI]: 1.1 [1.0, 1.2], p=0.04) were associated with relapse. During the off‐treatment phase, presence of CD19+ B‐cells (OR [95% CI]: 2.5 [1.2, 5.1], p=0.01) and reappearance of ANCA (OR [95% CI]: 3.2 [1.3, 7.7], p=0.01) were each associated with higher relapse risk. Multivariable analysis identified markers of inflammation (changes in platelets, white blood cells, and immunoglobulin A) associated with relapse. Risk factors for relapse in AAV vary by treatment phase. Monitoring markers of inflammation and immune reconstitution may identify patients at risk for relapse, particularly after treatment withdrawal.

Interstitial lung disease (ILD) is increasingly recognized as a common manifestation in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), particularly in patients with microscopic polyangiitis and myeloperoxidase (MPO)-ANCA. Its pathogenesis mainly involves MPO-ANCA production, oxidative stress, the formation of neutrophil extracellular traps, and genetic predisposition. The occurrence of ILD has major impacts on patients' quality of life and mortality risk. Usual interstitial pneumonia is reported as the most common CT pattern, and it is specifically associated with a poor prognosis. Treatment should be individualized, including immunosuppression, and antifibrotic therapy for progressive fibrosis, though the optimal management approach presently remains uncertain.

Abstract Purpose Despite vaccination, many patients remain vulnerable to COVID-19 infection and poorer outcomes, because of underlying health conditions resulting in sub-optimal vaccine responses. This study aims to demonstrate whether intranasal niclosamide confers additional protection against COVID-19 infection above standard preventative measures including vaccination. Methods PROTECT-V (PROphylaxis for paTiEnts at risk of COVID-19 infecTion) is a platform trial testing multiple pre-exposure COVID-19 prophylactic agents in vulnerable patients. This paper reports results from the randomised, double blind, placebo controlled intranasal niclosamide arm. 1651 adult patients on dialysis, with a kidney transplant or renal autoimmune conditions on immunosuppression were randomised from 48 sites (37 UK; 11 Indian). Intranasal niclosamide or matched placebo was administered twice daily, for up to nine months. Primary outcome was time to symptomatic COVID-19 infection. Results 1651 patients were randomised (826 niclosamide;825 placebo) between February 2021 to November 2022. 655(39.7%) were dialysis patients, 622(37.7%) kidney transplant recipients and 374(22.7%) had renal autoimmune disease. 97.5% patients in the UK and 66.4% patients in India with comparable proportions in both treatment groups had received COVID-19 vaccinations. Despite no adverse safety signal, there was a high withdrawal rate (40% niclosamide;23.8% placebo) due to local upper airway irritation leading to a significantly shorter treatment duration in the niclosamide group). Symptomatic COVID-19 infection during study treatment was observed in 103 patients in the niclosamide group and 133 in the placebo group (estimated hazard ratio 1.02(95%CI 0.79–1.32)). Conclusion Intranasal niclosamide did not reduce risk of symptomatic COVID-19 infection in this cohort compared to placebo. Trial Registration This study is registered with ClinicalTrials.gov: NCT04870333 (submitted 01/03/2021; posted 03/05/2021), EudraCT: 2020–004144-28 and the Clinical Trials Registry of India (CTRI):#CTRI/2022/03/040802.

Vitamin D deficiency is common in patients with end stage kidney disease (ESKD) and is a strong predictor of death from cardiovascular disease, infections and cancer. Currently only 68 https://doi.org/10.1186/ISRCTN15087616 ). Recruitment commenced in March 2017.

Introduction It remains unclear whether persisting proteinuria in ANCA-associated glomerulonephritis (AAGN) reflects damage from the initial injury or ongoing inflammation. Methods A retrospective, single-centre study of biopsy-proven AAGN was performed. The study defined the 'albuminuria' group as urine albumin-to-creatinine ratio (ACR) >300 mg/g and the 'no albuminuria' group as ACR <= 300 mg/g at 6 months. We sought the clinical and histopathological characteristics of both the initial and subsequent biopsies and long-term kidney outcomes stratified by albuminuria levels. Results Two hundred and eighteen patients were included. Within the first 6 months, 28 (13%) died or progressed to end-stage kidney disease (ESKD). Among the remaining 190 patients, 37% had an ACR >300 mg/g at 6 months. The albuminuria group more frequently presented with a Berden mixed or crescentic class and had higher glomerular activity on the initial biopsy. They were more often male (OR 2.75; 95% CI 1.15-6.54), younger age (OR 0.96; 95% CI 0.93-0.99), and had fewer normal glomeruli in the biopsy (OR 0.96; 95% CI 0.93-0.99) compared with the group without albuminuria. Over the initial 5-year period, the recovery in eGFR was lower in the albuminuria group (adjusted mean difference in Delta eGFR -12.5 mL/min per 1.73 m(2); 95% CI -15.8 to -9.1). In multivariable analysis, ACR >300 mg/g was associated with a higher risk of ESKD, even after adjusting for Berden classification and eGFR at diagnosis (hazard ratio 6.53; 95% CI 1.49-28.50). Conclusions In a well-defined cohort of AAGN, one-third of the patients, primarily younger males with a lower percentage of normal glomeruli, had persisting albuminuria after induction treatment which was associated with worse kidney outcomes independent of Berden class and eGFR at diagnosis.

BACKGROUND:The vast majority of healthcare research in the UK is investigator-led. While national progress in patient and public involvement (PPI) increasingly mandates patient consultation, research questions and outcomes still frequently misalign with patient priorities. This is particularly important in rare disease research, as more than 95% of 11 000 conditions have no effective or curative treatment, and around 20% are not clinically defined, making them difficult to diagnose and manage. The unmet physical, mental and emotional needs of people living with rare diseases are immense. Extensive guidance and toolkits exist to support investigators with PPI, but none target patient communities attempting to promote their own priorities, initiate or co-lead research. AIM:This communication article introduces the newly established patient-led Rare Disease Research Network (RDRN). WHAT IS THE RDRN, AND HOW CAN IT BE USEFUL?: Launched in November 2024, the RDRN is an open-access collaborative platform designed to support patient-driven and co-produced research, connecting patient and professional partners with similar research interests. Originally conceived by an ultra-rare patient group, the network was co-produced with the rare disease community, including individuals living with rare conditions, parents, carers and charity advocates, whose lived experience and priorities shaped every aspect of its design. Supported by academic and research networks, its collaborative development ensures RDRN removes barriers to participation while complementing existing initiatives. RDRN is a novel approach to driving new impactful research by aligning investigator priorities with real-world needs and building capacity from patients outward. Rare disease communities bring lived expertise, creativity and motivation. Yet without a structured route to collaborate, their insights are often lost. RDRN offers an inclusive space, fostering new partnerships and supporting upstream collaboration. The approach enables patients to become 'research ready' and empowers them to have an active role in generating ideas and delivering research from inception, leading to innovative research and driving meaningful change in patients' lives. With further development, RDRN could present a lasting, scalable and unified model for co-designed rare disease research. By enabling trust, capacity and shared purpose, it can drive discovery, improve outcomes and build a more resilient and self-sustaining research ecosystem, underpinning key pillars of the 2021 UK Rare Diseases Framework.

ABSTRACT Background Pulmonary haemorrhage with hypoxia caused by anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has a high early mortality. Avacopan, an oral C5a receptor antagonist, is an approved treatment for AAV, but patients with pulmonary haemorrhage requiring invasive pulmonary ventilation support were excluded from the Avacopan for the Treatment of ANCA-Associated Vasculitis (ADVOCATE) Trial. Methods A retrospective, observational, multicentre case series of AAV patients with hypoxic pulmonary haemorrhage, requiring oxygen support or mechanical ventilation, who received avacopan. Results Eight patients (62.5% female), median age 64 years (range 17–80), seven with kidney involvement, median estimated glomerular filtration rate (eGFR) 11 (range 5–99) mL/min/1.73 m2, were followed for a median of 6 months from presentation. Seven were newly diagnosed (87.5%), five were myeloperoxidase-ANCA and three proteinase 3-ANCA positive. All had hypoxia, four requiring mechanical ventilation (three invasive and one non-invasive). Intensive care unit (ICU) stay for the four patients lasted a median of 9 days (range 6–60). Four received rituximab and cyclophosphamide combination, three rituximab and one cyclophosphamide. Four underwent plasma exchange and one received 2 months of daily extracorporeal membrane oxygenation therapy. Following the initiation of avacopan after a median of 10 days (range 2–40), pulmonary haemorrhage resolved in all patients, even the two who had 1 month of refractory pulmonary haemorrhage prior to avacopan. Additionally, after 1 month, the median prednisolone dose was 5 mg/day (range 0–50), with three patients successfully discontinuing steroid use. Two patients suffered serious infections, two discontinued avacopan, one permanently due to a rash and one temporarily after 3 months due to neutropenia. All patients survived and no re-hospitalization occurred. Conclusion We report the use of avacopan as a component of the treatment for pulmonary haemorrhage with hypoxia in AAV. Despite the life-threatening presentations all patients recovered, but attribution of the positive outcomes to avacopan is limited by the concomitant therapies and retrospective observational design.

Abstract Background and Aims Interstitial lung disease (ILD) in ANCA-associated vasculitis (AAV) has the appearance of a progressive fibrotic disease on imaging and primarily affects the interstitial lung compartment and is usually associated with MPO-ANCA. Whether patients with AAV-ILD display a similar fibrotic pattern in their kidneys is unclear. Method A European multicentre retrospective study included patients with AAV-ILD. The diagnosis of ILD was confirmed by a CT chest pattern of usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), organising pneumonia or chronic hypersensitivity pneumonia. We aimed to determine if kidney involvement in AAV-ILD exhibited a more fibrotic pattern compared to AAV-related nephritis without ILD, using data from the Cambridge AAV cohort. Results 135 patients with AAV-ILD were included; 94 (70%) had also kidney involvement, in whom the mean age was 71 ± 11 years and 87% MPO-ANCA positive. The ILD diagnosis preceded AAV in 17%, 64% presented concurrently with kidney involvement, 20% with pulmonary haemorrhage. The most common lung radiological pattern was UIP (67%). At presentation, the median glomerular filtration rate (GFR) was 27 ml/min per 1.73 m2 (interquartile range 12-50), with a median albumin-to creatinine ratio 23 mg/mmol (IQR 10-97). Among 72 patients with available kidney biopsy, the most prevalent Berden class was focal in 45%, followed by mixed in 33%, crescentic in 18% and sclerotic in 4%. Although, the prevalence of Berden classes did not significantly differ between ILD-nephritis and no ILD-nephritis groups, the former group had a higher baseline GFR (p = 0.05), lower albuminuria level (p = 0.002), higher percentage of normal glomeruli (p = 0.027), lower glomerular necrosis percentage (p = 0.002) and higher interstitial fibrosis score (p = 0.049). Within five years, the ILD-nephritis group demonstrated renal recovery, as indicated by an adjusted mean delta GFR of 13.4 ml/min per 1.73 m2, without a significant difference compared to the no ILD-nephritis group. Over a median follow-up of 4.9 years (IQR 2-9), the progression to end-stage kidney disease (ESKD) was comparable between the groups. However, notably, the ILD-nephritis group experienced significantly poorer survival rates (mean 10.9 years vs 17.9 years, log-rank p < 0.001). Conclusion In AAV-ILD, kidney involvement is often characterized by fewer inflammatory and a higher prevalence of fibrotic lesions than on non-ILD-AAV. Despite initial differences in renal pathology and kidney function between these groups, both demonstrated similar risks of progressing to ESKD. Nevertheless, it's crucial to underscore the significant influence of ILD on the overall outcomes of AAV patients with kidney involvement.

BackgroundPatients with autoimmune/inflammatory conditions on anti-CD20 therapies, such as rituximab, have suboptimal humoral responses to vaccination and are vulnerable to poorer clinical outcomes following SARS-CoV-2 infection. We aimed to examine how the fundamental parameters of antibody responses, namely, affinity and concentration, shape the quality of humoral immunity after vaccination in these patients.MethodsWe performed in-depth antibody characterisation in sera collected 4 to 6 weeks after each of three vaccine doses to wild-type (WT) SARS-CoV-2 in rituximab-treated primary vasculitis patients (n = 14) using Luminex and pseudovirus neutralisation assays, whereas we used a novel microfluidic-based immunoassay to quantify polyclonal antibody affinity and concentration against both WT and Omicron (B.1.1.529) variants. We performed comparative antibody profiling at equivalent timepoints in healthy individuals after three antigenic exposures to WT SARS-CoV-2 (one infection and two vaccinations; n = 15) and in convalescent patients after WT SARS-CoV-2 infection (n = 30).ResultsRituximab-treated patients had lower antibody levels and neutralisation titres against both WT and Omicron SARS-CoV-2 variants compared to healthy individuals. Neutralisation capacity was weaker against Omicron versus WT both in rituximab-treated patients and in healthy individuals. In the rituximab cohort, this was driven by lower antibody affinity against Omicron versus WT [median (range) KD: 21.6 (9.7–38.8) nM vs. 4.6 (2.3–44.8) nM, p = 0.0004]. By contrast, healthy individuals with hybrid immunity produced a broader antibody response, a subset of which recognised Omicron with higher affinity than antibodies in rituximab-treated patients [median (range) KD: 1.05 (0.45–1.84) nM vs. 20.25 (13.2–38.8) nM, p = 0.0002], underpinning the stronger serum neutralisation capacity against Omicron in the former group. Rituximab-treated patients had similar anti-WT antibody levels and neutralisation titres to unvaccinated convalescent individuals, despite two more exposures to SARS-CoV-2 antigen. Temporal profiling of the antibody response showed evidence of affinity maturation in healthy convalescent patients after a single SARS-CoV-2 infection, which was not observed in rituximab-treated patients, despite repeated vaccination.DiscussionOur results enrich previous observations of impaired humoral immune responses to SARS-CoV-2 in rituximab-treated patients and highlight the significance of quantitative assessment of serum antibody affinity and concentration in monitoring anti-viral immunity, viral escape, and the evolution of the humoral response.