Vasculitis Activity Research Articles

Non-alcoholic fatty liver disease fibrosis score is a useful index for predicting all-cause mortality in patients with antineutrophil cytoplasmic antibody-associated vasculitis.

This study investigated whether the non-alcoholic fatty liver disease fibrosis score (NFS) could predict all-cause mortality during follow-up among patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The medical records of 256 AAV patients were retrospectively reviewed. AAV patients with clinically critical chronic liver diseases were excluded. NFS was calculated using the following equation: NFS = -1.675 + 0.037 - age + 0.094 - body mass index +1.13 × impaired fasting glucose/diabetes mellitus +0.99 × aspartate aminotransferase/alanine aminotransferase ratio - 0.013 × platelet count - 0.66 × serum albumin. The median age was 59.0 years, and 35.2% of the patients were male. The median Birmingham Vasculitis Activity Score (BVAS), five-factor score (FFS), and NFS were 12.0, 1.0, and - 4.7, respectively. Of the 256 patients, 33 (12.9%) died. Using the receiver operating characteristic curve, the optimal cut-off of NFS for all-cause mortality was obtained as-3.97. AAV patients with NFS at diagnosis ≥ - 3.97 exhibited a lower cumulative patients' survival rate than those with NFS at diagnosis <-3.97. The multivariable Cox analysis revealed that NFS at diagnosis ≥ - 3.97 (HR 2.232, 95% CI 1.011, 4.925) was independently associated with all-cause mortality in AAV patients. This study was the first to demonstrate that NFS at AAV diagnosis was clinically useful in predicting all-cause mortality during follow-up, regardless of both the degree of liver fibrosis and abnormal or normal liver function results.

Avacopan (Tavneos)

&#x0D; CADTH recommends that Tavneos not be reimbursed by public drug plans as adjunctive treatment for adults with severe active antineutrophil cytoplasmic autoantibody-associated vasculitis (ANCA-AV) (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]).&#x0D; One clinical trial demonstrated that Tavneos in combination with ANCA-AV background therapy (including glucocorticoids and drugs that reduce immune system function) was as good as oral prednisone (60 mg dose reduced over 20 weeks) in combination with ANCA-AV background therapy for showing a reduction in disease symptoms at week 26 and was better than oral prednisone for maintaining symptom improvement at week 52. However, it was unclear if Tavneos offered a meaningful clinical benefit over other treatments used for ANCA-AV mainly because rituximab was not used as maintenance therapy in the trial, as is currently recommended by Canadian guidelines, and there is uncertainty around the clinical meaningfulness of the differences between the treatment groups for outcomes that assessed renal function, relapse, and Short Form [36] Health Survey version 2 (SF-36v2).&#x0D; There was not enough evidence to conclude that Tavneos met patients’ needs for a treatment that reduces or eliminates the use of glucocorticoids and their side effects as well as improves their health-related quality of life (HRQoL).&#x0D;

150 Association between loss of immune checkpoint programmed cell death protein 1 and local synthesis of complement factor B in active ANCA-associated renal vasculitis

150 Association between loss of immune checkpoint programmed cell death protein 1 and local synthesis of complement factor B in active ANCA-associated renal vasculitis

Urine and Plasma Complement Ba Levels During Disease Flares in Patients With Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

Although the alternative complement pathway has been implicated in the pathogenesis of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), the specific nature of its involvement is unclear. This study measured levels of urine and plasma complement fragment Ba at multiple time points in a group of patients with AAV. The complement fragment Ba was measured by enzyme-linked immunosorbent assay in serial urine and plasma samples from 21 patients with AAV who developed a renal flare, 19 who developed a nonrenal flare, and 20 in long-term remission. Urine Ba levels were corrected for urine creatinine concentration. Changes in Ba levels were modeled using mixed linear-effect models. A logistic regression model was fit to predict a renal flare using Ba levels at the time of flare versus the nonrenal flare and long-term remission groups. Data from 60 patients with AAV were used for this analysis; 53% were male, 93% were White, and 74% had antiproteinase3-ANCA. Urine Ba levels increased at renal flare (P< 0.001) but remained stable during a nonrenal flare or long-term remission. Plasma Ba levels were stable over time in all groups. Urine Ba levels predicted a renal flare with an area under the curve of 0.76 (P< 0.001), with a cutoff of 12.53 ng/mg urine creatinine yielding a sensitivity of 76.2% and a specificity of 68.4%. Urine Ba levels, but not plasma Ba levels, are increased at the time of a renal flare in AAV, suggesting intrarenal complement activation and highlighting the potential use of this biomarker for surveillance of active renal vasculitis.

Benralizumab for eosinophilic granulomatosis with polyangiitis

BackgroundBenralizumab is effective in the treatment of eosinophilic asthma and is being investigated for the treatment of other eosinophil-associated diseases. Reports on the use of benralizumab for the treatment of...

Antineutrophil cytoplasmic antibody-associated vasculitis classification by cluster analysis based on clinical phenotypes: a single-center retrospective cohort study.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) refers to a group of small vessel inflammatory disorders. Overlapping clinical phenotypes of AAV subgroups continually provoke controversies over their diagnostic and classification criteria. Using the agglomerative hierarchical clustering method, we classified 210 Korean patients diagnosed with AAV into mutually exclusive clusters according to Birmingham Vasculitis Activity Score items, ANCA specificity, sex, and age. We analyzed the resulting clusters' outcomes to investigate the clinical significance of the classification. We proposed a distance-based algorithm of patient assignment and explored its clinically relevant modification. In total, 116 patients (55%) had microscopic polyangiitis, 53 (25%) had granulomatosis with polyangiitis, and 42 (20%) had eosinophilic granulomatosis with polyangiitis. Our model grouped the patients into five clusters, namely, "limited proteinase 3 (PR3)-ANCA vasculitis," "generalized PR3-ANCA vasculitis," "ANCA-negative vasculitis," "renal-limited vasculitis," and "myeloperoxidase-ANCA vasculitis." Patients clustered under "generalized PR3-ANCA vasculitis" had a higher relapse rate (hazard ratio [HR] = 2.12, P = 0.067). The incidence of end-stage renal disease was higher in patients belonging to the "renal-limited vasculitis" cluster (HR=1.50, P=0.03), and those in the "ANCA-negative vasculitis" cluster experienced a relatively milder clinical course of AAV (mortality = 0). Because the clusters were naturally derived from their distinguished phenotypes and have different clinical courses, our clustering method may be a more clinically relevant classification system for AAV, revealing its phenotypic diversity. We also proposed a simple and intuitive distance-based assignment algorithm, which can be easily modified according to specific clinical needs. Key Points • In this study with a single-center AAV cohort, we showed that AAV can be divided into five distinct subclasses with different disease courses based on the clinical and laboratory features of the patients. • Our study revealed ethnic differences in AAV manifestation and suggests that physicians may need to analyze their own AAV patients to assess the disease status of AAV patients. • We proposed a distance-based cluster membership assignment method that can be clinically modified to fit the specific purpose of grouping patients.

Clinical efficacy of protein A immunoadsorption therapy on severe ANCA-associated vasculitis renal injury.

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of diseases involving multiple systems, and kidney is one of the most commonly involved target organs. Some patients may rapidly progress to end-stage renal disease in a short time. Whereas some patients have poor remission and renal prognosis after standard induction therapy. As a selective blood purification therapy, protein a immunoadsorption (PAIA) has shown great advantages on treating of severe autoimmune diseases. This study aims to evaluate the short-term efficacy of PAIA therapy combined with glucocorticoids and immunosuppressants on treating of severe AAV renal injury. A total of 10 AAV cases with severe kidney involvement in the Second Xiangya Hospital of Central South University from 2019 to 2020 were selected for this retrospective study. During the induction remission stage, each patient was treated with PAIA on the basis of standard therapy of glucocorticoids and immunosuppressive treatment. Before and after the initial treatment, 1 month and 3 months after treatment, clinical data including demographic characteristics, immunological indicators, and Birmingham Vasculitis Activity Score (BVAS) were compared. The related adverse reactions during treatment were recorded to evaluate the short-term efficacy. In this study, all 10 patients were MPO positive, and 2 patients were PR3 positive (≥2.3 U/mL). There are 6 males and 4 females at (61.5±11.4) years old, with the median time from onset to admission to hospital at (2.8±1.8) months. Multisystem damage, especially kidney damage, can be seen with eGFR lower than 30 mL/(min·1.73 m2). During the 3-month follow-up, BVAS, erythrocyte sedimentation rate, and hemoglobin of 10 patients showed continuous improvement compared with the initial admission levels (all P<0.05). ANCA titer, serum creatinine and urine red blood cell were all decreased and eGFR levels were increased in 3 months after treatment (all P<0.05). Serum albumin, urinary protein, C-reactive protein and complement levels showed no significant changes after treatment (all P>0.05). One patient who had received renal replacement therapy was still dialysis dependent after PAIA treatment. One patient who had transient hypotension was corrected by routine treatment. The rest of the patients were all tolerant with PAIA during their treatments. Treatment with PAIA combined with glucocorticoids and cyclophosphamide can rapidly lower serum ANCA level and improve disease activity in patients with AAV complicated with severe kidney damage, suggesting a good short-term renal prognosis and good overall safety.

Subclinical microvascular changes in ANCA-vasculitides: the role of optical coherence tomography angiography and nailfold capillaroscopy in the detection of disease-related damage

BackgroundBoth cardiovascular and complement-mediated disorders might lead to microvascular damages in anti-neutrophil cytoplasm autoantibodies (ANCA)-associated vasculitides (AAV). We aimed at investigating, for the first time, subclinical microvascular abnormalities with non-invasive techniques in AAV patients by analyzing both retinal and nailfold capillary changes. Retinal plexi were investigated using optical coherence tomography angiography (OCT-A), while nailfold capillary changes by video-capillaroscopy (NVC). Potential correlations between microvessels’ abnormalities and disease damage were also explored.MethodsAn observational study was conducted on consecutive patients who met the inclusion criteria of defined diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA), age ≥ 18 ≤ 75 yrs, and no ophthalmological disorders. Disease activity was assessed by Birmingham Vasculitis Activity Score (BVAS), damage by Vasculitis Damage Index (VDI), and poorer prognosis by the Five Factor Score (FFS). Quantitative analysis of vessel density (VD) was performed by OCT-A in both superficial and deep capillary plexi. Figures and detailed analysis from NVC were performed for all subjects in the study.ResultsIncluded AAV patients (n = 23) were compared with 20 age/sex-matched healthy controls (HC). Retinal VD in superficial whole and parafoveal plexi resulted significantly decreased in AAV compared to HC (P = 0.02 and P = 0.01, respectively). Furthermore, deep whole and parafoveal vessel density was strongly reduced in AAV than HC (P ≤ 0.0001 for both). In AAV patients, significant inverse correlations occurred between VDI and OCTA-VD in both superficial (parafoveal, P = 0.03) and deep plexi (whole, P = 0.003, and parafoveal P = 0.02). Non-specific NVC pattern abnormalities occurred in 82% of AAV patients with a similar prevalence (75%) in HC. In AAV, common abnormalities were edema and tortuosity in a comparable distribution with HC. Correlations between NVC changes and OCT-A abnormalities have not been described.ConclusionSubclinical microvascular retinal changes occur in patients with AAV and correlate with the disease-related damage. In this context, the OCT-A can represent a useful tool in the early detection of vascular damage. AAV patients present microvascular abnormalities at NVC, whose clinical relevance requires further studies.

Relapse in patients with antineutrophil cytoplasmic antibody-associated vasculitis undergoing dialysis: a single-centre retrospective study in South Korea.

The disease activity of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) can decrease after dialysis, and relapse after dialysis is not well-studied. We investigated the clinical manifestations and factors associated with relapse in patients with AAV undergoing dialysis. This retrospective study included data of patients with AAV undergoing dialysis due to renal involvement from July 2005 to March 2021 in a single tertiary centre in Seoul, Korea. Cox regression analysis was performed to identify relapse-associated factors. The study cohort included 38 patients with a median age of 64.0 years; 28 (73.7%) were female, and 35 (92.1%) patients were diagnosed with microscopic polyangiitis (MPA). At diagnosis, the mean Birmingham vasculitis activity score (BVAS) was 18.3 and 66.3% of the patients exhibited pulmonary manifestations. During follow-up, 12 patients experienced AAV relapse, including nine patients with diffuse alveolar haemorrhage (DAH), two patients with aggravated interstitial lung disease, and one patient with DAH accompanied with neuropathy. Clinical features including age, sex, and baseline BVAS did not significantly differ between the relapse and non-relapse groups. By univariable analysis, lung infiltration, DAH, corticosteroid pulse therapy for induction, and mean corticosteroid dose were significantly associated with relapse. Multivariable analysis revealed that DAH (adjusted hazard ratio 5.509, 95% CI 1.569-19.339; P=0.008) and mean corticosteroid dose (adjusted hazard ratio 1.381, 95% CI 1.161-1.642; P<0.001) were significantly associated with relapse. In patients with AAV undergoing dialysis, DAH and mean corticosteroid dose were significantly associated with relapse, highlighting the importance of close monitoring.

Urinary isomorphic red blood cells for the prediction of disease severity and renal outcomes in MPO-ANCA-associated vasculitis: a retrospective cohort study.

Hematuria is common in myeloperoxidaseanti-neutrophil cytoplasmic antibodyassociated vasculitis(ANCA-MPO). Previous studies have mainly focused on urinary dysmorphic red blood cells and few have reported the clinical significance of isomorphic urinaryred blood cells. Therefore, the main aim of this study was to assess the predictive yield of urinary isomorphic red blood cells for disease severity and renal outcomes in patients with ANCA-MPO associated vasculitis. A total of 191 patients with ANCA-MPOassociated vasculitiswith hematuria were retrospectively selectedand were divided into two groups (withisomorphic red blood cells versus dysmorphic red blood cells) according to the percentage of isomorphic red blood cells on urinary sediment analysis. Clinical, biological and pathological data at diagnosis were compared. Patients were followed up for a median of 25months and progression to end-stage kidneydisease and death were regarded as main outcome events. Additionally, univariate and multivariate Cox regression models were used to estimate the risk factors for end-stage kidneydisease. Out of 191 patients, 115 (60%) had ≥ 70% and 76 (40%) had < 30% urine isomorphic red blood cells. Compared with patients in the dysmorphic red blood cell group, patients in the isomorphic red blood cell group had a significantly lower estimated glomerular filtration rate(eGFR) [10.41mL/min (IQR 5.84-17.06) versus 12.53 (6.81-29.26); P = 0.026], higher Birmingham Vasculitis Activity Score [16 (IQR 12-18) versus 14 (10-18); P = 0.005] and more oftenreceived plasma exchange [40.0% versus 23.7% (P = 0.019)] at diagnosis. Kidney biopsies revealed a higher proportion of patients with glomerular basement membrane fracture in the isomorphic red blood cell group [46.3% versus 22.9% (P = 0.033)]. Furthermore, patients with predominant urinary isomorphic red blood cells were more likely to progress to end-stage kidney disease [63.5% versus 47.4% (P = 0.028)] and had a higher risk ofdeath [31.3% versus 19.7% (P = 0.077)]. The end-stage kidney disease-free survival was lower in patients in the isomorphic red blood cell group (P = 0.024). However, urine isomorphic red blood cells ≥ 70% could not predict the presence of end-stage kidney disease in multivariate Cox analysis. Myeloperoxidase-anti-neutrophil cytoplasmic antibodyassociated vasculitis patients with predominant urinary isomorphic red blood cells at diagnosis had more severe clinical manifestations and a higher risk of poor renal outcomes. In this respect, urinary isomorphic red blood cells could be viewed as a promising biomarker of ANCA_MPO vasculitisseverity and progression.

Intravenous immunoglobulin therapy in antineutrophil cytoplasmic antibody-associated vasculitis

IntroductionAnti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) includes three heterogeneous and difficult to treat clinical entities. Intravenous immunoglobulins (IVIG) may constitute a good therapeutic option, although data hitherto are scarce. The aim of this study was to assess the effectiveness and safety of IVIG in AAV in a real-world setting. MethodsSingle center observational study of patients with AAV with at least one cycle of IVIG since January of 2000 to December of 2020. AAV diagnosis was based on a compatible clinical presentation and positive ANCA serology and/or compatible histology. Disease activity was assessed by the Birmingham Vasculitis Activity Score (BVAS). The effectiveness was evaluated by clinical and laboratory parameters (CRP, ESR) and its glucocorticoid-sparing effect. These variables were measured at one, six, twelve and twenty-four months of IVIG treatment. The doses of IVIG were 2g/kg in the following cycles of administration: 1 g/kg/day in 2 days (n=12); 0.5 g/kg/day in 4 days (n=11); 0.4 g/kg/day in 5 days (n=5). The clinical improvement was classified according to BVAS categories in remission, partial response and no response. ResultsTwenty-eight patients (15 granulomatosis-polyangiitis, 10 microscopic polyangiitis and 3 eosinophilic granulomatosis with polyangiitis) were included. Reasons for using IVIG were relapse/refractory disease (n=25), active or suspected infection (n=3), and both (n=5). We observed a rapid and maintained BVAS score improvement, increasing from 34.6% at 1 month to 56.5% at 2 years of follow-up (p=0.12), and a reduction of glucocorticoids dose. Therapy was well tolerated and adverse events mild and scarce. ConclusionIVIG represents an effective and relative safe therapeutic alternative in relapsing/refractory AAV or in presence of a concomitant active infection.

Measurement of superoxide dismutase: clinical usefulness for patients with anti-neutrophil cytoplasmic antibody-associated vasculitis

ObjectiveTo investigate the clinical usefulness of serum superoxide dismutase (SOD) measurement in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).MethodsIn this single-center retrospective study, demographic data, serum SOD levels, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), the Birmingham Vasculitis Activity Score (BVAS), ANCA, organ involvement, and outcomes were analyzed for 152 AAV patients hospitalized in the Second Affiliated Hospital of Chongqing Medical University. Meanwhile, the serum SOD levels of 150 healthy people were collected as the control group.ResultsCompared to the healthy control group, serum SOD levels of the AAV group were significantly lower (P < 0.001). SOD levels of AAV patients were negatively correlated to ESR, CRP, and BVAS (ESR rho = − 0.367, P < 0.001; CRP rho = − 0.590, P < 0.001; BVAS rho = − 0.488, P < 0.001). SOD levels for the MPO-ANCA group were significantly lower than the PR3-ANCA group (P = 0.045). SOD levels for the pulmonary involvement group and the renal involvement group were significantly lower than those for the non-pulmonary involvement group and the non-renal involvement group (P = 0.006; P < 0.001, respectively). SOD levels in the death group were significantly lower than the survival group (P = 0.001).ConclusionsIn AAV patients, low SOD levels might indicate disease associated oxidative stress. SOD levels in AAV patients were decreased with inflammation, suggesting that SOD levels could potentially be a surrogate marker for disease activity. SOD levels in AAV patients were closely related to ANCA serology, pulmonary involvement, and renal involvement, with low SOD levels an important indicator of a poor prognosis for AAV patients.

Total Globulin Fraction at Diagnosis Could Forecast All-Cause Mortality during the Disease Course in Patients with Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Total globulin fraction (TGF) is calculated by subtracting serum albumin levels from serum total protein levels. The present study examined whether TGF at diagnosis could forecast all-cause mortality during the disease course in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The present study included 283 patients with AAV. The variables at AAV diagnosis such as demographic data, AAV-specific data including the Birmingham vasculitis activity score (BVAS), five-factor score (FFS), and laboratory data including ANCA, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were collected. The number of deceased patients during the follow-up duration based on all-cause mortality was counted. The median age of the 283 AAV patients was 60 years, and 35.7% were men. ANCAs were detected in 228 patients, and the median TGF was 2.9. A total of 39 patients (13.8%) died within a median follow-up duration of 46.9 months. TGF at AAV diagnosis was significantly correlated with ESR and CRP rather than AAV activity. Patients with ANCA positivity exhibited a significantly higher median TGF at AAV diagnosis than those without. Patients with TGF ≥ 3.1 g/dL at AAV diagnosis exhibited a significantly lower cumulative survival rate than those without. Furthermore, in the multivariable Cox hazards model analysis, TGF ≥ 3.1 g/dL (hazard ratio 2.611) was independently associated with all-cause mortality, along with age, male sex, and body mass index. The present study is the first to demonstrate that TGF at AAV diagnosis can forecast all-cause mortality during the disease course in AAV patients.

#5611 ASSOCIATION BETWEEN LOSS OF IMMUNE CHECKPOINT PROGRAMMED CELL DEATH PROTEIN 1 AND ACTIVE ANCA-ASSOCIATED RENAL VASCULITIS

Abstract Background and Aims Immune checkpoint inhibitors (ICIs) have made an important contribution on the survival of patients with certain cancers. ICIs interrupt co-inhibitory signalling pathways mediated by programmed cell death protein 1 (PD-1), programmed cell death protein-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen (CTLA-4) that result in the elimination of cancer cells by stimulating the immune system. Immune-related adverse events have also been described and attributed to an enhanced immune system activation. Recent observations have suggested dysregulation of immune checkpoints in active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Therefore, we here aimed to analyze abundance of immune checkpoint molecules PD-1/PD-L1 and its implications in ANCA-associated renal vasculitis. Method We here analyzed intrarenal PD-1 and PD-L1 by immunostaining in a total number of 15 kidney biopsies with ANCA-associated renal vasculitis in correlation with glomerular and tubulointer-stitial lesions. For independent validation, publicly available datasets were analyzed for PD-1 expression (encoded by PDCD1). Results We here observed a predominant tubulointerstitial expression of PD-1 that is decreased in ANCA-associated renal vasculitis. Moreover, loss of tubulointerstitial PD-1 correlated with active ANCA-associated renal vasculitis. Consistent to the observed association with active glomerular and tubulointerstitial lesions, we identified that interstitial PD-1 correlated with tubular and/or glomerular PD-L1 positivity. Finally, PD-1 was associated with decreased local synthesis of complement factor B. Interestingly, we did not observe a correlation between PD-1 and complement C5 or its C5a receptor. Combined with our observations, this may implicate a link between im-paired PD-1/PD-L1 signalling, complement factor B, and active ANCA-associated renal vasculitis. Conclusion These findings could be of relevance because experimental data have already been described that PD-1 agonism can be used therapeutically to attenuate autoimmunity in multiple disease models. Furthermore, targeted therapy against complement C5/C5a receptor and factor B are both available and currently evolving in the treatment of AAV. Therefore, this pilot study expands our current knowledge and describes a potential interplay between immune checkpoints and the alternative complement pathway in active ANCA-associated renal vasculitis.

#3789 SERUM AND URINARY SOLUBLE PD-1, PD-L1 AND PD-L2 AS BIOMARKERS FOR CHECKPOINT INHIBITOR RELATED ACUTE INTERSTITIAL NEPHRITIS

Abstract Background and Aims Acute interstitial nephritis (AIN) related to Immune Checkpoint Inhibitors (ICI) is a frequently described adverse effect, although the mechanisms are not fully understood. The gold standard for the diagnosis is kidney biopsy. Although it is invasive, it is necessary as AIN can be confounded with other causes of acute kidney injury (AKI) in oncologic patients. The diagnosis of AIN has therapeutical consequences such as the need to withdraw the drug if confirmed, possibly diminishing patients’ life expectancy. Few biomarkers have been proposed for non-invasive diagnosis or the follow-up of these patients, which could be useful when the biopsy is contraindicated or not available. Our aim was to study the Immune Checkpoint pathway during the event, as well as analyse potential biomarkers directly related to the pathway. Method We performed an observational study. We recruited patients with incident diagnosis of AIN related to ICI in our institution from 2018 to 2022. We obtained serum and urine at the time of diagnosis after signing informed consent. We recruited n = 18 patients with the diagnosis of AIN related to ICI. For comparison, we recruited patients with non ICI-related AIN (n = 18), patients with active ANCA-vasculitis (n = 35), patients with acute tubular necrosis (ATN) (n = 22), and controls (n = 36) (patients with diagnosis of malignancy without AKI (n = 22), and healthy controls (n = 14)). We determined soluble PD-1 (sPD-1), sPD-L1 and sPD-L2 in serum and urine using a multiplex bead-based Luminex assay. Besides, we performed PD-L1 immunohistochemistry and PD-L2 immunofluorescence staining of kidney biopsies from patients with ICI-related AIN (n = 14) and compared to patients with non ICI-related AIN (n = 10). Results Serum sPD-1 was higher in patients with AIN compared to controls (p = 0.0004) and patients with ATN (p = 0.021). There were no differences between controls and ATN (p = 0.76). Urinary sPD-1 was lower in subjects with AKI compared to controls (control vs AIN (p = 0.019), control vs active vasculitis (p&amp;lt;0.0001) and control vs ATN (p = 0.0304)). Patients with ATN exhibited the lowest urinary sPD-1 levels, and there were statistically significant differences when compared to AIN (p = 0.0304). Focusing on oncologic patients, urinary sPD-1 concentration &amp;lt;129.3 pg/ml had a 71.43% sensitivity and 94.12% specificity to differentiate ATN from AIN, with a likelihood ratio of 12.14. Serum and urinary sPD-L1 and sPD-L2 did not show statistically significant differences between AIN and ATN. In kidney biopsies, patients with ICI related AIN showed higher density of PD-L1 positive tubules than patients with non-ICI related AIN (p = 0.037). Proportion of patients having more than 2.64/mm2 PD-L2 positive tubules was higher among patients with ICI related AIN compared to non ICI-related AIN (p = 0.034). There was a positive correlation (p = 0.009, r = 0.72) between urinary sPD-1 and the density of PD-L1 positive tubules (tubules/mm2). As for PD-L2, serum PD-L2 was higher in patients with positive tubular PD-L2 expression (p = 0.009). Conclusion Serum sPD-1 increases in AIN, contrary to patients with ATN and controls. Urinary sPD-1 decreases in patients with AKI. This decrease is more intense in the case of patients with ATN, thus being useful in the differentiation between ATN and AIN, especially in patients with neoplasms. Patients with ICI-related AIN exhibit higher positivity for PD-L1 and PD-L2 staining compared to other causes of AIN. Altogether, our findings suggest a role for these soluble molecules in the ICI-related AIN pathophysiology.

#5260 PLASMA AND URINE METABOLOMIC PROFILES REVEAL POTENTIAL BIOMARKERS AND PROVIDE VALUABLE INSIGHTS INTO THE MECHANISMS OF MPO-ANCA-GN

Abstract Background and Aims Currently, the precise mechanism of myeloperoxidase- anti-neutrophil cytoplasmic antibody associated glomerulonephritis (MPO-ANCA-GN) remains elusive. And there is a lack of dependable biomarkers for evaluating disease activity, therapeutic resistance, and risk of relapse. We try to seek valuable biomarkers and explore the mechanism of MPO-ANCA-GN by metabolomics. Method Urine and plasma samples from 63 MPO-ANCA-GN, 31 lupus nephritis (LN), 15 IgA nephropathy (IgAN), and 15 minimal change disease (MCD) patients and 30 HC were collected for metabolomics analysis. The samples were analyzed using Ultra Performance Liquid Chromatography (UPLC) and Tandem mass spectrometry (MS/MS). The different groups of samples were compared using Partial Least Squares-Discriminant Analysis. A Receiver Operator Characteristic (ROC) curve was constructed to assess the performance of the metabolite model in identifying active renal vasculitis. KEGG annotation and enrichment analysis were performed for key pathways. Results All metabolites in urine and plasma samples including hydrophilic compounds and hydrophobic compounds were identified. Compared with the disease control (DC) and HC, we observed 79 significantly upregulated metabolites (VIP&amp;gt;1, FDR&amp;lt;0.05, FC&amp;gt;1.5) and 32 downregulated metabolites (VIP&amp;gt;1, FDR &amp;lt;0.05, FC&amp;lt;0.67) in the plasma samples of MPO-ANCA-GN patients. KEGG enrichment analysis suggested that these upregulated metabolites were mainly associated with phenylalanine metabolism and galactose metabolism and downregulated metabolites were mainly associated with bile secretion, steroid biosynthesis, and ovarian steroidogenesis. Compared with the DC and HC, we identified a total of 122 differential metabolites in the urine samples of MPO-ANCA-GN patients, 40 of which were significantly upregulated (VIP&amp;gt;1, FDR&amp;lt;0.05, FC&amp;gt;1.5) and 68 of which significantly were downregulated (VIP&amp;gt;1, FDR &amp;lt;0.05, FC&amp;lt;0.67). Subsequently, KEGG analysis revealed that these upregulated metabolites were mainly enriched in glycerolipid metabolism, lipid and atherosclerosis, cholesterol metabolism, insulin resistance, regulation of lipolysis in adipocytes, vitamin digestion and absorption, fat digestion and absorption (Corrected P &amp;lt; 0.05). Downregulated metabolites were mainly enriched in steroid hormone biosynthesis (Corrected P &amp;lt; 0.05). Nine MPO-ANCA-GN patients with paired plasma and six MPO-ANCA-GN patients with paired urine during the active and remission phase were included in the study. A total of 504 differential metabolites in plasma samples were identified between the active and remission phase based on VIP value &amp;gt;1, P &amp;lt; 0.05, and FC &amp;gt;1.5 or FC &amp;lt; 0.6. Of these, 425 metabolites were downregulated, while 79 lipid metabolites were upregulated in the active group. MPO-ANCA-GN patients were divided into two groups according to Mayo Clinic/Renal Pathology Society Chronicity Score: Minimal-mild group and Moderate-severe group. In plasma samples, our data showed that 3-Methoxysalicylic Acid, Carnitine C20:5, and isoxanthopterin presented good ability in distinguishing between the minimal-mild group and the moderate-severe group, with an AUC &amp;gt; 0.7. In urine samples, cyclohexylamine and arachidonic acid (AUC &amp;gt; 0.8) can distinguish the two groups well. Conclusion We identified many novel potential metabolic biomarkers in urine and plasma samples for evaluating disease activity, therapeutic resistance, and risk of relapse in patients with MPO-ANCA-GN.

#3236 CHANGE IN ALBUMINURIA IN PATIENTS WITH ANCA-ASSOCIATED VASCULITIS TREATED WITH AVACOPAN

Abstract Background and Aims Urinary albumin:creatinine ratio (UACR) is an important biomarker of active glomerulonephritis, a common complication of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. In most glomerular diseases, high UACR levels and low estimated glomerular filtration rates are associated with the long-term risk of end-stage kidney disease, cardiovascular disease, and death.[1] In the double-dummy, double-blind, controlled ADVOCATE Phase 3 trial, patients were randomized to receive avacopan, an oral C5a receptor (C5aR) antagonist that blocks C5a-mediated neutrophil activation and migration, or a prednisone taper. All patients received background immunosuppression with either cyclophosphamide followed by azathioprine, or rituximab. Primary endpoints were remission at week 26 and sustained remission at week 52. Prespecified secondary endpoints included the evaluation of kidney function.[2] The effect of avacopan on UACR in patients with ANCA-associated vasculitis is described. Method This post hoc analysis compared the time to achieve the maximum mean difference in percent change in UACR from baseline between the avacopan and prednisone taper groups using Kaplan-Meier survival analysis. Change in UACR from baseline was a prespecified secondary endpoint but was not adjusted for multiplicity. This analysis included patients from the ADVOCATE trial with kidney involvement (based on the Birmingham Vasculitis Activity Score) and a UACR of at least 10 mg/g at baseline. Results The baseline geometric mean UACR mg/g (range) in the avacopan group (n = 125) and the prednisone taper group (n = 128) was 433 (20 to 6461) and 312 (11 to 5367), respectively. A statistically significant UACR reduction (based on least-square means) in the avacopan group compared to the prednisone taper group occurred as early as week 2 (−25% vs. 6%, p = 0.0068, difference between groups: −29%, 95% confidence interval (CI) [−45%, −9%]). UACR continued to decrease at week 4 to the maximum difference between the two groups (−40% vs. 0%, p&amp;lt;0.0001, difference between groups: −40%, 95% CI [−53%, −22%]) (Figure 1). UACR was comparable between the two groups by week 13 (−55% vs. −49%, p = 0.3028, difference between groups: −12%, 95% CI [−32%, 13%]). During the 52-week treatment period, 84% (105/125) of patients in the avacopan group achieved a 40% UACR reduction from baseline within a median time of 29 days (95% CI [29, 88]), compared to 83% (106/128) of patients in the prednisone taper group within a median time of 92 days (95% CI [91, 180]) (logrank p = 0.0450) (Figure 2). At week 52, there was a greater overall mean improvement in estimated glomerular filtration rate (eGFR) of 7.6 mL/min/1.73 m2 in the avacopan group compared to 4.6 mL/min/1.73 m2 in the prednisone taper group (p = 0.0432). Conclusion In the ADVOCATE trial, UACR, an important early indicator of improving kidney function, improved three times faster in the avacopan group compared to the prednisone taper group. The rapid reduction in UACR seen in patients with ANCA-associated vasculitis receiving avacopan suggests more rapid control of glomerular inflammation which may have contributed to the observed subsequent greater improvement in eGFR.

#3486 CELL-FREE CIRCULATING DNA IN ANCA-ASSOCIATED VASCULITIS – A COMPARISON OF PATIENTS DURING ACTIVE DISEASE AND REMISSION

Abstract Background and Aims Patients with ANCA-associated vasculitis (AAV) undergo immunosuppressive treatment to thwart organ failure and avoid relapse. However, the treatment is associated with risk of infections and malignancy. There are currently no reliable biomarkers which can be used in the clinic to assess disease activity. Neutrophil extracellular traps containing nuclear (n) and/or mitochondrial (mt) DNA have been implied in the pathogenesis of AAV. The aim of this study was to explore whether there is a difference in levels of circulating cell-free DNA (cfDNA) amongst AAV patients during active disease and in remission. Method Paired samples from 7 male and 9 female patients with AAV, of which 10 were diagnosed with GPA, were obtained during both active disease and clinical remission as part of an ongoing observational prospective study. Participants’ ages ranged from 21.8 to 80.0 years (median = 64.9), and 11 participants had a history of kidney engagement. After DNA-extraction digital droplet PCR was performed to obtain levels of mtDNA and nDNA. Clinical diagnosis (GPA or MPA), ANCA-positivity, kidney involvement, and Birmingham vasculitis activity score (BVAS) were also assessed. Results There were no significant differences in levels of mtDNA or nDNA in patients with active disease compared to remission; mtDNA (median = 14 520 and 11 985 copies/µL respectively, p = .379) and nDNA (median = 4.45 and 4.70 copies/µL, p = .569). The ratio between mtDNA and nDNA did not differ either (median 2100 and 2400, p = .679). A strong correlation between mtDNA- and nDNA levels (r = .920, p &amp;lt; .001) was found, whereas no correlations were found between cfDNA and age, sex, clinical phenotype, ANCA positivity, kidney engagement or BVAS (Tables 1 and 2). Conclusion This study provides additional information regarding levels of mtDNA and nDNA comparing AAV patients during active disease and in clinical remission. The lack of association with disease activity and the correlation between nDNA and mtDNA may indicate cell damage as a source of cfDNA. To further delineate the contribution of NETs to the levels of cfDNA, and the mechanisms behind cellular injury and inflammation, studies with larger samples with longitudinal follow-up and healthy controls are needed.

#3047 A NEW ADJUNCTIVE THERAPY WITH AVACOPAN FOR ANCA-ASSOCIATED VASCULITIS

Abstract Background and Aims Glucocorticoids have been the standard treatment for anti-neutrophil cytoplasm autoantibody-associated vasculitis (AAV). Avacopan, a complement C5a receptor inhibitor, has been approved for the treatment of AAV in Japan, the USA, Germany, and Austria. The use of avacopan is supported by evidence from trials demonstrating disease remission with limited use of glucocorticoids [1–3]. Avacopan is a new, promising adjunctive agent for standard induction therapy for AAV and may potentially reduce steroid use. Method We assessed treatment responses of patients with AAV who did not require dialysis between 2018 and 2023. Group 1 consisted of six adult patients who were treated with avacopan (30 mg, twice daily) plus reduced-dose prednisone, and Group 2 consisted of 14 patients who received high-dose prednisone. We compared the mean dose of prednisone, Birmingham Vasculitis Activity Score (BVAS), creatinine, urine protein/creatinine ratio (UPCR), and C-reactive protein (CRP) at weeks 0 and 12 between the two groups. Results The mean total prednisone dose of oral glucocorticoids at both weeks 0 and 12 was much lower in Group 1 than in Group 2 (p&amp;lt;0.05). Mean BVAS, creatinine, UPCR, and CRP in Group 1 was comparable to Group 2. Steroid-related toxicity occurred in three of six (50%) patients in Group 1, and 5 of 14 (36%) patients in Group 2. Liver damage related to avacopan occurred in two of six (33%) patients in Group 1. Conclusion Herein, we describe practice observations on the use of avacopan in patients with AAV. While further studies are needed to confirm the efficacy of avacopan because the number of cases treated with avacopan is still lacking, our findings suggest that avacopan was beneficial in AAV patients because of the absence of steroid dependence.

#4535 CLINICAL CHARACTERISTICS AND OUTCOMES IN PATIENTS ABOVE THE AGE OF 65 WITH ANCA-ASSOCIATED VASCULITIS: A SINGLE CENTRE EXPERIENCE.

Abstract Background and Aims ANCA-associated vasculitis (AAV) is common in patients above the age of 65 but there are limited data about the clinical characteristics and patient outcomes. This study intents to investigate the demographic features, treatment and outcomes in patients ≥ 65 years of age with AAV in Greece. Method In this retrospective observational study, we analyzed medical records of patients with ANCA positive AAV in a nephrology unit over the past 20 years. Patients with secondary causes of AAV were excluded. In total 37 patients were included in the study. Data are presented as median and interquartile range (IQR). Results Thirteen patients (35.1%) were above the age of 65 and 24 patients (64,9%) below the age of 65. The median age of diagnosis was 71.3 (67.5/75.1) vs 54.9 (40.4/57.3) and estimated glomerular filtration rate CKD-EPI was 30 (21.5/48) vs 17 (12.3/29.8) respectively. The Birmingham vasculitis activity score and organ involvement did not differ between the two groups. The median follow-up duration was 44.2 (15/108) months. Immunosuppressive therapy was similar in both groups, including glucocorticoids, cyclophosphamide or rituximab as induction and azathioprine or rituximab as maintenance therapy. The overall survival was significantly lower in the older group (69.2%) compared to the younger (95.8%) and renal survival was 69.2% and 91.2% respectively. Older age and elevated serum creatinine were related to increased mortality. Elevated creatinine at diagnosis was the only significant predictive factor of renal survival. Conclusion AAV is a disease with significant morbidity and mortality in patients above the age of 65. This study showed that the typical immunosuppressive therapy might not improve outcomes in the older patients.