small molecules

2026-07-28 | Advances in the Diagnosis, Treatment and Prognosis of ANCA-Associated Glomerulonephritis.

ANCA-associated vasculitis (AAV) with kidney involvement represents small-vessel vasculitis, characterized by rapidly progressive glomerulonephritis and a high risk of end-stage kidney disease (ESKD) and increased mortality. AAV typically presents with multisystem involvement, with renal manifestations occurring more frequently in microscopic polyangiitis (MPA) (90-100%) and granulomatosis with polyangiitis (GPA) (50-80%). The classic clinical presentation includes acute kidney injury with hematuria and proteinuria, accompanied by ANCA positivity (MPO-ANCA or PR3-ANCA). Histologically, the predominant pattern is segmental necrotizing glomerulonephritis with crescent formation. Treatment consists of two phases: (a) induction of remission with a lower cumulative dose of glucocorticoids (according to the reduced-dose PEXIVAS regimen) in combination with rituximab or cyclophosphamide and (b) maintenance of remission with rituximab for 2-4 years. The C5a receptor inhibitor avacopan can be used as a steroid-sparing agent in patients with severe kidney involvement or at high risk of corticosteroid-related complications. Beyond the traditional markers of disease activity (hematuria, proteinuria, eGFR), novel biomarkers such as urinary soluble CD163, MCP-1, complement activation products (C5a, sC5b-9), and urinary Treg/Th17 profiles have demonstrated prognostic value. Early diagnosis and prompt initiation of immunosuppressive therapy significantly improve both kidney and overall survival, while prevention of relapses and long-term complications plays a key role in improving the long-term prognosis of patients with AAV.

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2026-07-06 | Real-world retention of nintedanib and factors associated with treatment discontinuation in connective tissue disease-associated interstitial lung disease: a retrospective cohort study of 92 patients.

Treatment discontinuation of nintedanib is an important clinical issue in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). This study aimed to evaluate real-world retention of nintedanib across CTD subtypes and to explore factors associated with treatment discontinuation. We conducted a single-center retrospective study of consecutive patients with CTD-ILD who initiated nintedanib between June 2019 and December 2024. Clinical data, including baseline characteristics, concomitant therapies, and treatment outcomes, were collected. The primary outcome was the 48-week retention rate. Kaplan-Meier analysis and Cox proportional hazards models were used to evaluate factors associated with treatment discontinuation. A total of 92 patients were included (rheumatoid arthritis [RA], n = 25; idiopathic inflammatory myopathy [IIM], n = 25; systemic sclerosis [SSc], n = 21; microscopic polyangiitis [MPA], n = 10; Sjögren disease [SjD], n = 9). The 48-week retention rate was 82.6%, with a median treatment duration of 978 days (IQR, 586-1356). Retention was lowest in RA, with higher rates observed in other CTD subtypes. Stratified analyses showed that this difference was evident in patients aged < 65 years (p = 0.001) and those receiving an initial dose of 300 mg/day (p = 0.003), but not in older patients or those receiving < 300 mg/day. In univariable analysis, RA (HR 3.10, p = 0.024) and an initial dose of 300 mg/day (HR 2.67, p = 0.050) were associated with discontinuation. However, RA was not independently associated with discontinuation after adjustment for age and initial dose in the exploratory multivariable analysis. Nintedanib showed favorable retention in CTD-ILD. Although retention appeared lower in RA, this difference may be influenced by patient characteristics such as age and initial dosing. Individualized dose selection and appropriate management of adverse events may improve treatment persistence. Key Points • Nintedanib showed favorable 48-week retention in patients with CTD-ILD in a real-world setting. • Lower retention observed in RA was influenced by age and initial dosing, rather than disease subtype alone.

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2026-07-06 | Microscopic Polyangiitis With Temporal Artery Involvement Mimicking Giant Cell Arteritis.

A 63-year-old woman presented with a four-month history of bilateral hearing loss and three months of progressive, painful peripheral neuropathy. Her clinical course was complicated by deep vein thrombosis with pulmonary emboli and an incomplete response to initial empiric glucocorticoid therapy. Following glucocorticoid taper, she developed temporal headaches, jaw claudication, and scalp tenderness, raising concern for giant cell arteritis (GCA). Laboratory evaluation revealed markedly elevated inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), microcytic anemia, mild hematuria, and strongly positive myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) by antigen-specific immunoassay with negative proteinase-3 (PR3)-ANCA. Temporal artery biopsy demonstrated transmural inflammation affecting all vessel layers without giant cells or granulomata. The combination of multisystem small-vessel involvement, MPO-ANCA seropositivity with negative PR3-ANCA, and characteristic histopathological findings established the diagnosis of microscopic polyangiitis (MPA) with temporal arteritis rather than granulomatosis with polyangiitis (GPA) or GCA. Treatment with high-dose glucocorticoids (prednisone 80 mg daily), avacopan (30 mg twice daily), and rituximab (375 mg/m² weekly for four weeks) resulted in rapid improvement of constitutional and cranial symptoms. This case highlights the importance of integrating MPO-ANCA serology and histopathological findings when temporal arteritis is the presenting feature of systemic vasculitis. It illustrates the utility of avacopan-based, glucocorticoid-sparing combination immunosuppression in this context.

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2026-06-25 | No benefit of adding glucocorticoids to maintenance treatment in reducing the risk of major relapses in ANCA-associated vasculitis: real life data from a longitudinal cohort study.

To examine the role of low-dose glucocorticoids (GCs) in major relapse, hospitalisation and damage accumulation risk during maintenance therapy in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAVs). Retrospective cohort study of newly diagnosed patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) followed in three tertiary referral centres. We recorded relapses (Birmingham Vasculitis Activity Score increase >0), increases in Vasculitis Damage Index (VDI) and hospitalisations. We used time-varying and mixed-effects Cox models to examine the effect of GCs on the risk of major relapses, VDI accumulation and hospitalisations. Sensitivity analysis was also conducted to address potential confounding. 171 patients (GPA: 107, MPA: 64, median age: 61 years) were included with a median follow-up of 88.2 months (803.4 patient years (PY)). We recorded 65 major relapses (8.1/100 PY) in 48 patients (28%), 65 events of new damage (8.1/100 PY) and 132 hospitalisations (16.4/100 PY). By multivariable analysis, rituximab use was associated with a lower risk (HR=0.21, 95% CI 0.09 to 0.47, p=0.0001) while disease activity at diagnosis was associated with an increased risk (HR=1.17, 95% CI 1.03 to 1.33, p=0.013) of major relapses. Low-dose GCs were not associated with a reduced major relapse risk (HR=0.96, 95% CI 0.88 to 1.05, p=0.36) but they were associated with a risk of damage accumulation (HR=1.52, 95% CI 1.19 to 1.93, p=0.0007) and hospitalisations (HR=1.24, 95% CI 1.06 to 1.45, p=0.006). Higher GC exposure during maintenance therapy was not significantly associated with a lower major relapse risk whereas it was associated with damage accrual and hospitalisation. These findings may support decision making regarding long-term GC use in patients with GPA/MPA.

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2026-06-05 | Early relapse under the LoVAS reduced-dose glucocorticoid regimen in ANCA-associated vasculitis: a single-center retrospective observational study.

To evaluate early relapse and other clinical outcomes in patients with microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA) treated with reduced-dose glucocorticoid (GC) regimens, with a focus on the LoVAS regimen in comparison with the PEXIVAS regimen. We conducted a retrospective single-center cohort study of consecutive patients with newly diagnosed or relapsing MPA or GPA treated between March 2022 and September 2025. Patients were classified into LoVAS or PEXIVAS groups if they adhered to the assigned reduced-dose GC regimens for at least 14 days. The primary outcome was time to first relapse. Secondary outcomes included time to GC withdrawal, time to serious adverse events, and cumulative GC exposure. Time-to-event outcomes were analyzed descriptively using Kaplan-Meier curves and log-rank tests and were interpreted as exploratory because of the small sample size and limited number of events. A total of 21 patients were included (LoVAS, n = 5; PEXIVAS, n = 16). Relapse occurred in 3/5 patients in the LoVAS group and 2/16 patients in the PEXIVAS group. In the LoVAS group, relapses occurred on days 21, 52, and 128 after treatment initiation. GC was withdrawn in 5/5 patients in the LoVAS group and 5/16 patients in the PEXIVAS group. Serious adverse events occurred in 3/5 patients in the LoVAS group and 7/16 patients in the PEXIVAS group. The median average daily prednisolone-equivalent dose was lower in the LoVAS group than in the PEXIVAS group: 3.06 mg/day versus 14.5 mg/day. These findings were interpreted descriptively because of the small sample size and limited number of events. These findings should be interpreted as hypothesis-generating and suggest that early relapse may occur in some patients treated with the LoVAS regimen in real-world practice. Further studies with larger cohorts and appropriate adjustment for confounding factors are needed.

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antibodies

2026-07-31 | Biosimilar Rituximab in ANCA-Associated Vasculitis Compared to the Originator: A Multicenter Cohort Study.

To evaluate the six-month effectiveness and safety of rituximab biosimilars compared to the originator in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), and outcomes following originator to biosimilar switching. We recruited adults with GPA or MPA treated with the rituximab originator or a biosimilar for induction or maintenance, or who switched from originator to biosimilar maintenance (2018-2023). Participants either started the treatment within the preceding six months or were recruited from vasculitis research cohorts. Outcomes included six-month remission (Birmingham Vasculitis Activity Score [BVAS] version 3 of 0), relapse (BVAS rise after achieving remission requiring treatment), vasculitis damage, and serious adverse events (SAEs). We studied 207 participants from 9 centers: 132 starting induction (58 originator and 74 biosimilar), 59 starting maintenance (23 originator and 36 biosimilar), and 16 in the "switch" group. Mean age was 56.7 years (SD 17.5), 52% were female, 80% were White, and 70% had GPA. At six months from induction, 51 of 53 (96%) originator and 66 of 73 (90%) biosimilar recipients achieved remission (difference 6%, 95% confidence interval [CI] -4% to 15%), whereas at three months (exploratory) 48 of 51 (94%) and 57 of 72 (79%) recipients, respectively, had achieved remission (difference 15%, 95% CI 2% to 26%). All individuals in the maintenance and "switch" subgroups were in remission at six months. One minor relapse occurred in each of the induction groups and in the originator maintenance group. Change in vasculitis damage and SAEs were not significantly different between groups. This study found no significant differences in six-month outcomes between the rituximab originator and biosimilars for induction of GPA and MPA, with no concerning early signals in those initiating maintenance or switching from the originator to a biosimilar.

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2026-07-16 | Developing a prediction model for poor prognosis in MPA patients using initial admission examination results: a machine learning study from Southwest China.

Microscopic polyangiitis (MPA) is one of the main types of ANCA-associated vasculitis (AAV), but current admission examination indicators are limited in predicting poor prognosis for MPA. This study aims to develop a prediction model for adverse prognosis in MPA patients using initial admission examination results. We performed machine learning (ML) algorithms on initial admission examination data to predict adverse outcomes in MPA, such as in-hospital death or self-discharge due to critical condition. We analyzed data from 12,497 patients who underwent ANCA tests in Deyang People's Hospital between November 2017 and October 2025, focusing on 230 hospitalized patients. We used least absolute shrinkage and selection operator (LASSO), logistic regression (LR), and random forest (RF) to select variables, and evaluated the diagnostic efficacy using ML algorithms. SHapley Additive exPlanations (SHAP) was used for model interpretability. A nomogram model was developed to predict adverse outcomes, highlighting variable contributions and including calibration and decision curve analysis (DCA) curves. In this study of 230 MPA patients, 56 had poor prognosis while 174 had good prognosis. Seven indicators were identified using LASSO, LR and RF. They were appropriate use of immunosuppressants, age, serum albumin, infection, BVAS, C-reactive protein (CRP) and anti- myeloperoxidase. Among five ML models, support vector classification (SVC) had a high area under the curve (AUC) (AUC = 0.848, 95% confidence interval [CI]: 0.684-0.965) in the prediction model, and had the highest AUC (AUC = 0.886, 95% CI: 0.741-0.981). The SHAP analysis highlighted elevated CRP levels as the top predictor of poor prognosis. Standardized immunosuppressive therapy was found to mitigate this risk. Nomogram model confirmed these findings, and calibration and DCA curves showed this model was reliable and useful for clinical decisions. We developed a prediction model for adverse outcomes in MPA patients, utilizing clinical and laboratory data collected on the day of admission. SVC algorithm exhibited moderate predictive efficacy. Factors such as elevated serum CRP levels, moderate reductions in serum albumin, infection, advanced age, BVAS larger than 15, and anti-MPO were positively associated with adverse prognoses. Standardized immunosuppressive therapy was shown to mitigate this risk, offering a valuable reference for clinical decision-making.

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2026-07-01 | High Renal and Pulmonary Involvement and Mortality in Chinese Patients with Granulomatosis with Polyangiitis and Microscopic Polyangiitis: An Epidemiological Study in Hong Kong

Objectives: Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are the two major subtypes of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and are associated with substantial mortality. Geographic variation exists in the epidemiology and clinical manifestations of AAV, with Southeast Asian populations showing a predominance of MPA and higher mortality. However, data on Chinese populations remain limited. This study aimed to investigate the epidemiology, mortality risk, and prognostic factors of GPA or MPA in Chinese patients in Hong Kong. Methods: Newly diagnosed cases of GPA and MPA from 2013 to 2023 were identified using ICD-9 codes from databases across eight public hospitals in Hong Kong. Incidence rates were calculated using population denominators. Patient demographics, clinical features, treatments, and outcomes, including survival, relapse, and dialysis requirement, were analyzed using the Kaplan–Meier method and Cox proportional hazards regression. Results: A total of 35 patients with GPA and 127 patients with MPA were identified. The estimated incidence rates of GPA and MPA were 0.9 and 3.2 per million population, respectively. Renal and pulmonary involvement was common, occurring in 82.1% and 51.2% of patients, respectively. Mortality rates were 22.8% at 1 year and 34.0% at 5 years. The age- and sex-adjusted standardized mortality ratio was 6.51 ± 0.81. Multivariate analysis identified age, renal dysfunction, and pulmonary involvement as independent risk factors for mortality. Subgroup analysis showed better dialysis-free survival among patients treated with rituximab than among those treated with cyclophosphamide. Conclusions: Chinese patients with AAV presented with severe renal–pulmonary disease and markedly elevated mortality. Older age, renal dysfunction, and pulmonary involvement were associated with an increased risk of mortality. Rituximab appeared to be associated with better dialysis-free survival than cyclophosphamide.

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2026-06-22 | Laryngeal manifestations of microscopic polyangiitis in a pediatric patient: a case report

Microscopic polyangiitis is a rare small-vessel vasculitis associated with antineutrophil cytoplasmic antibodies.Otorhinolaryngological manifestations are uncommon, particularly in pediatric patients, which may delay diagnosis and appropriate treatment.We report the case of a 16 year-old female with a history of Graves disease on methimazole who presented to the emergency department with nonspecific otorhinolaryngological symptoms, followed by rapid clinical deterioration that required advanced resuscitation and admission to the pediatric intensive care unit.Clinical evaluation revealed epiglottic edema, yellowish lesions on the oropharyngeal mucosa, and right vocal fold paralysis.Laboratory findings demonstrated positive anti-myeloperoxidase antibodies, confirming the diagnosis of microscopic polyangiitis.The patient received two cycles of rituximab with marked clinical improvement and preserved vocal fold mobility.This case underscores the diagnostic challenge of microscopic polyangiitis with initial laryngeal involvement in a pediatric patient and highlights the importance of close observation and an interdisciplinary approach.

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2026-06-20 | An update on the pharmacotherapy of ANCA-associated vasculitis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are rare, life-threatening autoimmune conditions requiring complex pharmacological management. Contemporary strategies have transitioned from empirical cytotoxic therapy toward mechanistically targeted approaches, reflecting a deeper understanding of B-cell immunity and the alternative complement pathway. This review synthesizes current guidance and presents recent evidence on treatment modalities and emerging options. This paper reviews and synthesizes current international guidance from the European League Against Rheumatism (EULAR), the British Society for Rheumatology (BSR), and the American College of Rheumatology (ACR) on remission induction and maintenance for granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Key shifts discussed include the established role of rituximab as a primary induction agent, the implementation of reduced-dose glucocorticoid tapering, and the integration of anti-IL-5 therapies for eosinophilic phenotypes. In our opinion, the management of AAV has entered a precision era defined by targeted, steroid-sparing regimens. The most significant progress lies in standardizing B‑cell depletion and the emergence of complement inhibition. Despite the evolution of steroid-sparing protocols, mitigation of treatment-related morbidity remains a primary challenge. Ultimately, AAV management must transition toward biomarker-driven precision medicine to individualize therapy and improve long-term outcomes.

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cell therapies

2026-05-01 | B35-54 When Evidence Is Evolving: Individualized Use of Plasma Exchange in Life-threatening Microscopic Polyangiitis

Abstract Microscopic polyangiitis (MPA) is a pauci-immune small-vessel vasculitis most commonly associated with myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA). It frequently presents with rapidly progressive glomerulonephritis (RPGN) and diffuse alveolar hemorrhage (DAH), both markers of increased morbidity and mortality. While high-dose corticosteroids with rituximab or cyclophosphamide remain standard therapy, the role of plasma exchange (PLEX) is evolving, with selective benefit suggested in cases of severe renal dysfunction and hypoxemic DAH. A 70-year-old woman with estrogen/progesterone receptor-positive invasive lobular carcinoma in remission, type 2 diabetes presented five days after discharge for presumed community-acquired pneumonia. During the prior admission, creatinine rose from 1.0 to 3.6 mg/dL with frank hematuria, though opacities in the right upper lobe were attributed to infection. On readmission, she appeared fatigued but hemodynamically stable with O2 saturation 94% on 2 L nasal cannula. Laboratory results showed Cr 4.66 mg/dL, BUN 31 mg/dL, Hgb 8.6 g/dL (from 13 g/dL baseline), and urinalysis positive for dysmorphic RBCs and 3+ protein. CXR demonstrated new bilateral patchy infiltrates. Empiric broad-spectrum antibiotics were initiated. Over the next 48 hours, she experienced rapid respiratory decline with increasing oxygen requirement to 14 L HFNC, diffuse crackles, and escalating bloody secretions. CT chest revealed diffuse bilateral ground-glass opacities. Bronchoscopy confirmed DAH with bloody return from serial aliquots and clot burden requiring suctioning. She was intubated for hypoxemic respiratory failure, and methylprednisolone 1 g/day x3 days was initiated. MPO-ANCA level was 217 U (normal &lt;20), PR3 negative. Renal biopsy showed cellular crescents in &gt; 50% of glomeruli without immune-complex deposition, consistent with pauci-immune crescentic glomerulonephritis. Hemodialysis was started due to rising creatinine (peak 6.46 mg/dL) and concern for uremic platelet dysfunction. Plasma exchange was initiated daily. Cyclophosphamide was administered on hospital day 7 followed by rituximab on day 9, timed around PLEX and HD sessions. After the fourth PLEX session, her oxygenation improved with cessation of hemorrhage and decreased bloody airway secretions. She was extubated successfully and dialysis was discontinued by hospital day 17 with improving urine output. At four-week follow-up, creatinine improved to 3.1 mg/dL with adequate urine output, and she remained oxygen-independent while transitioning to avacopan-based maintenance therapy.While PLEX is no longer recommended routinely for all cases of ANCA-associated vasculitis, this case demonstrates that it remains an important adjunct in selected patients presenting with concurrent DAH and advanced renal dysfunction. Tailoring therapy to disease severity, patient comorbidities, and evolving evidence can optimize outcomes in life-threatening presentations of MPA This abstract is funded by: none

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2025-12-31 | Plasma Exchange as an Adjunctive Therapeutic Option for Severe and Refractory Antineutrophil Cytoplasmic Antibody-Negative Microscopic Polyangiitis and Granulomatosis with Polyangiitis.

Background and Objectives: This study investigated and compared the efficacy of therapeutic plasma exchange (PEX) between antineutrophil cytoplasmic antibody (ANCA)-positive and ANCA-negative patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) presenting with diffuse alveolar haemorrhage (DAH) and rapidly progressive glomerulonephritis (RPGN). Materials and Methods: A total of 336 patients with ANCA-associated vasculitis were screened, and 34 patients with MPA/GPA receiving PEX for DAH or RPGN were included. PEX was performed a total of 5-6 times consecutively (three times a week × 2 weeks) in all 34 patients. All-cause mortality (ACM) and end-stage kidney disease (ESKD) were evaluated as poor outcomes of MPA/GPA. Clinical data and poor outcomes were compared between ANCA-positive and ANCA-negative MPA/GPA patients receiving PEX. Results: The median age of the 34 MPA/GPA patients was 67 years (15 men and 19 women), of whom two were diagnosed with ANCA-negative vasculitis. Among the 34 patients, 28 (82.4%) received PEX owing to RPGN, and 6 (17.6%) due to DAH. During follow-up, 13 patients (38.2%) died, and 15 (44.1%) progressed to ESKD. Serum protein and C-reactive protein levels at AAV diagnosis were higher in ANCA-positive MPA/GPA patients than in ANCA-negative patients, although the difference was not statistically significant. Similarly, there were no differences in ACM or ESKD between the two groups during follow-up. Survival analysis showed that ANCA-positive MPA/GPA patients did not have significantly different cumulative patient or ESKD-free survival rates compared to ANCA-negative patients. Conclusions: This pilot study is the first to demonstrate the clinical feasibility of PEX in managing severe and refractory ANCA-negative MPA and GPA.

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2025-10-01 | In Selected Patients with Severe ANCA-Associated Vasculitis (AAV) and Diffuse Alveolar Hemorrhage (DAH), Plasma Exchange (PLEX) May Provide Benefit in Addition to Glucocorticoid: A Challenging Case

Introduction: AAV encompasses a group of diseases characterized by inflammation of small- to medium-sized blood vessels, including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).[1] The incidence and prevalence of AAV have been increasing over the past few decades. The global pooled incidence is approximately 17.2 per million person-years, with a prevalence of 198 per million persons.[2] Kidney involvement in AAV is common, with more than 75% of patients presenting with rapidly progressive glomerulonephritis, which can lead to end-stage kidney disease (ESKD).[3] The pathogenesis involves the formation of pauci-immune necrotizing glomerulonephritis, often associated with either proteinase 3 (PR3)-ANCA or myeloperoxidase (MPO)-ANCA.[3] DAH is a severe and potentially life-threatening manifestation of AAV.[4] Case Description: 74-year-old male with history of CKD stage III/IV,AAV,DAH, biopsy-proven ANCA associated GN, who was managed with rituximab and pulse dose steroids which was transitioned to prednisone. Shortly after starting the treatment, the patient presented to the ER and was admitted for acute hypoxic respiratory failure. Patient was managed with PLEX that showed significant improvement. Lab:ANA 1:1280,dsDNA 5,pANCA + >1:640 with positive MPO >800 and PR3 of 14.1, with negative SCL-70,Sm,SM/RNP,Ribosomal P Ab,SSA,SSB CT Chest: Upper predominant lung opacities compatible with DAH, confirmed with bronchoscopy Discussion: PLEX has been evaluated as an adjunctive therapy in AAV with DAH. The PEXIVAS trial found no significant benefit of PLEX in reducing mortality or progression to ESKD, even among patients with DAH[5,6]. However, in selected cases, particularly those with pulmonar involvement, PLEX may offer additional clinical benefit beyond standard high-dose corticosteroid therapy. In our patient, DAH was refractory to initial high-dose steroids but showed marked improvement following initiation of PLEX. This case supports consideration of early PLEX use in patients with AAV and DAH, as it may contribute to improved outcomes in appropriately selected individuals

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2024-01-05 | CD19-targeting CAR T cells protect from ANCA-induced acute kidney injury

Objectives Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are life-threatening systemic autoimmune diseases manifesting in the kidneys as necrotizing crescentic glomerulonephritis (NCGN). ANCA antigens are myeloperoxidase (MPO) or proteinase 3. Current treatments include steroids, cytotoxic drugs and B cell-depleting antibodies. The use of chimeric antigen receptor (CAR) T cells in autoimmune diseases is a promising new therapeutic approach. We tested the hypothesis that CAR T cells targeting CD19 deplete B cells, including MPO-ANCA-producing B cells, thereby protecting from ANCA-induced NCGN. Methods We tested this hypothesis in a preclinical MPO-AAV mouse model. NCGN was established by immunisation of MPO −/− mice with murine MPO, followed by irradiation and transplantation with haematopoietic cells from wild-type mice alone or together with either CD19-targeting CAR T cells or control CAR T cells. Results CD19 CAR T cells efficiently migrated to and persisted in bone marrow, spleen, peripheral blood and kidneys for up to 8 weeks. CD19 CAR T cells, but not control CAR T cells, depleted B cells and plasmablasts, enhanced the MPO-ANCA decline, and most importantly protected from NCGN. Conclusion Our proof-of-principle study may encourage further exploration of CAR T cells as a treatment for ANCA-vasculitis patients with the goal of drug-free remission.

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2023-03-01 | Double filtration plasmapheresis for children with different types of critical kidney diseases: a single-center retrospective cohort study

Background: Double filtration plasmapheresis (DFPP) was initially used to facilitate the conduction of ABO-incompatible renal transplantation.The applicability of DFPP has recently expanded to cover the removal of various antibodies in adults with immune-mediated diseases.However, DFPP is seldom used in children, with few reports addressing its efficacy and safety in this population.This study aimed to explore the efficacy and adverse effects of DFPP for pediatric patients with renal indications.Methods: Children who received DFPP between December 2017 and December 2020 at Tongji Hospital were retrospectively studied, and sub-grouped for analysis according to the types of disease.All children received 3 to 6 DFPP sessions within 2 to 3 weeks, and were assessed for clinical outcomes according to glomerular filtration rate, proteinuria and extra-renal symptoms.Pre-and post-DFPP plasma were collected to measure the levels of pathogenic autoantibodies, immunoglobulins, fibrinogen, albumin, calcium, etc. Inhospital complications were also recorded.Results: Totally there were 10 children receiving 44 sessions of DFPP, including 2 males and 8 females, with a median age of 11.2 years old (5-13 years) and a median weight of 42.1 kg (20-59 kg).Five patients were treated for systemic lupus erythematosus (SLE), three patients for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), one for C3 glomerulopathy and one for ABO-incompatible renal transplantation.Plasma autoantibodies decreased substantially by 93% and 89% in those with SLE and AAV after the last session, respectively.Complete or partial responses were achieved in 80%, 33.3%, 100% and 100% of patients with SLE, AAV, C3 glomerulopathy, and ABO-incompatible renal transplantation, respectively.The proportion of cumulative IgG, fibrinogen, and albumin removal at the end of the last sessions were 58.8%, 67.69%, and 14.05% respectively.The removal of calcium, potassium and creatinine were not statistically significant.A few episodes (4.55%) of hypotension were observed when fresh frozen plasma was used as the replacement fluid, and no bleeding nor severe anaphylaxis was noted. Conclusions:The efficacy and safety of DFPP treatment in children with SLE, AAV, C3 glomerulopathy and ABO-incompatible renal transplantation were described in the present study.DFPP is proven to be a safe apheresis method for children weighing more than 20 kg.

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proteins

2024-08-11 | Dynamics of scFv-targeted VAP2 correlating with IL-16, MIF and IL-1Ra in ANCA-associated vasculitis.

Using a mouse model of MPA with microvascular lesion with a clone (VasSF) of recombinant single chain fragments of the variable region of human IgG, we previously showed that vasculitis-associated apolipoprotein A2 (VAP2) may be a therapeutic target for vasculitis. The present study estimated the target molecules for VasSF and the association between VAP2 and cytokine levels in patient sera in terms of microvascular lesion severity. Sera and clinical information were collected from patients with microscopic polyangiitis and granulomatosis with polyangiitis (MPA/GPA) and infectious disease. Neutrophil counts, levels of C-reactive protein (CRP), creatinine, total cholesterol associated with microvascular lesion, HDL cholesterol, low-density lipoprotein cholesterol, triglycerides, glomerular filtration rate (eGFR), and cytokines were estimated. Serum VAP2 signals were determined with Western blotting. VasSF bound to a 24 kDa molecule in the serum of active MPA/GPA patients. Anti-AP2 antibody also bound with the same 24 kDa molecule, named VAP2, because of size difference from normal APOA2. The VAP2 signal was significantly stronger in the active-disease group but significantly weakened in remission. The signal correlated positively with eGFR but not with the Birmingham Vasculitis Activity Score, CRP, MPO-ANCA, or PR3-ANCA levels. It correlated negatively with MPO activity, IL-16, MIF, and IL-1Ra. Moreover, VasSF bound to a 17 kDa molecule in the remission phase. The 24 kDa VAP2 molecule may be associated with neutrophil functions because of its inverse correlation with MPO activity, IL-16, MIF, and IL-1Ra, suggesting that VAP2-APOA1 formation in HDL triggers microvascular injury. VasSF may reverse the injury by removing APOA1-VAP2 heterodimers from peripheral blood vessels.

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2024-03-13 | Enhanced efficacy of the novel recombinant clone VasSF in a mouse model of antineutrophil cytoplasmic antibody-associated vasculitis.

Based on the efficacy of intravenous immunoglobulin (IVIg) for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), we developed a recombinant single-chain-fragment variable clone, VasSF, therapeutic against AAV in a mouse model (SCG/Kj mice). VasSF is thought to bind to vasculitis-associated apolipoprotein A-II (APOA2) as a target molecule. VasSF is a promising new drug against AAV, but difficulties in the yield and purification of VasSF remain unresolved. We produced monomers of new VasSF molecules by modifying the plasmid structure for VasSF expression and simplifying the purification method using high-performance liquid chromatography. We compared the therapeutic effects between 5-day continuous administration of the monomers, as in IVIg treatment, and single shots of 5-day-equivalent doses. We also evaluated the life-prolonging effect of the single-shot treatment. Two-dimensional western blots were used to examine the binding of VasSF to APOA2. Our improved manufacturing method resulted in a 100-fold higher yield of VasSF than in our previous study. Monomerization of VasSF stabilized its efficacy. Single shots of a small amount (1/80 000 of IVIg) produced sufficient therapeutic effects, including decreased glomerular crescent formation, a decreasing trend of serum ANCA against myeloperoxidase (MPO-ANCA), decreases in multiple proinflammatory cytokines, and a trend toward prolonged survival. Two-dimensional western blots confirmed the binding of VasSF to APOA2. The newly produced pure VasSF monomers are stable and therapeutic for AAV with a single low-dose injection, possibly by removing vasculitis-associated APOA2. Thus, the new VasSF described herein is a promising drug against AAV.

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2023-02-08 | Moonlighting chromatin: when DNA escapes nuclear control

Abstract Extracellular chromatin, for example in the form of neutrophil extracellular traps (NETs), is an important element that propels the pathological progression of a plethora of diseases. DNA drives the interferon system, serves as autoantigen, and forms the extracellular scaffold for proteins of the innate immune system. An insufficient clearance of extruded chromatin after the release of DNA from the nucleus into the extracellular milieu can perform a secret task of moonlighting in immune-inflammatory and occlusive disorders. Here, we discuss (I) the cellular events involved in the extracellular release of chromatin and NET formation, (II) the devastating consequence of a dysregulated NET formation, and (III) the imbalance between NET formation and clearance. We include the role of NET formation in the occlusion of vessels and ducts, in lung disease, in autoimmune diseases, in chronic oral disorders, in cancer, in the formation of adhesions, and in traumatic spinal cord injury. To develop effective therapies, it is of utmost importance to target pathways that cause decondensation of chromatin during exaggerated NET formation and aggregation. Alternatively, therapies that support the clearance of extracellular chromatin are conceivable.

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2022-08-17 | Short-term and low-dose IL-2 therapy increases the reduced Treg cells in patients with microscopic polyangiitis.

The breakdown of immune tolerance mediated by the reduced regulatory T (Treg) cell contributes to autoimmune diseases, which can be recovered by the short-term and low-dose interleukin 2 (IL-2). However, the role of Treg cells in microscopic polyangiitis (MPA) and the efficacy of short-term and low-dose IL-2 for MPA remain unclear. Therefore, we performed a retrospective study to explore the role of Treg cells and evaluate the efficacy of short-term and low-dose IL-2 therapy in MPA. 52 MPA were collected as research objects, and 15 of them voluntarily received short-term and low-dose IL-2 subcutaneous injection combined with conventional therapy. 60 volunteers were recruited as health controls (HC) according to the inclusion and exclusion criteria. The number of circulating CD4 + T cell subsets was detected by flow cytometry. Patients with MPA had reduced circulating Treg cells than HCs (P < 0.001), and the level of Treg cells were reduced in MPA-activity and ANCA-positive group (P = 0.018 and P = 0.008 respectively). The patients with lower Treg cells had the higher incidence of the organ involvement (P = 0.006). The level of Treg cells in MPA was doubled after the short-term and low-dose IL-2 combined with conventional therapy (P = 0.001), and the disease activity indicators such as ESR and CRP were improved (P < 0.05) with no apparent side effects. Patients with MPA had reduced circulating Treg cells, especially the MPA-activity and ANCA-positive patients. And the patients with lower Treg cells were more likely to exhibit the organ involvement. Short-term and low-dose IL-2 therapy increased the reduced Treg cells and promoted the remission of the disease at a certain extent with well tolerance.

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2020-10-01 | MICROSCOPIC POLYANGIITIS PRESENTING AS DIFFUSE PULMONARY HEMORRHAGE AND ACUTE TYPE-1 RESPIRATORY FAILURE

SESSION TITLE: Medical Student/Resident Pulmonary Manifestations of Systemic Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Microscopic polyangiitis is one of the causes of pulmonary-renal syndrome, a grave diagnosis with high mortality rate. Pulmonary symptoms include chest pain, dyspnea, and hemoptysis, with imaging showing diffuse pulmonary infiltrates. High degree of suspicion is required for timely diagnosis and management as delay in treatment increases mortality rate. CASE PRESENTATION: 59-year-old white Caucasian male with multiple comorbidities was admitted with acute type one respiratory failure requiring intubation due to diffuse pulmonary hemorrhage. During intubation, copious bloody secretions within the airway were noted, making intubation technically difficult. Patient was not taking any anticoagulant prior to admission and prophylactic anticoagulation was not initiated due to profound anemia on admission and concerns of airway hemorrhage.His clinical course was complicated by hemorrhagic shock, ischemic hepatitis, and worsening acute kidney injury that required dialysis, patient was treated with pulse steroid therapy, erythropoeitin was given in an attempt to improve anemia. Physical examination at presentation showed diffuse bilateral coarse breath sounds on auscultation. Pertinent blood work was hemoglobin of 6.8 gm/dl, Creatinine of 2.1 mg/dl, ALT of 1369 U/L, AST of 1812 U/L, positive MPO antibody with ANCA titer of 1:40, and low C3 complement level, pulmonary-renal syndrome was suspected with hemorrhagic airway and worsening kidney injury. CT scan of chest without contrast showed diffuse bilateral ground-glass opacities. Patient's family refused blood products due to religious beliefs and had continued worsening. Unfortunately, the patient did not respond to treatment and passed away. DISCUSSION: Microscopic polyangiitis (MPA) is an ANCA positive small vessel vasculitis and one of the causes of pulmonary-renal syndrome. MPA is associated with a 90% positive ANCA antibody and causes necrotizing vasculitis of small vessels without granuloma formation. Despite appropriate management, ANCA vasculitis remains a grave diagnosis with a mortality rate of 10% at one year.Intubating a patient with suspected alveolar hemorrhage can be technically difficult, placing a large diameter ETT considered safe, elective intuabtion of non-bleeding lung if bleeding lung can be indetified using bronchoscopy. Double lumen ETT is less preferable and comes with serious consequences of poor positioning and limiting bronchoscopy due to smaller-diameter lumen.Patients who declines blood transfusion can be challenging. Minimizing blood loss, reducing blood draws as well as optimizing RBC cell production along with reducing oxygen demand, improving oxygen delivery and using erythyroipesis stimulating agents have been used to improve anemia in such patients. CONCLUSIONS: Clinicians should be aware of the possibility of pulmonary-renal syndrome in a patient presenting with hemoptysis, hypoxia, and renal impairment. Reference #1: https://www.ncbi.nlm.nih.gov/pubmed/25984050 Reference #2: https://www.ncbi.nlm.nih.gov/pubmed/32185342 Reference #3: https://www.ncbi.nlm.nih.gov/books/NBK554372/ DISCLOSURES: No relevant relationships by Adel El Abbassi, source=Web Response No relevant relationships by Mahmoud El Iskandarani, source=Web Response No relevant relationships by Ibrahim Haddad, source=Web Response No relevant relationships by Sajin Karakattu, source=Web Response No relevant relationships by Lana Makahleh, source=Web Response No relevant relationships by Rasheed Musa, source=Web Response

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2024-05-19 | Association between CBL gene polymorphism and susceptibility of microscopic polyangiitis in a Chinese population: A case-control analysis.

To assess whether Casitas B-lineage lymphoma (CBL) gene polymorphism influences the risk of microscopic polyangiitis (MPA) in Chinese populations. In total, 266 MPA patients and 297 healthy controls were recruited for a case-control study. Five CBL SNPs were genotyped using multiplex polymerase chain reaction and high-throughput sequencing. The relationship between SNPs and the risk of MPA under different genetic models was evaluated by SNPstats. SNP-SNP interaction was analyzed by generalized multifactor dimensionality reduction (GMDR). Finally, the association between CBL SNPs and treatment effects were assessed. The results showed that CBL rs2276083 was associated with decreasing MPA risk under dominant (OR: 0.53; p = 0.014) and recessive models (OR: 0.52; p = 0.0034). Stratification analysis indicated that rs2276083 and rs2509671 in age < 60 years, rs2276083 in female or in Han population were protective factors for MPA. The CBL haplotype (A-A-G-C-T) was associated with an increased risk of MPA. GMDR suggested that CBL rs2276083, phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PI3KCA) rs1607237, and autophagy-related gene 7 (ATG7) rs7549008 might interact with each other in MPA development (p = 0.0107). CBL rs1047417 with AG genotype and rs11217234 with AG genotype had better clinical treatment effects than other two genotypes (p = 0.048 and p = 0.025, respectively). The genetic polymorphism of CBL had a potential association with the risk of MPA and clinical treatment effects in Guangxi population in China.

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2023-08-21 | BA.1/BA.5 Immunogenicity, Reactogenicity, and Disease Activity after COVID-19 Vaccination in Patients with ANCA-Associated Vasculitis: A Prospective Observational Cohort Study

Emerging omicron subtypes with immune escape lead to inadequate vaccine response with breakthrough infections in immunocompromised individuals such as Anti-neutrophil Cytoplasmic Antibody (ANCA)-associated vasculitis (AAV) patients. As AAV is considered an orphan disease, there are still limited data on SARS-CoV-2 vaccination and prospective studies that have focused exclusively on AAV patients are lacking. In addition, there are safety concerns regarding the use of highly immunogenic mRNA vaccines in autoimmune diseases, and further studies investigating reactogenicity are urgently needed. In this prospective observational cohort study, we performed a detailed characterization of neutralizing antibody responses against omicron subtypes and provided a longitudinal assessment of vaccine reactogenicity and AAV disease activity. Different vaccine doses were generally well tolerated and no AAV relapses occurred during follow-up. AAV patients had significantly lower anti-S1 IgG and surrogate-neutralizing antibodies after first, second, and third vaccine doses as compared to healthy controls, respectively. Live-virus neutralization assays against omicron subtypes BA.1 and BA.5 revealed that previous SARS-CoV-2 vaccines result in an inadequate neutralizing immune response in immunocompromised AAV patients. These data demonstrate that new vaccination strategies including adapted mRNA vaccines against epitopes of emerging variants are needed to help protect highly vulnerable individuals such as AAV patients.

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2023-02-06 | Microscopic polyangiitis plasma-derived exosomal miR-1287-5p induces endothelial inflammatory injury and neutrophil adhesion by targeting CBL.

An inflammatory environment around the vessel wall caused by leukocyte infiltration is one of the characteristic histopathological features of microscopic polyangiitis (MPA); however, the pathogenic mechanisms are not fully understood. Studies have found that circulating microRNA (miRNA) can be used as potential biomarkers for the diagnosis and classification of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV), and the E3 ubiquitin ligase casitas B-lineage lymphoma (CBL) seems to be associated with inflammation. In addition, evidence indicates that miRNA can be tracked into exosomes and transferred into recipient cells to mediate the process of vascular endothelial injury. Herein, we aimed to identify the profiles of exosomal miRNA, and determine the effect of exosomal miR-1287-5p and its target gene CBL on vascular endothelial cells in MPA. We isolated plasma exosomes from patients with MPA (MPA-exo) and healthy controls (HC-exo) by ultracentrifugation and conducted exosome small-RNA sequencing to screen differential miRNA expression in MPA-exo (n = 3) compared to HC-exo (n = 3). We measured the expression levels of miR-1303, miR-1287-5p, and miR-129-1-3p using quantitative reverse transcription-polymerase chain reaction (qRT-PCR, n = 6) and performed dual luciferase reporter gene assays to confirm the downstream target gene of miR-1287-5p. In addition, we treated human umbilical vein endothelial cell (HUVEC) with MPA-exo, or transfected them with miR-1287-5p mimic/inhibitor or with CBL-siRNA/CBL-siRNA+ miR-1287-5p inhibitor. After cell culture, we evaluated the effects on vascular endothelial cells by examining the mRNA levels of IL-6, IL-8, MCP-1, ICAM-1 and E-selectin using qRT-PCR and performed neutrophil adhesion assay with haematoxylin staining. Transmission electron microscopy, Western blot and nanoparticle tracking analysis showed that we successfully purified exosomes and MPA-exo could be absorbed into HUVEC. We screened a total of 1,077 miRNA by sequencing and observed a high abundance of miR-1287-5p in the exosomes obtained from MPA plasma. The dual luciferase reporter assay identified CBL as a downstream target gene of miR-1287-5p, and the results revealed that MPA-exo decreased CBL protein expression in HUVEC. In addition, treatment with MPA-exo, up-regulating miR-1287-5p or silencing of CBL in HUVEC significantly increased the mRNA expression of inflammatory factors (including IL-6, IL-8, and MCP-1) and adhesion molecules (including ICAM-1 and E-selection) and promoted the adhesion of neutrophils to HUVEC. However, down-regulating miR-1287-5p had the opposite effect. Our study revealed that MPA-exo was involved in the intercellular transfer of miR-1287-5p and subsequently promote the development of acute endothelial injury in MPA. MiR-1287-5p and CBL agonists may be promising therapeutic approach for MPA-induced vascular inflammatory injury.

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2023-01-27 | Peer Review #2 of "Microscopic polyangiitis plasma-derived exosomal miR-1287-5p induces endothelial inflammatory injury and neutrophil adhesion by targeting CBL (v0.2)"

Background: An inflammatory environment around the vessel wall caused by leukocyte infiltration is one of the characteristic histopathological features of Microscopic polyangiitis (MPA); however, the pathogenic mechanisms are not fully understood.Studies have found that circulating microRNA (miRNA) can be used as potential biomarkers for the diagnosis and classification of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV), and the E3 ubiquitin ligase casitas B-lineage lymphoma (CBL) seems to be associated with inflammation.In addition, evidence indicates that miRNA can be tracked into exosomes and transferred into recipient cells to mediate the process of vascular endothelial injury.Herein, we aimed to identify the profiles of exosomal miRNA, and determine the effect of exosomal miR-1287-5p and its target gene CBL on vascular endothelial cells in MPA. Method:We isolated plasma exosomes from patients with MPA (MPA-exo) and healthy controls (HC-exo) by ultracentrifugation and conducted exosome small-RNA sequencing to screen differential miRNA expression in MPA-exo (n=3) compared to HC-exo (n=3).We measured the expression levels of miR-1303, miR-1287-5p, and miR-129-1-3p using quantitative reverse transcription-polymerase chain reaction (qRT-PCR, n=6) and performed dual luciferase reporter gene assays to confirm the downstream target gene of miR-1287-5p.In addition, we treated human umbilical vein endothelial cell (HUVEC) with MPA-exo, or transfected them with miR-1287-5p mimic/inhibitor or with CBL-siRNA/CBL-siRNA+ miR-1287-5p inhibitor.After cell culture, we evaluated the effects on vascular endothelial cells by examining the mRNA levels of IL-6, IL-8, MCP-1, ICAM-1 and E-selectin using qRT-PCR and performed neutrophil adhesion assay with haematoxylin staining.Result: Transmission electron microscopy, Western blot and nanoparticle tracking analysis showed that we successfully purified exosomes and MPA-exo could be absorbed into HUVEC.We screened a total of 1077 miRNA by sequencing and observed a high abundance of miR-1287-5p in the exosomes obtained from MPA plasma.The dual luciferase reporter assay identified CBL as a downstream target gene of miR-1287-5p, and the results revealed that MPA-exo decreased CBL protein expression in HUVEC.In addition, treatment with MPA-exo, up-regulating miR-1287-5p or silencing of CBL in HUVEC significantly increased the mRNA expression of inflammatory factors (including IL-6, IL-8, and MCP-1) and adhesion molecules (including ICAM-1 and E-selection) and promoted the adhesion of neutrophils to HUVEC.However, down-regulating miR-1287-5p had the opposite effect. Conclusion:Our study revealed that MPA-exo was involved in the intercellular transfer of miR-1287-5p and subsequently promote the development of acute endothelial injury in MPA.MiR-1287-5p and CBL agonists may be promising therapeutic approach for MPA-induced vascular inflammatory injury.

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2022-12-14 | Analysis and Validation of Antineutrophil cytoplasmic antibody-associated vasculitis with renal injury of the ferroptosis-related gene CD44 and Pan-Cancer

Abstract Objective : To investigate the role of ferroptosis in Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with renal injury. Methods : GSE104954 and GSE108112 were retrieved from the GEO database and concatenated into one dataset. Expression of ferroptosis-related genes (FRGs) was extracted for differential analysis. The ferroptosis signature genes were identified by LASSO regression and SVM-RFE, and their differential expression levels and diagnostic efficacy were verified by independent data sets. The ceRNA (miRNA-TF-mRNA) regulatory network and clinical diagnostic model were constructed respectively. By using consensus clustering, ferroptosis subtypes were identified. ssGSEA and GSVA were employed to assess immune response and pathway activation. Pan-cancer genes were found in TCGA and GTEx. Differential expression of CD44 in was validated by qPCR and immunohistochemistry from HPA database. Results: Twenty-four FRGs were differentially expressed in patients with AAV kidney injury. Furthermore, five ferroptosis signature genes were identified by two machine learning algorithms. Not only were differentially expressed in independent datasets, the clinical diagnostic model constructed by these genes provided reference for clinical decision-making, but also the ceRNA network revealed their complex regulatory mechanisms. Unsupervised clustering analysis discovered two ferroptosis subtypes with distinct gene expression, immunological microenvironment, and biological functioning pathways. Notably, CD44 was found to be closely associated with many immune cells, most immune responses, and HLA genes, as well as prognosis, immune cell infiltration, TMB, and MSI in patients with a variety of tumors, suggesting it may be a potential intervention target for human diseases including AAV renal injury and tumors. Conclusions: Ferroptosis in AAV with renal injury is significantly correlated with the immunological microenvironment. For AAV with renal injury and tumors, CD44 could be a useful intervention target.

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