Constitutive and induced forms of membrane-bound proteinase 3 interact with antineutrophil cytoplasmic antibodies and promote immune activation of neutrophils.

Proteinase 3 (PR3) is the main target antigen of antineutrophil cytoplasmic antibodies (ANCAs) in PR3-ANCA-associated vasculitis. A small fraction of PR3 is constitutively exposed on the surface of quiescent blood neutrophils in a proteolytically inactive form. When activated, neutrophils expose an induced form of membrane-bound PR3 (PR3mb) on their surface as well, which is enzymatically less active than unbound PR3 in solution due to its altered conformation. In this work, our objective was to understand the respective role of constitutive and induced PR3mb in the immune activation of neutrophils triggered by murine anti-PR3 mAbs and human PR3-ANCA. We quantified immune activation of neutrophils by the measurement of the production of superoxide anions and secreted protease activity in the cell supernatant before and after treatment of the cells by alpha-1 protease inhibitor that clears induced PR3mb from the cell surface. Incubation of TNFα-primed neutrophils with anti-PR3 antibodies resulted in a significant increase in superoxide anion production, membrane activation marker exposition, and secreted protease activity. When primed neutrophils were first treated with alpha-1 protease inhibitor, we observed a partial reduction in antibody-induced neutrophil activation, suggesting that constitutive PR3mb is sufficient to activate neutrophils. The pretreatment of primed neutrophils with purified antigen-binding fragments used as competitor significantly reduced cell activation by whole antibodies. This led us to the conclusion that PR3mb promoted immune activation of neutrophils. We propose that blocking and/or elimination of PR3mb offers a new therapeutic strategy to attenuate neutrophil activation in patients with PR3-ANCA-associated vasculitis.

Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

Activation of the alternative pathway (AP) of complement is involved in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), although the underlying molecular mechanisms are unclear. To gain insight into the role of the AP, common gene variants in CFH/CFHR1-5, CFB, C3 and MCP, and longitudinal determinations of plasma C3, C4, FH, FHR-1, FHR-2, FHR-5, FB, properdin and sC5b-9 levels were analyzed in a Spanish AAV cohort consisting of 102 patients; 54 with active AAV (active cohort) and 48 in remission not receiving immunosuppressants or dialysis therapy (remission cohort). The validation cohort consisted of 100 patients with ANCA-associated glomerulonephritis. Here, we demonstrated that common genetic variants in complement components of the AP are associated with disease susceptibility (CFB32Q/W) or severity of kidney damage in AAV (CFH-H1, CFH1H2 and ΔCFHR3/1). Plasma levels of complement components were significantly different between active and remission cohorts. In longitudinal observations, a high degree of AP activation at diagnosis was associated with worse disease outcome, while high basal FHR-1 levels and lower FH/FHR-1 ratios determined severe forms of kidney associated AAV. These genetic and plasmatic findings were confirmed in the validation cohort. Additionally, autoantibodies against FH and C3 convertase were identified in one and five active patients, respectively. Thus, our study identified key genetic and plasma components of the AP that determine disease susceptibility, prognosis, and severity in AAV. Our data also suggests that balance between FH and FHR-1 is critical and supports FHR-1 as a novel AP-specific therapeutic target in AAV.

Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated Vasculitis.

In 2021, the Kidney Disease: Improving Global Outcomes (KDIGO) Guideline for the Management of Glomerular Diseases was published. KDIGO is committed to providing the nephrology community with periodic updates, based on new developments for each disease. For patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), avacopan received regulatory approval in late 2021, leading to this KDIGO guideline update. In addition, the evidence supporting a lower-dose glucocorticoid induction regimen or even complete replacement of glucocorticoids has become stronger. Herein, an executive summary of the most important guideline changes from the AAV chapter is provided as a quick reference.

Significance of clinical-immunological patterns and diagnostic yield of biopsies in microscopic polyangiitis and granulomatosis with polyangiitis.

BACKGROUND: Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are the two major antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). OBJECTIVES: To characterize a homogenous AAV cohort and to assess the impact of clinicopathological profiles and ANCA serotypes on clinical presentation and prognosis. Clinical differences in GPA patients according to ANCA serotype and the diagnostic yield for vasculitis of biopsies in different territories were also investigated. RESULTS: This retrospective study (2000-2021) included 152 patients with AAV (77 MPA/75 GPA). MPA patients (96.1% myeloperoxidase [MPO]-ANCA and 2.6% proteinase 3 [PR3]-ANCA) presented more often with weight loss, myalgia, renal involvement, interstitial lung disease (ILD), cutaneous purpura, and peripheral nerve involvement. Patients with GPA (44% PR3-ANCA, 33.3% MPO, and 22.7% negative/atypical ANCA) presented more commonly with ear, nose, and throat and eye/orbital manifestations, more relapses, and higher survival than patients with MPA. GPA was the only independent risk factor for relapse. Poor survival predictors were older age at diagnosis and peripheral nerve involvement. ANCA serotypes differentiated clinical features in a lesser degree than clinical phenotypes. A mean of 1.5 biopsies were performed in 93.4% of patients in different territories. Overall, vasculitis was identified in 80.3% (97.3% in MPA and 61.8% in GPA) of patients. CONCLUSIONS: The identification of GPA presentations associated with MPO-ANCA and awareness of risk factors for relapse and mortality are important to guide proper therapeutic strategies in AAV patients. Biopsies of different affected territories should be pursued in difficult-to-diagnose patients based on their significant diagnostic yield.

Risk factors for hypogammaglobulinemia and association with relapse and severe infections in ANCA-associated vasculitis: A cohort study.

OBJECTIVES: B-cell depletion induced by rituximab (RTX) in ANCA-associated vasculitis (AAV) is a risk factor for hypogammaglobulinemia. Aggregating data on gammaglobulin levels kinetics during RTX and its association with the risk of relapse and severe infection is of interest. METHODS: Gammaglobulin levels were collected before induction therapy and during RTX maintenance therapy. We used different definitions of gammaglobulin decline: 1/gammaglobulin levels <6 g/L after induction; 2/>25 % decline in gammaglobulin levels between induction and maintenance, and 3/both. Our primary objective was the impact of gammaglobulin decline on the risk of relapse and severe infections. RESULTS: We included 98 patients. Patients with gammaglobulin level <6 g/L after induction and gammaglobulin decline >25 % were older (OR 3.9; 95%CI 1.1-16.1), had more frequently baseline gammaglobulin levels <10 g/L (OR 6.0; 95%CI 1.7-25.8) and received more frequent pulses of methylprednisolone at induction (OR 4.6; 95%CI 1.3-18.5). Severe infection-free survival was significantly poorer in patients with both gammaglobulin <6 g/L and gammaglobulin decline >25 % (adjusted HR 2.3; 95%CI 1.0-5.1) and in those who received pulses of methylprednisolone (HR 5.6; 95%CI 2.3-13.4). Gammaglobulin decline was in contrast not associated with the risk of relapse. CONCLUSION: Older age, low gammaglobulin levels and pulses of methylprednisolone at induction increase the likelihood of gammaglobulin decline after induction therapy. Such decline was associated with an increased risk of severe infections but not lower risk of vasculitis relapse. Pulses of methylprednisolone at induction had an independent negative impact on gammaglobulin levels and the risk of severe infections.

Balancing efficacy and safety of complement inhibitors.

Complement inhibitors have been approved for several immune-mediated diseases and they are considered the next paradigm-shifting approach in the treatment of glomerulonephritis. The hierarchical organization of the complement system offers numerous molecular targets for therapeutic intervention. However, complement is an integral element of host defense and therefore complement inhibition can be associated with serious infectious complications. Here we give a closer look to the hierarchical complement system and how interfering with proximal versus distal or selective versus unselective molecular targets could determine efficacy and safety. Furthermore, we propose to consider the type of disease, immunological activity, and patient immunocompetence when stratifying patients, e.g., proximal/unselective targets for highly active and potentially fatal diseases while distal and selective targets may suit more chronic disease conditions with low or moderate disease activity requiring persistent complement blockade in patients with concomitant immunodeficiency. Certainly, there exists substantial promise for anti-complement therapeutics. However, balancing efficacy and safety will be key to establish powerful treatment effects with minimal adverse events, especially when complement blockade is continued over longer periods of time in chronic disorders.

Regulatory T cells effectively downregulate the autoimmune anti-MPO response and ameliorate anti-MPO induced glomerulonephritis in mice.

Regulation of autoreactive cells is key for both prevention and amelioration of autoimmune disease. A better understanding of the key cell population(s) responsible for downregulation of autoreactive cells would provide necessary foundational insight for cellular-based therapies in autoimmune disease. Utilizing a mouse model of anti-myeloperoxidase (MPO) glomerulonephritis, we sought to understand which immune cells contribute to downregulation of the anti-MPO autoimmune response. MPO-/- mice were immunized with whole MPO to induce an anti-MPO response. Anti-MPO splenocytes were then transferred into recipient mice (Rag2-/- mice or WT mice). Anti-MPO titers were followed over time. After anti-MPO splenocyte transfer, WT mice are able to downregulate the anti-MPO response while anti-MPO titers persist in Rag2-/- recipients. Reconstitution with WT splenocytes into Rag2-/- recipients prior to anti-MPO splenocyte transfer enabled mice to downregulate the anti-MPO immune response. Therefore, wildtype splenocytes contain a cellular population that is capable of downregulating the autoimmune response. Through splenocyte transfer, antibody depletion experiments, and purified cell population transfers, we confirmed that the regulatory T cell (Treg) population is responsible for the downregulation of the anti-MPO autoimmune response. Further investigation revealed that functional Tregs from WT mice are capable of downregulating anti-MPO antibody production and ameliorate anti-MPO induced glomerulonephritis. These data underscore the importance of functional Tregs for control of autoimmune responses and prevention of end-organ damage due to autoimmunity.

Circulating immune profile in granulomatosis with polyangiitis reveals distinct patterns related to disease activity.

Granulomatosis with polyangiitis (GPA) is an autoimmune disorder characterized by recurrent relapses that can cause severe tissue damage and life-threatening organ dysfunction. Multiple immune cells and cytokines/chemokines are involved in the different stages of the disease. Immune profiling of patients may be useful for tracking disease activity, however, reliable immune signatures for GPA activity are lacking. In this study, we examined circulating immune profiles in GPA patients during active and remission disease states to identify potential immune patterns associated with disease activity. The distribution and phenotypic characteristics of major circulating immune cells, and the profiles of circulating cytokines/chemokines, were studied on cryopreserved peripheral blood mononuclear cells from GPA patients (active, n = 20; remission, n = 20) and healthy controls (n = 20) leveraging a 40-color optimized multicolor immunofluorescence panel (OMIP-69) and in serum using a 46-plex Luminex multiplex assay, respectively. Deep phenotyping uncovered a distinct composition of major circulating immune cells in active GPA and GPA in remission, with the most significant findings emerging within the monocyte compartment. Our detailed analysis revealed circulating monocyte diversity beyond the conventional monocyte subsets. We identified eight classical monocyte populations, two intermediate monocyte populations, and one non-classical monocyte population. Notably, active GPA had a higher frequency of CD45RA+CCR5+CCR6-CCR7+/lowCD127-HLA-DR+CD2- classical monocytes and a lower frequency of CD45RA-CCR5-/lowCCR6-CCR7-CD127-HLA-DR+CD2+/- classical monocytes, which both strongly correlated with disease activity. Furthermore, serum levels of CXCL1, CXCL2, and CCL20, all linked to monocyte biology, were elevated in active GPA and correlated strongly with disease activity. These findings shed light on the circulating immune profile of GPA and may lead to immune signature profiles for assessing disease activity. Monocytes in particular may be studied further as potential markers for monitoring GPA.

Performance of clinical and histological prognostic scores for kidney survival in ANCA-associated vasculitis.

OBJECTIVES: Integrating clinical and histological parameters into prognostic scores may enhance the prediction of progression to kidney failure in anti-neutrophil cytoplasm antibodies-associated vasculitis (AAV). This study aimed to evaluate the prognostic performance of histological classifications and scoring systems for kidney survival in AAV. METHODS: This retrospective cohort study included 101 AAV patients with kidney involvement diagnosed by biopsy and followed for ≥12 months. The main outcome was the time to kidney failure. The prognostic performance of each histological and prognostic score was evaluated using Harrell's C statistic and Akaike's Information Criteria. RESULTS: Among the 101 patients, 37 progressed to kidney failure over a median follow-up of 75 months (IQR 39-123). The Harrell's C statistic was 0.702 (0.620-0.784), 0.606 (0.473-0.738), 0.801 (0.736-0.867), 0.782 (0.706-0.858), and 0.817 (0.749-0.885) for the EUVAS/Berden classification, Mayo Clinic Chronicity Score, Percentage of ANCA Crescentic Score (PACS), ANCA renal risk score (ARRS), and the improved ANCA kidney risk score (AKRiS), respectively. The AKRiS best discriminated the risk of kidney failure progression among subgroups. The AKRiS performance decreased with longer follow-up intervals. Adding the peak estimated glomerular filtration rate attained post-therapy improved the AKRiS performance at all follow-up intervals. Kidney relapses precipitated kidney failure in 71% of cases that progressed after the first year of follow-up. CONCLUSION: The novel AKRiS enhances the prediction of kidney failure in AAV with kidney involvement. As the prognostic yield of AKRiS decreases over time, a second calculation of AKRiS, including post-therapy kidney function, may improve its long-term performance.

FTY720 ameliorates experimental MPO-ANCA-associated vasculitis by regulating fatty acid oxidation via the neutrophil PPARα-CPT1a pathway.

OBJECTIVES: Increasing studies demonstrated the importance of C5a and anti-neutrophil cytoplasmic antibody (ANCA)-induced neutrophil activation in the pathogenesis of ANCA-associated vasculitis (AAV). Sphingosine-1-phosphate (S1P) acts as a downstream effector molecule of C5a and enhances neutrophil activation induced by C5a and ANCA. The current study investigated the role of a S1P receptor modulator FTY720 in experimental autoimmune vasculitis (EAV) and explored the immunometabolism-related mechanisms of FTY720 in modulating ANCA-induced neutrophil activation. METHODS: The effects of FTY720 in EAV were evaluated by quantifying hematuria, proteinuria, crescent formation, tubulointerstitial injury and pulmonary hemorrhage. RNA sequencing of renal cortex and gene enrichment analysis were performed. The proteins of key identified pathways were analyzed in neutrophils isolated from peripheral blood of patients with active AAV and normal controls. We assessed the effects of FTY720 on ANCA-induced neutrophil respiratory burst and neutrophil extracellular traps formation (NETosis). RESULTS: FTY720 treatment significantly attenuated renal injury and pulmonary hemorrhage in EAV. RNA sequencing analyses of renal cortex demonstrated enhanced fatty acid oxidation (FAO) and peroxisome proliferators-activated receptors (PPAR) signalling in FTY720-treated rats. Compared with normal controls, patients with active AAV showed decreased FAO in neutrophils. FTY720-treated differentiated HL-60 cells showed increased expression of carnitine palmitoyltransferase 1A (CPT1a) and PPARα. Blocking or knockdown of CPT1a or PPARα in isolated human neutrophils and HL-60 cells reversed the inhibitory effects of FTY720 on ANCA-induced neutrophil respiratory burst and NETosis. CONCLUSION: FTY720 attenuated renal injury in EAV through upregulating FAO via the PPARα-CPT1a pathway in neutrophils, offering potential immunometabolic targets in AAV treatment.

ANCA-associated scleritis: impact of ANCA on presentation, response to therapy and outcome.

OBJECTIVES: To describe the characteristics, treatment and outcome of isolated ANCA-associated scleritis at diagnosis compared with idiopathic scleritis with negative ANCA tests. METHODS: This retrospective multicentre case-control study was performed within the French Vasculitis Study Group (FVSG) network and in three French tertiary ophthalmologic centres. Data from patients with scleritis without any systemic manifestation and with positive ANCA results were compared with those of a control group of patients with idiopathic scleritis with negative ANCA tests. RESULTS: A total of 120 patients, including 38 patients with ANCA-associated scleritis and 82 control patients, diagnosed between January 2007 and April 2022 were included. The median follow-up was 28 months (IQR 10-60). The median age at diagnosis was 48 years (IQR 33-60) and 75% were females. Scleromalacia was more frequent in ANCA-positive patients (P = 0.027) and 54% had associated ophthalmologic manifestations, without significant differences. ANCA-associated scleritis more frequently required systemic medications, including glucocorticoids (76% vs 34%; P < 0.001), and rituximab (P = 0.03) and had a lower remission rate after the first- and second-line treatment. Systemic ANCA-associated vasculitis (AAV) occurred in 30.7% of patients with PR3- or MPO-ANCA, after a median interval of 30 months (IQR 16.3-44). Increased CRP >5 mg/l at diagnosis was the only significant risk factor of progression to systemic AAV [adjusted hazard ratio 5.85 (95% CI 1.10, 31.01), P = 0.038]. CONCLUSION: Isolated ANCA-associated scleritis is mostly anterior scleritis with a higher risk of scleromalacia than ANCA-negative idiopathic scleritis and is more often difficult to treat. One-third of patients with PR3- or MPO-ANCA scleritis progressed to systemic AAV.

Association of the AAV-PRO questionnaire with established outcome measures in AAV.

OBJECTIVES: The ANCA-associated vasculitis (AAV) patient-reported outcome (AAV-PRO) questionnaire was developed to capture the impact of AAV and its treatment. We investigated the association of specific AAV-PRO domains with disease activity and extent, damage, depression, health-related quality of life, and treatment. METHODS: In a prospective longitudinal study, AAV-PRO, Beck's depression inventory (BDI), Short Form 36 (SF-36), BVAS and Vasculitis Damage Index (VDI) were completed at baseline (t1) and after 3-6 months (t2). In addition, patient data (including diagnosis, therapies, relapses, and organ manifestations) were recorded. Data were analysed by t-tests and correlation-based regression analyses. RESULTS: A total of 156 patients with AAV participated. The mean BVAS at the time of enrolment was 1.4 ± 3.74. The median AAV-PRO domain scores were higher in patients reporting 'active disease' compared with those reporting 'in remission' (P < 0.001). In the correlation analyses, all AAV-PRO domain scores correlated strongly with the BDI (all r ≥ 0.319, all P ≤ 0.001) as well as with all eight SF-36 subdomains (all |r|≥0.267, all P ≤ 0.001). The regression analyses showed that AAV-PRO domains were strongly predicted by the BDI and SF-36 domains (|ß| ≥ 0.240 for the strongest predictor of each domain). In the longitudinal comparison (t1/t2), there were no significant changes in the overall results. CONCLUSION: Our data show convergent validity for all AAV-PRO subdomains, using the established questionnaires BDI and SF-36. The AAV-PRO domains scores were not correlated with clinician-derived instruments (including the BVAS and the VDI). Thus, we regard the AAV-PRO questionnaire as a valuable measure of outcomes that might complement traditional end-points in clinical trials.

Dual MPO/PR3 ANCA positivity and vasculitis: insights from a 7-cases study and an AI-powered literature review.

OBJECTIVES: Anti-neutrophil cytoplasm antibodies (ANCA)-associated vasculitides (AAV) are rare conditions characterized by inflammatory cell infiltration in small blood vessels, leading to tissue necrosis. While most patients with AAV present antibodies against either myeloperoxidase (MPO) or proteinase 3 (PR3), rare cases of dual positivity for both antibodies (DP-ANCA) have been reported, and their impact on the clinical picture remains unclear. The goal of this study was to investigate the clinical implications, phenotypic profiles, and outcomes of patients with DP-ANCA. METHODS: A retrospective screening for DP-ANCA cases was conducted at Brest University Hospital's immunology laboratory (France), analyzing ANCA results from March 2013 to March 2022. Clinical, biological, imaging, and histological data were collected for each DP-ANCA case. Additionally, a comprehensive literature review on DP-ANCA was performed, combining an AI-based search using BIBOT software with a manual PUBMED database search. RESULTS: The report of our cases over the last 9 years and those from the literature yielded 103 described cases of patients with DP-ANCA. We identified four distinct phenotypic profiles: (i) idiopathic AAV (∼30%), (ii) drug-induced AAV (∼25%), (iii) autoimmune disease associated with a low risk of developing vasculitis (∼20%), and (iv) immune-disrupting comorbidities (infections, cancers, etc) not associated with AAV (∼25%). CONCLUSION: This analysis of over a hundred DP-ANCA cases suggests substantial diversity in clinical and immunopathological presentations. Approximatively 50% of DP-ANCA patients develop AAV, either as drug-induced or idiopathic forms, while the remaining 50%, characterized by pre-existing dysimmune conditions, demonstrates a remarkably low vasculitis risk. These findings underscore the complex nature of DP-ANCA, its variable impact on patient health, and the necessity for personalized diagnostic and management approaches in these cases.

Kv1.3 blockade by ShK186 modulates CD4+ effector memory T-cell activity of patients with granulomatosis with polyangiitis.

OBJECTIVES: Granulomatosis with polyangiitis (GPA) is a chronic relapsing systemic autoimmune vasculitis. Current treatment of GPA is unsatisfactory, as it relies on strong immunosuppressive regimens, with either CYC or rituximab, which reduce the immunogenicity of several vaccines and are risk factors for a severe form of COVID-19. This emphasizes the need to identify new drug targets and to develop treatment strategies with less harmful side effects. Since CD4+ effector memory T cells (TEM) play a key role in the pathogenesis of GPA, we aimed in this study to modulate CD4+TEM cell activity via Kv1.3 blockade using the specific peptide inhibiter, ShK-186. METHODS: Peripheral blood samples from 27 patients with GPA in remission and 16 age- and sex-matched healthy controls (HCs) were pre-incubated in vitro in the presence or absence of ShK-186, followed by stimulation with phorbol myristate acetate, calcium ionophore and brefeldin-A. The effect of ShK-186 on the cytokine production (IFNγ, TNFα, IL-4, IL-17, IL-21) within total and subsets of CD4+ T helper (CD4+TH) cells were assessed using flow cytometry. RESULTS: ShK-186 reduced the expression level of IFNγ, TNFα, IL-4, IL-17 and IL-21 in CD4+TH cells from patients with GPA in vitro. Further analysis performed on sorted CD4+T cell subsets, revealed that ShK-186 predominantly inhibited the cytokine production of CD4+TEM cells. ShK-186 treatment reduced the production of the pro-inflammatory cytokines to the level seen in CD4+ TH cells from HCs. CONCLUSIONS: Modulation of cellular effector function by ShK-186 may constitute a novel treatment strategy for GPA with high specificity and less harmful side effects.

Health-related quality of life in patients with ANCA vasculitides compared to rheumatoid arthritis: a cross-sectional comparative study.

OBJECTIVES: There are limited data regarding health-related quality of life (HRQoL) in patients with ANCA-associated vasculitides (AAVs). We aimed to evaluate the HRQoL in patients with AAVs and compare it to another chronic inflammatory disease like RA and to healthy controls (HC). METHODS: This was a multicentre, cross-sectional study of patients with AAVs and RA recruited from three tertiary rheumatology clinics. HRQoL was assessed with the Short Form 36 Health Survey, which included the physical and mental component summary scores (PCS and MCS). Data from 1007 HC served as historical controls. RESULTS: Sixty-six patients with AAVs and 71 with RA were included. Both AAV and RA patients had significantly lower PCS and MCS scores compared with HC (P < 0.05). HRQoL in AAV patients was worse in patients with microscopic polyangiitis compared with granulomatosis with polyangiitis (physical components) and those with high (VDI ≥ 3) vs low (VDI < 3) damage scores while it did not differ between those with active (BVASv3 ≥ 1) vs. inactive (BVASv3 < 1) disease. In contrast, in RA patients, HRQoL correlated both with disease activity (assessed by the DAS28-ESR) and functional impairment/damage (assessed by the HAQ). Although overall patients with RA had similar HRQoL compared with those with AAVs, those with active RA had worse HRQoL compared with those with active AAV. CONCLUSIONS: In patients with AAVs, HRQoL correlated more with organ damage and less with disease activity whereas in RA patients, it correlated with both. These data emphasize the need for AAV therapies aiming at preventing organ damage and thus improving HRQoL.

Distinct features of ANCA-associated hypertrophic pachymeningitis compared to other etiologies: findings from a study of 74 patients.

OBJECTIVES: We aimed to characterize the clinical and radiological features, and outcomes, of a large cohort of hypertrophic pachymeningitis (HP) patients from a single center. METHODS: We conducted a retrospective study at a tertiary referral center, encompassing patients diagnosed with HP between 2003 and 2022. The diagnosis of HP relied on the identification of thickening of the dura mater via magnetic resonance imaging (MRI) of the brain or spine. RESULTS: We included 74 patients with a mean age of 43.6 ± 14.2 years, of whom 37 (50%) were male. Among them, 32 (43.2%) had an immune-mediated origin, including 21 with granulomatosis with polyangiitis (GPA) (predominantly PR3-ANCA positive), four with systemic lupus erythematosus, three with IgG4-related disease, three with idiopathic HP, and one with rheumatoid arthritis. Non-immune-mediated HP accounted for 45 cases (56.8%). Within this category, 21 (28.4%) were infectious cases, with 14 being Mycobacterium tuberculosis infection (TB-HP), and 21 (28.4%) were malignancy-associated HP. Clinical and MRI characteristics exhibited variations among the four etiological groups. Hypoglycorrhachia was primarily observed in infectious and malignancy-associated HP. Immune-mediated HP was associated with a peripheral pattern of contrast enhancement and the Eiffel-by-night sign. MRI features strongly indicative of TB-HP included leptomeningeal involvement, brain parenchymal lesions, and arterial stroke. MPO-ANCA GPA was associated with a higher prevalence of spinal HP. CONCLUSIONS: Within our cohort, GPA and Mycobacterium tuberculosis emerged as the predominant causes of HP. We identified significant disparities in clinical and radiological features among different etiologies, which could have implications for diagnosis.

A systematic review of patient reported outcome measures in patients with anti-neutrophil cytoplasmic antibody associated vasculitis.

OBJECTIVES: ANCA associated vasculitis (AAV) is associated with significant morbidity, fatigue, pain and poor health-related quality of life (HRQoL). This review aims to assess the comprehensiveness of existing patient reported outcome measures (PROMs) used in AAV and identify associations with poorer HRQoL outcomes. METHODS: A literature review of studies using PROMs, including those labelled HRQoL in people with AAV as a primary or secondary study outcome were screened and reviewed up to July 2023. Quality was assessed using the Critical Appraisal Skills Programme. RESULTS: A total of 30 articles were included which utilised 22 different PROM tools. 76.7% (n = 23) used the SF-36 or a variation as a generic measure of health status and or HRQoL. Two studies developed a disease specific PROM. The AAV-PRO showed good psychometric properties but potential limitations in capturing all relevant aspects of the disease experience for AAV patients. Factors associated with poorer HRQoL included: neurological and sinonasal involvement, women and younger patients. 86.6% of studies showed no meaningful relationships between the SF-36 and BVAS, VDI or disease duration. Depression and anxiety were common and socioeconomic factors such as unemployment were significantly associated with poorer mental health outcomes. Glucocorticoids were found to be independently associated with worse SF-36 scores. CONCLUSION: Generic PROMs are useful in measuring significant changes but lack sensitivity to specific symptoms and unique AAV-related issues, while existing disease specific PROMs have limitations and may not fully capture AAV patient's perspective on disease and treatment burden.

Endothelial dysfunction and complement activation are independently associated with disease duration in patients with systemic vasculitis.

OBJECTIVES: Systemic vasculitis is a heterogenous group of autoimmune diseases characterized by enhanced cardiovascular mortality. Endothelial dysfunction is associated with accelerated vascular damage, representing a core pathophysiologic mechanism contributing to excess CV risk. Recent studies have also shown that complement activation holds significant role in the pathogenesis of Anti-Neutrophilic Cytoplasmic Autoantibody (ANCA) -associated vasculitis (AAV). Given the potential crosstalk between the endothelium and complement, we aimed to assess, for the first time simultaneously, easily accessible biomarkers of endothelial dysfunction and complement activation in SV. METHODS: We measured circulating endothelial microvesicles (EMVs) and soluble complement components representative of alternative, classical and terminal activation (C5b-9, C1q, Bb fragments, respectively) in a meticulously selected group of patients with systemic vasculitis, but without cardiovascular disease. Individuals free from systemic diseases, who were matched with patients for cardiovascular risk factors(hypertension, diabetes, smoking, dyslipidemia), comprised the control group. RESULTS: We studied 60 individuals (30 in each group). Patients with systemic vasculitis had elevated EMVs, higher levels of C5b-9 [536.4(463.4) vs 1200.94457.3), p = 0.003] and C1q [136.2(146.5 vs 204.2(232.9), p = 0.0129], compared to controls [232.0 (243.5) vs 139.3(52.1), p < 0.001]. In multivariate analysis both EMVs and C5b-9 were independently associated with disease duration (p = 0.005 and p = 0.004 respectively), yet not with disease activity. CONCLUSION: Patients with systemic vasculitis exhibit impaired endothelial function and complement activation, both assessed by easily accessible biomarkers, even in the absence of cardiovascular disease manifestations. EMVs and soluble complement components such as C5b-9 and C1q could be used as early biomarkers of endothelial dysfunction and complement activation, respectively, in clinical practice during the course of SV, yet their predictive value in terms of future cardiovascular disease warrants further verification in appropriately designed studies.

Sustained post-rituximab B-cell depletion is common in ANCA-associated vasculitis and is affected by sex and renal function.

OBJECTIVE: Despite the increasing use of rituximab in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), it remains unclear what the optimal dosing is, especially for maintenance of remission. A deeper understanding of post-rituximab B-cell repopulation patterns may aid better-tailored treatment. METHODS: This is a monocentric, retrospective study including ANCA-positive AAV patients receiving a single course of rituximab induction. CD19+ B cells were longitudinally monitored with flow cytometry. B-cell repopulation was defined as CD19+ >10 cells/µL. RESULTS: Seventy-one patients were included, the majority with microscopic polyangiitis (75%), myeloperoxidase-ANCA positivity (75%) and with renal involvement (79%). During a median follow-up of 54 months since the first rituximab infusion, 44 patients (62%) repopulated B cells, with a median time to repopulation of 39 months (range 7-102). Patients experiencing B-cell depletion lasting longer than the overall median time to repopulation (39 months) exhibited a lower risk of flare and higher risk of serious infection. In multivariate Cox regression, higher estimated glomerular filtration rate (eGFR) [hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.13-2.98 per 30 mL/min/1.73 m2 eGFR] and female sex (HR 2.70, 95% CI 1.37-5.31) were independent predictors of increased rate of B-cell repopulation. CONCLUSION: A subset of AAV patients develop sustained post-rituximab B-cell depletion, which associates with reduced risk of flare and increased risk of serious infection in the long term. Preserved renal function and female sex are associated with faster B-cell repopulation. These observations further highlight the need to personalize immunosuppression to improve clinical outcomes.

Avacopan for ANCA-associated vasculitis with hypoxic pulmonary haemorrhage.

BACKGROUND AND HYPOTHESIS: Pulmonary haemorrhage with hypoxia caused by ANCA-associated vasculitis (AAV) has a high early mortality. Avacopan, an oral C5a receptor antagonist, is an approved treatment for AAV, but patients with pulmonary haemorrhage requiring invasive pulmonary ventilation support were excluded from the ADVOCATE trial. METHODS: A retrospective, observational, multicentre case series of AAV patients with hypoxic pulmonary haemorrhage, requiring oxygen support or mechanical ventilation, who received avacopan. RESULTS: Eight patients (62.5% female), median age 64 years (range 17-80), seven with kidney involvement, median glomerular filtration rate (GFR) 11 (range 5-99) ml/min per 1.73m2, were followed for a median of 6 months from presentation. Seven were newly diagnosed (87.5%), five were MPO-ANCA and three PR3-ANCA positive. All had hypoxia, four requiring mechanical ventilation (three invasive and one non-invasive). Intensive care unit (ICU) stay for the four patients lasted a median of 9 days (range 6-60). Four received rituximab and cyclophosphamide combination, three rituximab and one cyclophosphamide. Four underwent plasma exchange and one received two months of daily extracorporeal membrane oxygenation (ECMO) therapy. Following the initiation of avacopan after a median of 10 days (range 2-40), pulmonary haemorrhage resolved in all patients, even two who had one month of refractory pulmonary haemorrhage prior to avacopan. Additionally, after one month, the median prednisolone dose was 5 mg/day (range 0-50), with three patients successfully discontinuing steroid use. Two patients suffered serious infections, two discontinued avacopan, one permanently due to a rash and one temporarily after three months due to neutropenia. All patients survived and no re-hospitalization occurred. CONCLUSION: We report the use of avacopan as a component of the treatment for pulmonary haemorrhage with hypoxia in AAV. Despite the life-threatening presentations all patients recovered, but attribution of the positive outcomes to avacopan is limited by the concomitant therapies and retrospective observational design.