Antineutrophil Cytoplasm Research Articles

Autoantibodies towards HFE and SYT5 in anti-neutrophil cytoplasm antibody-associated vasculitis relapse.

Identification of those at high and low risk of disease relapse is a major unmet need in the management of patients with ANCA-associated vasculitis (AAV). Precise stratification would allow tailoring of immunosuppressive medication. We profiled the autoantibody repertoire of AAV patients in remission to identify novel autoantibodies associated with relapse risk. Plasma samples collected from 246 AAV patients in remission were screened for novel autoantibodies using in-house generated protein arrays including 42 000 protein fragments representing 18 000 unique human proteins. Patients were categorized based on the occurrence and frequency of relapses. We modelled the association between these antibodies and relapse occurrence using descriptive and high dimensional regression approaches. We observed nine autoantibodies at higher frequency in samples from AAV patients experiencing multiple relapses compared with patients in long-term remission off therapy (LTROT). LASSO analysis identified six autoantibodies that exhibited an association with relapse occurrence after sample collection. Antibodies targeting HFE and SYT5 were identified as associated with relapse in both analyses. Through a broad protein array-based autoantibody screening, we identified two novel autoantibodies directed against HFE and SYT5 as candidate biomarkers of relapse in AAV.

Characteristics of Severe Asthma Clinic Patients With Eosinophilic Granulomatosis With Polyangiitis

BackgroundEosinophilic granulomatosis with polyangiitis (EGPA) is a rare form of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis associated with varying clinical presentations and overlapping multiorgan involvement. Asthma is a predominant feature of EGPA, typically in its prodromal phase, often severe and precedes vasculitic complications. However, there is paucity of studies describing the prevalence and characteristics of EGPA in the asthma population. ObjectiveWe aim to describe the clinical and serological characteristics and longitudinal therapeutic outcomes of patients with EGPA in the severe asthma (SA) cohort. MethodsRetrospective study of patients with EGPA attending the multidisciplinary SA clinic in a tertiary hospital from 2011 to 2023 was conducted. Baseline demographics, organ manifestations, biological markers, lung function and therapeutic outcomes were assessed. Results23 out of 596 patients in the SA registry were identified to have EGPA. Median time interval between asthma and EGPA diagnosis was 10 years (range 2.5 to 32 years). Almost all patients (95.7%) had peak blood eosinophil count of >1.0 x 109/L (range 0.47 – 14.08 x 109/L). Upper airway involvement was the most detected manifestation in addition to asthma, followed by neuropathy and renal involvement. Patients who were treated with biologic therapy were significantly younger, had more upper airway, renal, pulmonary involvement and lower five factor score (FFS). ConclusionThe prevalence of EGPA in the SA population was 3.9% in our cohort. Its diagnosis requires high clinical suspicion in patients with SA and blood eosinophilia, prompting stringent evaluation for extrapulmonary manifestations and multidisciplinary involvement.

Avacopan for anti-neutrophil cytoplasm antibodies-associated vasculitis: a multicenter real-world study.

Avacopan, a selective C5aR1 inhibitor, recently emerged as a glucocorticoid (GCs) sparing agent in ANCA-associated vasculitis (AAV). We aim to evaluate the tolerance and efficacy of avacopan given outside randomized clinical trials or with severe kidney involvement. In this multicentre retrospective study, we reviewed the clinical charts of patients with AAV and contraindication to high dose of GCs who received avacopan 30 mg b.i.d plus standard-of-care regimen owing to the French early access program between 2020 and 2023. Efficacy and safety data were recorded using a standardized case report form. Among the 31 patients (median age 72 years), 10 had a relapsing AAV, twenty had anti-myeloperoxidase antibodies, and thirty had kidney vasculitis. Induction regimen included rituximab (n = 27), cyclophosphamide (n = 2), or both (n = 2). Five patients did not receive GCs. Despite rapid GCs tapering (which were withdrawn in 23 patients before month 3), 25 patients (81%) had a favorable outcome and no severe adverse event. The estimated glomerular filtration rate increased from 19 [15; 34] to 35 mL/min/1.73m2 [23; 45] at month 12 (p< 0.05), independently of kidney biopsies findings. One patient developed refractory AAV and two had a relapse while receiving avacopan. At month 12, ANCA remained positive in 10/18 patients (55.5%). Two patients developed severe adverse events leading to a withdrawal of avacopan (hepatitis and age-related macular degeneration). The GCs' sparing effect of avacopan was confirmed, even in patients with severe kidney vasculitis, but further studies are required to identify the optimal dosing of GCs when avacopan is used.

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

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. 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. 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. 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.

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

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. A retrospective screening for DP-ANCA cases was conducted at Brest University Hospital's immunology laboratory (France), analysing 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 artificial intelligence (AI)-based search using BIBOT software with a manual PUBMED database search. 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%). 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.

CD36 regulates macrophage and endothelial cell activation and multinucleate giant cell formation in anti neutrophil cytoplasm antibody vasculitis

ObjectiveTo investigate CD36 in ANCA-associated vasculitis (AAV), a condition characterized by monocyte/macrophage activation and vascular damage. MethodsCD36 expression was assessed in AAV patients and healthy controls (HC). The impact of palmitic acid (PA) stimulation on multinucleate giant cell (MNGC) formation, macrophage, and endothelial cell activation, with or without CD36 knockdown, was examined. ResultsCD36 was overexpressed on AAV patients' monocytes compared to HC, regardless of disease activity. AAV patients exhibited elevated soluble CD36 levels in serum and plasma and PR3-ANCA patients' monocytes demonstrated increased MNGC formation following PA stimulation compared to HC. PA stimulation of macrophages or endothelial cells resulted in heightened CD36 expression, cell activation, increased macrophage migration inhibitory factor (MIF) production, and c-Myc expression, with attenuation upon CD36 knockdown. ConclusionCD36 participates in macrophage and endothelial cell activation and MNGC formation, features of AAV pathogenesis. AAV treatment may involve targeting CD36 or MIF.

Intestinal homeostasis in the gut-lung-kidney axis: a prospective therapeutic target in immune-related chronic kidney diseases.

In recent years, the role of intestinal homeostasis in health has received increasing interest, significantly improving our understanding of the complex pathophysiological interactions of the gut with other organs. Microbiota dysbiosis, impaired intestinal barrier, and aberrant intestinal immunity appear to contribute to the pathogenesis of immune-related chronic kidney diseases (CKD). Meanwhile, the relationship between the pathological changes in the respiratory tract (e.g., infection, fibrosis, granuloma) and immune-related CKD cannot be ignored. The present review aimed to elucidate the new underlying mechanism of immune-related CKD. The lungs may affect kidney function through intestinal mediation. Communication is believed to exist between the gut and lung microbiota across long physiological distances. Following the inhalation of various pathogenic factors (e.g., particulate matter 2.5 mum or less in diameter, pathogen) in the air through the mouth and nose, considering the anatomical connection between the nasopharynx and lungs, gut microbiome regulates oxidative stress and inflammatory states in the lungs and kidneys. Meanwhile, the intestine participates in the differentiation of T cells and promotes the migration of various immune cells to specific organs. This better explain the occurrence and progression of CKD caused by upper respiratory tract precursor infection and suggests the relationship between the lungs and kidney complications in some autoimmune diseases (e.g., anti-neutrophil cytoplasm antibodies -associated vasculitis, systemic lupus erythematosus). CKD can also affect the progression of lung diseases (e.g., acute respiratory distress syndrome and chronic obstructive pulmonary disease). We conclude that damage to the gut barrier appears to contribute to the development of immune-related CKD through gut-lung-kidney interplay, leading us to establish the gut-lung-kidney axis hypothesis. Further, we discuss possible therapeutic interventions and targets. For example, using prebiotics, probiotics, and laxatives (e.g., Rhubarb officinale) to regulate the gut ecology to alleviate oxidative stress, as well as improve the local immune system of the intestine and immune communication with the lungs and kidneys.

Cost-minimization analysis of individually tailored or fixed-scheduled rituximab maintenance therapy for antineutrophil-cytoplasm antibody associated vasculitides

ObjectivePatients included in MAINRITSAN2 trial received either an individually tailored or a fixed-schedule therapy with rituximab as maintenance treatment of antineutrophil cytoplasm antibody associated vasculitides. The aim of this study was to compare the real-world costs of both arms. MethodWe performed a cost-minimization analysis over an 18-month time period, estimating direct costs –drug acquisition, preparation, administration and monitoring costs- from the health system perspective. We conducted a number of additional sensitivity analyses with different assumptions for unit costs, with further scenarios including the interquartile range of the tailored-infusion group results, different number of monitoring visits for fixed-schedule regimen and different number of reported severe adverse events. A cost-effectiveness analysis was conducted as a sensitivity analysis using the absolute difference in the relapse rate and its confidence interval. ResultsThe individually tailored maintenance therapy with rituximab was shown to be a cost-saving treatment compared to the fixed-schedule therapy (6,049 euros vs. 7,850 euros). Savings resulted primarily from lower drug acquisition costs (2,861 vs. 4,768 euros) and lower preparation and administration costs (892 vs. 1,486 euros), due to the lower number of infusions per patient in the tailored-infusion regimen. The tailored-infusion regimen presented higher monitoring costs (2,296 vs. 1,596 euros). This result was replicated in all assumptions considered in the sensitivity analysis of cost-minimization approach. ConclusionsFrom the perspective of the health system, the tailored-therapy regimen seems to be the preferable option in terms of direct costs. Further studies assessing all the effects and costs associated to vasculitides maintenance treatment with rituximab are needed to support clinical management and healthcare planning.

Augmented thrombin formation is related to circulating levels of extracellular vesicles exposing tissue factor and citrullinated histone-3 in anti-neutrophil cytoplasmic antibody-associated vasculitides.

To study circulating myeloperoxidase (MPO)-positive extracellular vesicles (MPO+EVs) exposing citrullinated histone-3 (H3Cit), tissue factor (TF), and plasminogen (Plg) in association to thrombin generation in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). We have involved well-characterized patients with AAV together with population-based controls. Flow cytometry was used to assess the levels of MPO+EVs in citrated plasma. MPO+EVs were phenotyped by anti-MPO-antibodies together with anti-CD142 (anti-TF), anti-H3Cit, and anti-Plg antibodies. A modified Calibrated Automated Thrombogram (CAT) assay was utilized to measure thrombin generation in plasma initiated by EVs-enriched pellets. The activity of AAV was evaluated with the Birmingham Vasculitis Activity Score (BVAS). This study comprised 46 AAV patients, 23 in the active stage of the disease and 23 in remission, as well as 23 age- and sex matched population-based controls. Augmented levels of all investigated MPO+ EVs were found in active AAV patients in comparison to the subgroup of patients in remission and controls. Thrombin generation, measured by endogenous thrombin potential (ETP) and peak of thrombin formation, was higher in plasma when triggered by EVs-enriched pellet from AAV patients. ETP and peak were associated with the levels of MPO+TF+ and MPO+H3Cit+ EVs. Additionally, MPO+TF+ EVs correlated with the disease activity evaluated with BVAS. Augmented thrombin generation is found in AAV patients regardless of disease activity and is associated with higher exposure of TF and H3Cit on MPO+EVs. This may contribute to the increased risk of thrombosis seen in AAV patients.

THU280 Acute Interstitial Nephritis- A Complication Of Semaglutide Use

Abstract Disclosure: M. Alsayed Hasan: None. J. Doroshow: None. Background: With the widespread use of glucagon-like peptide 1 (GLP-1) agonists in diabetes, several cases have been reported of GLP-1 induced acute interstitial nephritis (AIN) with variable recovery in kidney function (1). Although it is a rare side effect, the primary management requires early identification and removal of the offending agent. Clinical Case: A 75-year-old male presented with a week of nausea, vomiting, abdominal pain, and reduced urine output. He was started on semaglutide 4 months prior to admission when his creatinine was 1.16 mg/dL. Initial lab abnormalities included an elevated blood urea nitrogen 119 mg/dL (n 8-20 mg/dL), elevated creatinine 13.8 mg/dL (n 0.7-1.3 mg/dL), anion gap acidosis with a CO2 of 15 mEq/L (n 22-32 mEq/L) and an anion gap of 18 (n&amp;lt;12), lipase 659 U/L (n 20-51 U/L). His urinalysis demonstrated too numerous to count red blood cells, 4-10 white blood cells, rare eosinophils and no casts or crystals. Urine culture was negative. The fractional excretion of sodium and urea were 5.56% and 56% respectively, consistent with intrinsic renal disease. CT of the abdomen and pelvis demonstrated peri-pancreatic inflammation. A follow up renal ultrasound showed normal echotexture with no hydronephrosis or renal calculi. His picture was concerning for pancreatitis and pre-renal/acute tubular necrosis from diuretic use and vomiting. Despite aggressive fluid resuscitation, there was minimal improvement in his creatinine. Further work up for his renal injury was negative for monoclonal antibodies on protein electrophoresis and immunofixation. An autoimmune work up was negative for antinuclear antibody, anti-double stranded DNA, antineutrophil cytoplasmic (ANCA) myeloperoxidase IgG, anti-proteinase 3 ANCA IgG, glomerular basement membrane antibody, hepatitis B and C antibodies, and HIV. Complements and immunoglobin G subclasses were normal. A renal biopsy was performed which showed active interstitial inflammation with eosinophils consistent with allergic interstitial nephritis without an immune complex mediated glomerular lesion. He was started on intravenous methyl prednisone for 3 days followed by a prednisone taper. His home metformin, ramipril and hydrochlorothiazide were discontinued on discharge. He was eventually started on mycophenolate as the creatinine did not return to baseline with steroids. Conclusion: AIN is a rare, yet serious complication of GLP-1 use that requires early identification and discontinuation of the medication. A rapid or unexplained decline in renal function after starting a GLP-1 should be evaluated early on with concern for AIN once volume depletion is ruled out (1). Reference: (1) Chaudhury N., Liarakos A., Gopalakrishnan K., Ayub W., Murthy N., Rao R. Antidiabetic medication-induced acute interstitial nephritis: case report and literature search. British Journal of Diabetes. 2021;21(2);228-32. Presentation: Thursday, June 15, 2023

Serum calprotectin and renal function decline in ANCA-associated vasculitides: a post hoc analysis of MAINRITSAN trial

ObjectiveSerum calprotectin appears to be an interesting biomarker associated with renal vascular disease activity in antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). The aim of this study was to assess whether...

Reduced-dose versus high-dose glucocorticoids added to rituximab on remission induction in ANCA-associated vasculitis: predefined 2-year follow-up study

ObjectivesThe LoVAS trial reported non-inferiority in remission induction rates between the reduced-dose and conventional high-dose glucocorticoid regimens plus rituximab for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 6 months; however, maintenance...

Renal involvement in eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing vasculitis, which typically affects small-to medium-sized blood vessels. It is characterized by the presence of tissue infiltrates rich in eosinophils, along with the formation of granulomatous lesions. About 40% of cases have positive anti-neutrophil cytoplasm antibodies (ANCA), with predominant perinuclear staining, and anti-myeloperoxidase (anti-MPO) specificity in about 65% of cases. Typical manifestations of EGPA include the late onset of asthma, nasal and sinus-related symptoms, peripheral neuropathy, and significant eosinophilia observed in the peripheral blood. In contrast to granulomatosis with polyangiitis and microscopic polyangiitis, renal involvement in EGPA is less frequent (about 25%) and poorly studied. Necrotizing pauci-immune crescentic glomerulonephritis is the most common renal presentation in patients with ANCA-positive EGPA. Although rarely, other forms of renal involvement may also be observed, such as eosinophilic interstitial nephritis, mesangial glomerulonephritis, membranous nephropathy, or focal sclerosis. A standardized treatment for EGPA with renal involvement has not been defined, however the survival and the renal outcomes are usually better than in the other ANCA-associated vasculitides. Nonetheless, kidney disease is an adverse prognostic factor for EGPA patients. Larger studies are required to better describe the renal involvement, in particular for patterns different from crescentic glomerulonephritis, and to favor the development of a consensual therapeutic approach. In this article, in addition to personal data, we will review recent findings on patient clinical phenotypes based on ANCA, genetics and the impact of biological drugs on disease management.

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

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

Systematic literature review informing the 2022 update of the EULAR recommendations for the management of ANCA-associated vasculitis (AAV): part 1—treatment of granulomatosis with polyangiitis and microscopic polyangiitis

ObjectiveTo summarise and update evidence to inform the 2022 update of the EULAR recommendations for the management of antineutrophil cytoplasm antibody-associated vasculitis (AAV).MethodsA systematic literature review (SLR) was performed to...

CPC14 A truly VEXing diagnosis

Abstract A 50-year-old man with a background of prostate cancer was admitted with fever, weight loss, polyarthritis, symptomatic anaemia and raised inflammatory markers. Multiple tender indurated violaceous plaques on the trunk and limbs were suggestive of Sweet syndrome. Skin biopsies revealed a neutrophilic dermal infiltrate and a pandermal vasculitis affecting small vessels. Laboratory screening (including rheumatoid factor, anticyclic citrullinated peptide, antinuclear antibody, antineutrophil cytoplasm antibodies, HIV, hepatitis B and C serology, antiphospholipid antibodies and cryoglobulins) was negative. Upper and lower endoscopies and gastrointestinal biopsies were normal. Biopsy of an axillary lymph node revealed reactive changes only. Computed tomography (CT) of the thorax, abdomen and pelvis showed sacroiliitis. A diffuse low signal on T1-weighted magnetic resonance imaging of his spine was suggestive of conversion of fatty marrow to red marrow. His cutaneous findings resolved fully with oral prednisolone 0.5 mg kg−1; however, he had ongoing transfusion-dependent anaemia and arthritis. Infliximab was started for presumed ankylosing spondylitis by rheumatology without improvement. Six months later, he was readmitted with multifocal ulceration of both feet. Histology demonstrated a leucocytoclastic vasculitis. He developed haemoptysis and chest pain. CT of the thorax showed multifocal, bilateral, ground–glass change consistent with pulmonary vasculitis. Bone marrow biopsy revealed hypercellular marrow with markedly increased granulopoiesis. A pathogenic missense mutation in UBA1 (c121A.G; pMet41Val) was found on next-generation sequencing of the bone marrow aspirate (Leeds Cancer Centre). Somatic variants at this codon have been implicated in vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome (Beck DB, Ferrada MA, Sikora KA et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med 2020; 383:2628–38). First described in 2020, VEXAS syndrome is a somatic monogenic autoinflammatory disorder of adulthood. Affected patients develop predominantly inflammatory and haematological symptoms. Cutaneous findings have been reported in up to 89% of cases (Georgin-Lavialle S, Terrier B, Guedon AF et al. Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients. Br J Dermatol 2022; 186:564–74) and include neutrophilic dermatosis, vasculitis, urticaria, angioedema, erythematous papules and chondritis. Systemic manifestations are protean, but fever of noninfectious origin, weight loss, and ocular and pulmonary manifestations are most prevalent. Fifty per cent of patients with VEXAS have myelodysplastic syndrome (Georgin-Lavialle et al.). In our case, persistent haematological abnormalities coupled with multisystem inflammation (arthritis, vasculitis) prompted testing for VEXAS syndrome. This novel condition should be considered when assessing adult patients with neutrophilic dermatosis or cutaneous vasculitis who manifest other autoinflammatory phenomena. He was commenced on tocilizumab but, despite this, has ongoing acral vasculopathy.

P09 A case of suspected COVID-19 vaccine-induced antiphospholipid syndrome

Abstract A 50-year-old man presented with an acute onset, painful leg ulcer affecting his right calf. This developed 2 weeks after his second COVID-19 vaccine. It started with a painful erythematous plaque, which evolved slowly into a deep-seated 5-cm ulcer over a 6-week period. A thorough review was unremarkable. He had no significant medical history and was a keen athlete and nonsmoker. His father had an unspecified stroke in his 80s. Examination revealed no signs of chronic venous insufficiency or discoloration to his foot, and his neurovascular examination was unremarkable. Investigations for antineutrophil cytoplasm antibodies, antinuclear antibody, complement, paraprotein, HIV and hepatitis were all unremarkable. Biopsy demonstrated nonspecific inflammatory changes, and wound swabs were unremarkable. Initial treatment with oral antibiotics, regular dressings, compression, topical emollients, Dermovate® and prednisolone (0.5 mg kg−1) was only partially effective. He subsequently developed additional painful superficial erosions and ulcers affecting the same limb involving the calf and shin, with a surrounding erythematous livedoid-like rash involving his shin. Rebiopsy demonstrated superficial and deep dermal and subcutaneous thrombosis without vasculitis. Direct immunofluorescence showed the presence of fibrinogen within dermal vessels. Further investigations demonstrated the presence of lupus anticoagulant. Factor V Leiden, protein C and S, anti-B2-GP1 and anticardiolipin antibodies, antithrombin III, homocysteine and coagulation profile were all unremarkable. Histological confirmation of thrombosis and the presence of serum lupus anticoagulant confirmed the diagnosis of antiphospholipid syndrome (APS). He was started on warfarin and the ulcers improved. APS is a rare autoimmune disorder characterized by recurrent miscarriage, thrombophilia and the presence of antiphospholipid autoantibodies (either serum lupus anticoagulant, anti-B2-GP1 or anticardiolipin autoantibodies). Positivity for APS antibodies can be found in up to 5% of the general population. An individual must have the clinical features and antibody positivity to be diagnosed with APS. The temporal relationship with his second COVID-19 vaccine raises the possibility of vaccine-induced APS. COVID-19 vaccine-induced APS is limited to just a few case reports (Moreno-Torres V, Gutiérrez A, Valdenbro M et al. Catastrophic antiphospholipid syndrome triggered by mRNA COVID-19 vaccine. Clin Exp Rheumatol 2022; 40:1054–5). It is postulated that mRNA vaccines may induce a rare complex immunogenic response characterized by a type 1 interferon reaction. This results in a prothrombotic cascade in individuals with pre-existing APS autoantibody positivity (Talotta R, Robertson E. Antiphospholipid antibodies and risk of post-COVID 19 vaccination thrombophilia: the straw that breaks the camel’s back? Cytokine Growth Factor Rev 2021; 60:52–60).

Perspectives on Mycophenolate Mofetil in the Management of Autoimmunity.

Before becoming a cornerstone in the treatment of numerous immune-mediated diseases, mycophenolate mofetil (MMF) was first introduced as an immunosuppressive agent in transplant immunology and later received the attention of rheumatologists and clinicians involved in the management of autoimmune diseases. MMF is now a widespread immunosuppressive drug for the treatment of several conditions, including lupus nephritis, interstitial lung disease associated with systemic sclerosis, and anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis while being efficacious also as rescue therapy in various orphan diseases, including dermatomyositis and IgA-associated nephropathy. Similarly, case reports or series support a possible use of MMF in other rare autoimmune diseases. Beyond modulating lymphocyte activation, MMF acts on other immune and non-immune cells and these effects may explain the therapeutic profile of this medication. The effects of MMF are broadly characterized by the impact on the immune system and the antiproliferative and antifibrotic changes induced. In this latter case, mechanistic data on fibroblasts may in the future allow to reevaluate the use of MMF in selected patients with inflammatory arthritis or systemic sclerosis. Attention must be paid towards the possible occurrence of adverse events, such as gastrointestinal complaints and teratogenicity, while the risk of infections and cancer related to MMF needs to be further investigated.

#5390 INTENSIFIED B CELL DEPLETION THERAPY IN ANCA-VASCULITIS WITH SEVERE RENAL IMPAIRMENT AS COMPARED TO CONVENTIONAL IMMUNOSUPPRESSION

Abstract Background and Aims Rituximab (RTX) has shown to be an effective induction treatment for small-vessel vasculitides associated with antineutrophil cytoplasm antibodies (AAV) in both newly diagnosed and relapsing patients. However, the role of RTX in the management of the most severe cases of AAV remains to be fully elucidated. The aim of this study was to assess both safety and efficacy of an intensified B-cell depletion therapy (IBCDT) protocol, including RTX, cyclophosphamide (CYC), and methylprednisolone pulses without additional maintenance immunosuppressive therapy in a cohort of 15 AAV patients with the most severe features of AVV renal involvement (as &amp;lt;15 ml/min GFR and histological findings of paucimmune necrotizing glomerulonephritis with more than 50% crescents of non-sclerotic glomeruli at the renal biopsy). Method Results of the IBCDT regimen have been compared to those obtained in a control cohort of 10 patients with AAV treated with a conventional therapy regimen based on oral CYC and steroids followed by a prolonged maintenance therapy with azathioprine (AZA). Plasma exchange was equally employed in the study and the control group. Results Complete clinical remission (BVAS 0) was observed at 6 months in 14 of 15 patients treated with IBCDT (93%). All cases who achieved a complete clinical remission experienced a depletion of peripheral blood B cells at the end of therapy. Of the 10 dialysis dependent patients at onset, 6 subjects (60%) experienced a functional recovery allowing the suspension of dialysis treatment. When compared to the control group, no statistically significant difference was observed in patients treated with IBCDT in terms of overall survival, 6-month therapeutic response rate, and 6-, and 12-month functional renal recovery. The cumulative total dose of CYC in the case group was on average 1 g/patient while in the control group on average 8.5 g/patient (p = 0.00008). Conclusion Despite the retrospective design and relative limited sample size, IBCDT appeared to be safe and had the same efficacy profile when compared to the conventional therapy with CYC plus AZA in the management of the most severe patients with AAV. Additionally, this avoided the need of prolonged maintenance therapy for long, and limited the exposure to CYC with consequent reduced toxicity and drug-related side effect rates.

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

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