Helper T cell immunity in humans with inherited CD4 deficiency.

CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCRαß+CD4-CD8- T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4-CD8- αß T cells exhibit intact responses to HLA class II-restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei.

Polymyalgia rheumatica and giant cell arteritis following COVID-19 vaccination: Results from a nationwide survey.

We conducted a national in-depth analysis including pharmacovigilance reports and clinical study to assess the reporting rate (RR) and to determine the clinical profile of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) in COVID-19-vaccinated individuals. First, based on the French pharmacovigilance database, we estimated the RR of PMR and GCA cases in individuals aged over 50 who developed their initial symptoms within one month of receiving the BNT162b2 mRNA, mRNA-1273, ChAdOx1 nCoV-19, and Ad26.COV2.S vaccines. We then conducted a nationwide survey to gather clinical profiles, therapeutic management, and follow-up data from individuals registered in the pharmacovigilance study. A total of 70 854 684 COVID-19 vaccine doses were administered to 25 260 485 adults, among which, 179 cases of PMR (RR 7. 1 cases/1 000 000 persons) and 54 cases of GCA (RR 2. 1 cases/1 000 000 persons) have been reported. The nationwide survey allowed the characterization of 60 PMR and 35 GCA cases. Median time to the onset of first symptoms was 10 (range 2-30) and 7 (range 2-25) days for PMR and GCA, respectively. Phenotype, GCA-related ischemic complications and -large vessel vasculitis as well as therapeutic management and follow-up seemed similar according to the number of vaccine shots received and when compared to the literature data of unvaccinated population. Although rare, the short time between immunization and the onset of first symptoms of PMR and GCA suggests a temporal association. Physician should be aware of this potential vaccine-related phenomenon.

Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by eosinophilic inflammation. Benralizumab, a monoclonal antibody against the interleukin-5α receptor expressed on eosinophils, may be an option for treating EGPA. METHODS: We conducted a multicenter, double-blind, phase 3, randomized, active-controlled noninferiority trial to evaluate the efficacy and safety of benralizumab as compared with mepolizumab. Adults with relapsing or refractory EGPA who were receiving standard care were randomly assigned in a 1:1 ratio to receive benralizumab (30 mg) or mepolizumab (300 mg) subcutaneously every 4 weeks for 52 weeks. The primary end point was remission at weeks 36 and 48 (prespecified noninferiority margin, -25 percentage points). Secondary end points included the accrued duration of remission, time to first relapse, oral glucocorticoid use, eosinophil count, and safety. RESULTS: A total of 140 patients underwent randomization (70 assigned to each group). The adjusted percentage of patients with remission at weeks 36 and 48 was 59% in the benralizumab group and 56% in the mepolizumab group (difference, 3 percentage points; 95% confidence interval [CI], -13 to 18; P = 0.73 for superiority), showing noninferiority but not superiority of benralizumab to mepolizumab. The accrued duration of remission and the time to first relapse were similar in the two groups. Complete withdrawal of oral glucocorticoids during weeks 48 through 52 was achieved in 41% of the patients who received benralizumab and 26% of those who received mepolizumab. The mean (±SD) blood eosinophil count at baseline was 306.0±225.0 per microliter in the benralizumab group and 384.9±563.6 per microliter in the mepolizumab group, decreasing to 32.4±40.8 and 71.8±54.4 per microliter, respectively, at week 52. Adverse events were reported in 90% of the patients in the benralizumab group and 96% of those in the mepolizumab group; serious adverse events were reported in 6% and 13%, respectively. CONCLUSIONS: Benralizumab was noninferior to mepolizumab for the induction of remission in patients with relapsing or refractory EGPA. (Funded by AstraZeneca; MANDARA ClinicalTrials.gov number, NCT04157348.).

Immunomodulatory and clinical effects of receptor-interacting protein kinase 1 (RIPK1) inhibitor eclitasertib (SAR443122) in patients with severe COVID-19: a phase 1b, randomized, double-blinded, placebo-controlled study.

BACKGROUND: Targeting receptor-interacting serine/threonine protein kinase 1 could mitigate the devastating sequelae of the hyperinflammatory state observed in severe cases of COVID-19. This study explored the immunomodulatory and clinical effects of the receptor-interacting serine/threonine protein kinase 1 inhibitor SAR443122 (eclitasertib) in patients with severe COVID-19. METHODS: In this Phase 1b, double-blinded, placebo-controlled study (NCT04469621) a total of 82 patients were screened, of whom 68 patients were eligible and randomized (2:1) to receive eclitasertib 600 mg (300 mg twice daily) or placebo up to 14 days. Primary outcome was relative change in C-reactive protein from baseline to Day 7. Time to clinical improvement using 7-point ordinal scale, ventilator/respiratory failure-free days, change in SpO2/FiO2 ratio, and biomarkers of severe COVID-19 were explored. RESULTS: Geometric mean ratio (point estimate [90% confidence interval]) of the relative change from baseline in C-reactive protein with eclitasertib vs. placebo on Day 7 was 0.85 (0.49-1.45; p = 0.30). Median time to 50% decrease in C-reactive protein from baseline was 3 days vs. 5 days (p = 0.056) with eclitasertib vs. placebo. Median time to ≥ 2-point improvement on 7-point clinical symptoms scale was 8 days vs. 10 days with eclitasertib vs. placebo (p = 0.38). Mean ventilator/respiratory failure-free days, change in baseline-adjusted SpO2/FiO2 ratio, and clinical biomarkers showed consistent numerical improvements with eclitasertib vs. placebo. The most frequently reported treatment-emergent adverse events were gastrointestinal disorders and condition aggravated/worsened COVID-19 pneumonia. CONCLUSIONS: Eclitasertib was well tolerated with consistent trends toward more rapid resolution of inflammatory biomarkers and clinical improvement in severe COVID-19 patients than placebo. GOV IDENTIFIER: NCT04469621, first posted on clinicaltrials.gov on July 14, 2020.

Shared and distinct mechanisms of UBA1 inactivation across different diseases.

Most cellular ubiquitin signaling is initiated by UBA1, which activates and transfers ubiquitin to tens of E2 enzymes. Clonally acquired UBA1 missense mutations cause an inflammatory-hematologic overlap disease called VEXAS (vacuoles, E1, X-linked, autoinflammatory, somatic) syndrome. Despite extensive clinical investigation into this lethal disease, little is known about the underlying molecular mechanisms. Here, by dissecting VEXAS-causing UBA1 mutations, we discovered that p.Met41 mutations alter cytoplasmic isoform expression, whereas other mutations reduce catalytic activity of nuclear and cytoplasmic isoforms by diverse mechanisms, including aberrant oxyester formation. Strikingly, non-p.Met41 mutations most prominently affect transthioesterification, revealing ubiquitin transfer to cytoplasmic E2 enzymes as a shared property of pathogenesis amongst different VEXAS syndrome genotypes. A similar E2 charging bottleneck exists in some lung cancer-associated UBA1 mutations, but not in spinal muscular atrophy-causing UBA1 mutations, which instead, render UBA1 thermolabile. Collectively, our results highlight the precision of conformational changes required for faithful ubiquitin transfer, define distinct and shared mechanisms of UBA1 inactivation in diverse diseases, and suggest that specific E1-E2 modules control different aspects of tissue differentiation and maintenance.

Mepolizumab has clinical benefits including oral corticosteroid sparing irrespective of baseline EGPA characteristics.

Background: The Mepolizumab in Relapsing or Refractory EGPA (MIRRA) trial (GSK ID: 115921/NCT02020889) demonstrated that mepolizumab increased remission time and reduced oral corticosteroid (OCS) use compared with placebo in patients with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA). The present analysis investigated the impact of baseline characteristics on clinical outcomes and characterised the OCS-sparing effect of mepolizumab. Methods: In a phase 3, randomised controlled trial for patients with EGPA (MIRRA), patients received standard of care plus mepolizumab 300 mg or placebo every 4 weeks for 52 weeks. The accrued duration of remission, the proportion of patients in remission at weeks 36 and 48, and the proportion of patients with clinical benefit (remission, OCS or relapse-related) were assessed according to baseline EGPA characteristic subgroups (post hoc). Mepolizumab-related OCS-sparing benefits were also quantified. Results: Accrued duration of remission and the proportion of patients in remission at weeks 36 and 48 were greater with mepolizumab than placebo across the baseline subgroups of refractory disease, immunosuppressant use, EGPA duration, relapse number and OCS use ≤20 mg·day-1. The proportion of patients with clinical benefit was greater with mepolizumab versus placebo (range 76-81% versus 25-39%), irrespective of immunosuppressant use or EGPA duration. Patients treated with mepolizumab versus placebo accrued significantly more weeks on OCS ≤4 mg·day-1 (OR 5.06, 95% CI 2.47-10.38) and had a mean of 1423.1 mg less per-patient OCS exposure over 52 weeks. Conclusions: Mepolizumab treatment provided benefits to patients with EGPA across varying baseline clinical characteristics and can be considered an OCS-sparing treatment in EGPA.

VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation.

Acquired mutations in the UBA1 gene were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). However, the precise physiological and clinical impact of these mutations remains poorly defined. Here we study a unique prospective cohort of VEXAS patients. We show that monocytes from VEXAS are quantitatively and qualitatively impaired and display features of exhaustion with aberrant expression of chemokine receptors. In peripheral blood from VEXAS patients, we identify an increase in circulating levels of many proinflammatory cytokines, including IL-1ß and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirms these findings and also reveals a significant enrichment of TNF-α and NFκB signaling pathways that can mediate cell death and inflammation. This study suggests that the control of the nflammasome activation and inflammatory cell death could be therapeutic targets in VEXAS syndrome.

EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update.

BACKGROUND: Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been published that have the potential to change clinical care and support the need for an update. METHODS: Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations. RESULTS: Four overarching principles and 17 recommendations were formulated. We recommend biopsies and ANCA testing to assist in establishing a diagnosis of AAV. For remission induction in life-threatening or organ-threatening AAV, we recommend a combination of high-dose glucocorticoids (GCs) in combination with either rituximab or cyclophosphamide. We recommend tapering of the GC dose to a target of 5 mg prednisolone equivalent/day within 4-5 months. Avacopan may be considered as part of a strategy to reduce exposure to GC in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis. For remission maintenance of GPA/MPA, we recommend rituximab. In patients with relapsing or refractory eosinophilic GPA, we recommend the use of mepolizumab. Azathioprine and methotrexate are alternatives to biologics for remission maintenance in AAV. CONCLUSIONS: In the light of recent advancements, these recommendations provide updated guidance on AAV management. As substantial data gaps still exist, informed decision-making between physicians and patients remains of key relevance.

EBV-Positive Inflammatory Follicular Dendritic Cell Sarcoma of the Spleen: Report of an Aggressive Form With Molecular Characterization.

EBV-positive inflammatory follicular dendritic cell sarcoma (EBV+ inflammatory FDCS) is a rare neoplasm almost exclusively located in the spleen or liver. It is characterized by a proliferation of EBV-positive spindle-shaped cells bearing follicular dendritic cell markers, associated with an abundant lymphoplasmacytic infiltrate. EBV+ inflammatory FDCS is often asymptomatic or responsible for mild symptoms. It usually displays an indolent course and its prognosis is excellent after tumor removal, although relapsing and metastatic forms exist. Herein, we describe an aggressive form of splenic EBV+ inflammatory FDCS in a 79-year-old woman presenting with abdominal pain, deterioration of general health status, major inflammatory syndrome, and symptomatic hypercalcemia. A splenectomy was performed leading to a rapid improvement in her clinical condition and normalization of laboratory abnormalities. Unfortunately, her symptoms and laboratory abnormalities reappeared 4 months later. Computed tomography showed a mass in the splenectomy site and multiple liver and peritoneal nodules. Further analyses were performed on tumor tissue and showed positive phospho-ERK staining of tumoral cells indicating activation of MAPK pathway. Inactivating mutations were found on CDKN2A and NF1 genes. Subsequently, the patient's condition deteriorated rapidly. Since interleukin-6 levels were dramatically increased, tocilizumab was used but only had a transient effect on the patient's symptoms and inflammatory syndrome. Antitumor agent gemcitabine was initiated but her clinical condition continued to deteriorate and the patient died 2 weeks later. The management of aggressive forms of EBV+ inflammatory FDCS remains challenging. However, since these tumors seem to display genetic alterations, better characterization could lead to molecular targeted therapies.

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.

Risk of Hypertensive Disorders and Preterm Birth in Pregnant Women With Systemic Vasculitides: A Nationwide Population-Based Cohort Study.

OBJECTIVE: Even though systemic vasculitides (SVs) affect primarily patients over 50 years of age, they can occur among women of childbearing age. Preterm birth (PTB) and hypertensive disorders are frequent complications of pregnancy in SVs. This study aims to evaluate the risk of hypertensive disorders and PTB among pregnant women with SVs, and to identify associated risk factors. METHOD: Using the French health insurance data warehouse, we conducted a nationwide cohort study including all pregnancies between 2013 and 2018 in women with SVs. Theses pregnancies were matched to pregnancies among women without SVs. We estimated risk of hypertensive disorders and PTB risk during pregnancy among women with SVs and investigated associated risk factors using a nested case-control design. RESULTS: Among 3,155,723 pregnancies, we identified 646 pregnancies in women with SVs, matched to 3,230 controls. SVs were significantly associated with hypertensive disorders (odds ratio [OR] 1.7, 95% confidence interval [95% CI] 1.3-2.2) and PTB (OR 1.8, 95% CI 1.4-2.3). Chronic renal failure before pregnancy, history of or treated arterial hypertension, the occurrence of vasculitides flare during pregnancy, and the subgroup of SVs were independently associated with the occurrence of hypertensive disorders. Maternal age at delivery, chronic renal failure before conception, and the occurrence of vasculitides flare during pregnancy were independently associated with the occurrence of PTB. CONCLUSION: About one of seven pregnancies in women with SVs is associated with hypertensive disorders or preterm birth. The occurrence of vasculitides flare was associated with these complications. Our findings support the importance of prepregnancy counseling to ensure disease stability.

Data quality and patient characteristics in European ANCA-associated vasculitis registries: data retrieval by federated querying.

OBJECTIVES: This study aims to describe the data structure and harmonisation process, explore data quality and define characteristics, treatment, and outcomes of patients across six federated antineutrophil cytoplasmic antibody-associated vasculitis (AAV) registries. METHODS: Through creation of the vasculitis-specific Findable, Accessible, Interoperable, Reusable, VASCulitis ontology, we harmonised the registries and enabled semantic interoperability. We assessed data quality across the domains of uniqueness, consistency, completeness and correctness. Aggregated data were retrieved using the semantic query language SPARQL Protocol and Resource Description Framework Query Language (SPARQL) and outcome rates were assessed through random effects meta-analysis. RESULTS: A total of 5282 cases of AAV were identified. Uniqueness and data-type consistency were 100% across all assessed variables. Completeness and correctness varied from 49%-100% to 60%-100%, respectively. There were 2754 (52.1%) cases classified as granulomatosis with polyangiitis (GPA), 1580 (29.9%) as microscopic polyangiitis and 937 (17.7%) as eosinophilic GPA. The pattern of organ involvement included: lung in 3281 (65.1%), ear-nose-throat in 2860 (56.7%) and kidney in 2534 (50.2%). Intravenous cyclophosphamide was used as remission induction therapy in 982 (50.7%), rituximab in 505 (17.7%) and pulsed intravenous glucocorticoid use was highly variable (11%-91%). Overall mortality and incidence rates of end-stage kidney disease were 28.8 (95% CI 19.7 to 42.2) and 24.8 (95% CI 19.7 to 31.1) per 1000 patient-years, respectively. CONCLUSIONS: In the largest reported AAV cohort-study, we federated patient registries using semantic web technologies and highlighted concerns about data quality. The comparison of patient characteristics, treatment and outcomes was hampered by heterogeneous recruitment settings.

Rituximab as maintenance therapy for ANCA-associated vasculitides: pooled analysis and long-term outcome of 277 patients included in the MAINRITSAN trials.

OBJECTIVE: To compare the long-term efficacy and safety of azathioprine (AZA), 18-month fixed-schedule rituximab (RTX), 18-month tailored RTX and 36-month RTX in preventing relapses in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis who achieved a complete remission after induction therapy. Patients treated with 36-month RTX received either a fixed or a tailored regimen for the first 18 months and a fixed regimen for the last 18 months (36-month fixed/fixed RTX and 36-month tailored/fixed RTX, respectively). METHODS: The Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trials sequentially compared: 18-month fixed-schedule RTX versus AZA (MAINRITSAN); 18-month fixed-schedule RTX versus 18-month tailored-RTX (MAINRITSAN2); and extended therapy to 36 months with four additional RTX infusions after MAINRITSAN2 versus placebo (MAINRITSAN3). Patients were then followed prospectively through month 84 and their data were pooled to analyse relapses and adverse events. The primary endpoint was relapse-free survival at month 84. RESULTS: 277 patients were enrolled and divided in 5 groups: AZA (n=58), 18-month fixed-schedule RTX (n=97), 18-month tailored-RTX (n=40), 36-month tailored/fixed RTX (n=42), 36-month fixed/fixed RTX (n=41). After adjustment for prognostic factors, 18-month fixed-schedule RTX was superior to AZA in preventing major relapses at month 84 (HR 0.38, 95% CI 0.20 to 0.71). The 18-month tailored-RTX regimen was associated with an increased risk of major relapse compared with fixed-schedule regimen (HR 2.92, 95% CI 1.43 to 5.96). The risk of major relapse was similar between 36-month fixed/fixed and 18-month fixed-RTX (HR 0.69, 95% CI 0.38 to 1.25). CONCLUSIONS: According to these results, it appears that the 84-month remission rate is higher with an 18-month fixed RTX regimen compared with AZA and 18-month tailored RTX. Also, extending RTX to 36 months does not appear to reduce the long-term relapse rate compared with the 18-month fixed RTX regimen. However, as this study was underpowered to make this comparison, further prospective studies are needed to determine the potential long-term benefits of extending treatment in these patients.

Standardized high-dimensional spectral cytometry protocol and panels for whole blood immune phenotyping in clinical and translational studies.

Flow cytometry is the method of choice for immunophenotyping in the context of clinical, translational, and systems immunology studies. Among the latter, the Milieu Intérieur (MI) project aims at defining the boundaries of a healthy immune response to identify determinants of immune response variation. MI used immunophenotyping of a 1000 healthy donor cohort by flow cytometry as a principal outcome for immune variance at steady state. New generation spectral cytometers now enable high-dimensional immune cell characterization from small sample volumes. Therefore, for the MI 10-year follow up study, we have developed two high-dimensional spectral flow cytometry panels for deep characterization of innate and adaptive whole blood immune cells (35 and 34 fluorescent markers, respectively). We have standardized the protocol for sample handling, staining, acquisition, and data analysis. This approach enables the reproducible quantification of over 182 immune cell phenotypes at a single site. We have applied the protocol to discern minor differences between healthy and patient samples and validated its value for application in immunomonitoring studies. Our protocol is currently used for characterization of the impact of age and environmental factors on peripheral blood immune phenotypes of >400 donors from the initial MI cohort.

Neutralizing Antibody Levels as a Correlate of Protection Against SARS-CoV-2 Infection: A Modeling Analysis.

Although anti-severe acute respiratory syndrome-coronavirus 2 antibody kinetics have been described in large populations of vaccinated individuals, we still poorly understand how they evolve during a natural infection and how this impacts viral clearance. For that purpose, we analyzed the kinetics of both viral load and neutralizing antibody levels in a prospective cohort of individuals during acute infection with alpha variant. Using a mathematical model, we show that the progressive increase in neutralizing antibodies leads to a shortening of the half-life of both infected cells and infectious viral particles. We estimated that the neutralizing activity reached 90% of its maximal level within 11 days after symptom onset and could reduce the half-life of both infected cells and circulating virus by a 6-fold factor, thus playing a key role to achieve rapid viral clearance. Using this model, we conducted a simulation study to predict in a more general context the protection conferred by pre-existing neutralization titers, due to either vaccination or prior infection. We predicted that a neutralizing activity, as measured by 50% effective dose > 103 , could reduce by 46% the risk of having viral load detectable by standard polymerase chain reaction assays and by 98% the risk of having viral load above the threshold of infectiousness. Our model shows that neutralizing activity could be used to define correlates of protection against infection and transmission.

Serious infections in patients with VEXAS syndrome: data from the French VEXAS registry.

INTRODUCTION: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an acquired autoinflammatory monogenic disease with a poor prognosis whose determinants are not well understood. We aimed to describe serious infectious complications and their potential risk factors. METHODS: Retrospective multicentre study including patients with VEXAS syndrome from the French VEXAS Registry. Episodes of serious infections were described, and their risk factors were analysed using multivariable Cox proportional hazards models. RESULTS: Seventy-four patients with 133 serious infections were included. The most common sites of infection were lung (59%), skin (10%) and urinary tract (9%). Microbiological confirmation was obtained in 76%: 52% bacterial, 30% viral, 15% fungal and 3% mycobacterial. Among the pulmonary infections, the main pathogens were SARS-CoV-2 (28%), Legionella pneumophila (21%) and Pneumocystis jirovecii (19%). Sixteen per cent of severe infections occurred without any immunosuppressive treatment and with a daily glucocorticoid dose ≤10 mg. In multivariate analysis, age >75 years (HR (95% CI) 1.81 (1.02 to 3.24)), p.Met41Val mutation (2.29 (1.10 to 5.10)) and arthralgia (2.14 (1.18 to 3.52)) were associated with the risk of serious infections. JAK inhibitors were most associated with serious infections (3.84 (1.89 to 7.81)) compared with biologics and azacitidine. After a median follow-up of 4.4 (2.5-7.7) years, 27 (36%) patients died, including 15 (56%) due to serious infections. CONCLUSION: VEXAS syndrome is associated with a high incidence of serious infections, especially in older patients carrying the p.Met41Val mutation and treated with JAK inhibitors. The high frequency of atypical infections, especially in patients without treatment, may indicate an intrinsic immunodeficiency.

Impact of gender on baseline presentation and outcome in adult IgA vasculitis.

OBJECTIVES: Adult IgA vasculitis (IgAV) is more common in males, but the potential impact of gender remains unclear. We aimed to describe the impact of gender on presentation and outcome in adult IgAV. METHODS: We retrospectively analysed data from a multicentre retrospective cohort of 260 patients (IGAVAS). Comparisons were made according to gender status. RESULTS: Data from 259 patients (95 females and 164 males) were analysed. Compared with females, baseline presentation in males was similar for cutaneous involvement (100% vs 100%, p= 1.0), joint involvement (60% vs 63%, p= 0.7), gastrointestinal involvement (57% vs 45%, p= 0.093) and glomerulonephritis (73% vs 64%, p= 0.16). Glomerulonephritis was more severe at baseline in males than in females, with a lower median estimated glomerular filtration rate (eGFR) (90 [IQR 59-105] vs 97 ml/min/1.73m2 [76-116], p= 0.015) and increased median proteinuria (0.84 vs 0.58 g/day, p= 0.01). There were no differences in histological findings in patients who had a kidney biopsy. Methylprednisolone was more frequently used in males (40% vs22%, p= 0.015), as were immunosuppressants, especially cyclophosphamide 24% vs 6%, p= 0.0025) and azathioprine (10% vs 2%, p= 0.038). Analysis of treatment response showed that males had more frequent refractory disease (30% vs 13%, p= 0.004). Long-term outcomes (mortality and progression to chronic kidney failure) did not differ. CONCLUSION: Kidney involvement in IgAV appears to more severe in males, which is supported by more intensive treatment contrasting with a lower response rate. This study raises the question of gender as a new prognostic factor in adult IgAV.

Dysregulation of neutrophil oxidant production and interleukin-1-related cytokines in granulomatosis with polyangiitis.

OBJECTIVES: Neutrophils play a key role in ANCA-associated vasculitis, both as targets of autoimmunity and facilitators of vascular damage. In granulomatosis with polyangiitis (GPA), data regarding the production of reactive oxygen species (ROS) in neutrophils are unclear. Further, recent data suggests that ROS production could have an anti-inflammatory effect through the regulation of the inflammasome and IL-1-related cytokines. We aimed to analyse the ROS production in neutrophils from patients with GPA and investigate its association with IL-1-related cytokines and the autoantigen proteinase 3 (PR3). METHODS: Seventy-two GPA patients with disease flare were included in the NEUTROVASC prospective cohort study. ROS production was evaluated in whole blood of patients with active GPA and compared with the same patients in remission or healthy controls. Associations between ROS production, PR3 membrane expression on neutrophils, serum levels of IL-1-related cytokines as well as inflammasome-related proteins were analyzed. RESULTS: We observed a robust defect in ROS production by neutrophils from patients with active GPA compared with healthy controls, independent of glucocorticoid treatment. Serum levels of IL-1-related cytokines were significantly increased in GPA patients, particularly in patients with kidney involvement, and levels of these cytokines returned to normal after patients achieved remission. Further, inflammasome-related proteins were significantly dysregulated in the cytosol of neutrophils as well as the serum from GPA patients. CONCLUSION: Our data suggests that ROS production and regulation of the inflammasome in neutrophils from patients with GPA are disturbed and may be a potential therapeutic target. CLINICAL TRIAL REGISTRATION NUMBER: NCT01862068, clinicaltrials.gov, https://www.clinicaltrials.gov.