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.

A specific diagnostic metabolome signature in adult IgA vasculitis.

INTRODUCTION: IgA vasculitis diagnosis relies primarily on clinical features and is confirmed by pathological findings. To date, there is no reliable noninvasive diagnostic biomarker. OBJECTIVE: We aimed to explore the baseline serum metabolome of adult patients with IgA vasculitis to identify potential diagnostic biomarkers. METHODS: We performed a study comparing the serum metabolome of patients with IgA vasculitis to that of patients with inflammatory condition, namely spondyloarthritis. Serum analyses were performed by high-performance liquid chromatography-mass spectrometry. RESULTS: Fifty-five patients with IgA vasculitis and 77 controls with spondyloarthritis (age- and sex-matched) were included in this study. The median age of IgA vasculitis patients was 53 years. Two-thirds of patients were female (n = 32). At the time of vasculitis diagnosis, 100% of patients had skin involvement and 69% presented with glomerulonephritis (n = 38). Joint and digestive involvement were observed in 56% (n = 31) and 42% (n = 23) of patients. Four discriminative metabolites between the two groups were identified: 1-methyladenosine, L-glutamic acid, serotonin, and thymidine. The multivariate model built from the serum metabolomes of patients with IgA vasculitis and spondyloarthritis revealed an accuracy > 90%. As this model was significant according to the permutation test (p < 0.01), independent validation showed an excellent predictive value of the test set: sensitivity 98%; specificity 98%, positive predictive value 97% and negative predictive value 98%. CONCLUSION: To our knowledge, this study is the first to use the metabolomic approach for diagnostic purposes in adult IgA vasculitis, highlighting a specific diagnostic metabolome signature.

Prone position versus usual care in hypoxemic COVID-19 patients in medical wards: a randomised controlled trial.

BACKGROUND: Benefit of early awake prone positioning for COVID-19 patients hospitalised in medical wards and who need oxygen therapy remains to be demonstrated. The question was considered at the time of COVID-19 pandemic to avoid overloading the intensive care units. We aimed to determine whether prone position plus usual care could reduce the rate of non-invasive ventilation (NIV) or intubation or death as compared to usual care alone. METHODS: In this multicentre randomised clinical trial, 268 patients were randomly assigned to awake prone position plus usual care (N = 135) or usual care alone (N = 132). The primary outcome was the proportion of patients who underwent NIV or intubation or died within 28 days. Main secondary outcomes included the rates of NIV, of intubation or death, within 28 days. RESULTS: Median time spent each day in the prone position within 72 h of randomisation was 90 min (IQR 30-133). The proportion of NIV or intubation or death within 28 days was 14.1% (19/135) in the prone position group and 12.9% (17/132) in the usual care group [odds ratio adjusted for stratification (aOR) 0.43; 95% confidence interval (CI) 0.14-1.35]. The probability of intubation, or intubation or death (secondary outcomes) was lower in the prone position group than in the usual care group (aOR 0.11; 95% CI 0.01-0.89 and aOR 0.09; 95% CI 0.01-0.76, respectively) in the whole study population and in the prespecified subgroup of patients with SpO2 ≥ 95% on inclusion (aOR 0.11; 95% CI 0.01-0.90, and aOR 0.09; 95% CI 0.03-0.27, respectively). CONCLUSIONS: Awake prone position plus usual care in COVID-19 patients in medical wards did not decrease the composite outcome of need for NIV or intubation or death. Trial registration ClinicalTrials.gov Identifier: NCT04363463 . Registered 27 April 2020.

Biopsy-proven kidney involvement in hypocomplementemic urticarial vasculitis.

BACKGROUND: Hypocomplementemic urticarial vasculitis (HUV) is a rare systemic vasculitis. We aimed to describe the kidney involvement of HUV in a multicenter national cohort with an extended follow-up. METHODS: All patients with HUV (international Schwartz criteria) with a biopsy-proven kidney involvement, identified through a survey of the French Vasculitis Study Group (FVSG), were included. A systematic literature review on kidney involvement of HUV was performed. RESULTS: Twelve patients were included, among whom 8 had positive anti-C1q antibodies. All presented with proteinuria, from mild to nephrotic, and 8 displayed acute kidney injury (AKI), requiring temporary haemodialysis in 2. Kidney biopsy showed membrano-proliferative glomerulonephritis (MPGN) in 8 patients, pauci-immune crescentic GN or necrotizing vasculitis in 3 patients (with a mild to severe interstitial inflammation), and an isolated interstitial nephritis in 1 patient. C1q deposits were observed in the glomeruli (n = 6), tubules (n = 4) or renal arterioles (n = 3) of 8 patients. All patients received corticosteroids, and 9 were also treated with immunosuppressants or apheresis. After a mean follow-up of 8.9 years, 6 patients had a preserved renal function, but 2 patients had developed stage 3-4 chronic kidney disease (CKD) and 4 patients had reached end-stage kidney disease (ESKD), among whom 1 had received a kidney transplant. CONCLUSION: Renal involvement of HUV can be responsible for severe AKI, CKD and ESRD. It is not always associated with circulating anti-C1q antibodies. Kidney biopsy shows mostly MPGN or crescentic GN, with frequent C1q deposits in the glomeruli, tubules or arterioles.

Neonatal Fc receptor expression in lymphoid and myeloid cells in systemic lupus erythematosus.

The neonatal Fc receptor (FcRn) is a ubiquitously expressed protein historically involved in IgG and albumin recycling. Recent data suggest an involvement in the pathophysiology of antibody-mediated autoimmune diseases. Among them, systemic lupus erythematosus (SLE) implies clinical and biological abnormalities of innate and adaptive circulating immune cells, potentially involving newly described functions of FcRn. In this study, FcRn expression was assessed by flow cytometry in peripheral blood leukocytes of 41 SLE patients with either active or inactive disease and 32 healthy donors. FcRn expression in B cells, natural killer cells, and T cells of SLE patients was statistically lower as compared to healthy donors. Conversely, FcRn level was statistically higher in non-classical monocyte subpopulations (CD14+CD16+ monocytes) of SLE patients versus healthy donors providing an interesting perspective to further explore its role in SLE pathophysiology.

Adult-onset diagnosis of urea cycle disorders: Results of a French cohort of 71 patients.

Urea cycle disorders (UCD) are rare diseases that usually affect neonates or young children. During decompensations, hyperammonemia is neurotoxic, leading to severe symptoms and even coma and death if not treated rapidly. The aim was to describe a cohort of patients with adult onset of UCDs in a multicentric, retrospective and descriptive study of French adult patients with a diagnosis after 16 years of age of UCDs due to a deficiency in one of the 6 enzymes (arginase, ASL, ASS, CPS1, NAGS, OTC) or the two transporters (ORNT1 or citrin). Seventy-one patients were included (68% female, 32% male). The diagnosis was made in the context of (a) a metabolic decompensation (42%), (b) family history (55%), or (c) chronic symptoms (3%). The median age at diagnosis was 33 years (range 16-86). Eighty-nine percent of patients were diagnosed with OTC deficiency, 7% CPS1 deficiency, 3% HHH syndrome and 1% argininosuccinic aciduria. For those diagnosed during decompensations (including 23 OTC cases, mostly female), 89% required an admission in intensive care units. Seven deaths were attributed to UCD-6 decompensations and 1 epilepsy secondary to inaugural decompensation. This is the largest cohort of UCDs diagnosed in adulthood, which confirms the triad of neurological, gastrointestinal and psychiatric symptoms during hyperammonemic decompensations. We stress that females with OTC deficiency can be symptomatic. With 10% of deaths in this cohort, UCDs in adults remain a life-threatening condition. Physicians working in adult care must be aware of late-onset presentations given the implications for patients and their families.

Dual Ureaplasma parvum arthritis: a case report of U. parvum septic arthritis following contralateral reactive arthritis in an immunosuppressed patient.

BACKGROUND: Ureaplasma parvum is usually part of the normal genital flora. Rarely can it cause invasive infections such as genitourinary infections, septic arthritis, or meningitis. CASE PRESENTATION: Here we present the first description of chronic ureterocystitis in a 56-year-old immunocompromised patient, complicated first by reactive arthritis and secondarily by contralateral septic arthritis due to U. parvum infection. U. parvum was detected in synovial fluid and in a urine sample. Treatment consisted of double-J stenting and targeted antibiotic therapy. Evolution showed resolution of urinary symptoms and clinical improvement of arthritis despite functional sequelae. CONCLUSIONS: Given the high prevalence of U. parvum colonisation, this diagnosis should remain a diagnosis of exclusion. However, because of the difficulty in detecting this microorganism, it should be considered in unexplained subacute urethritis or arthritis, including reactive arthritis, especially in immunosuppressed patients. Real-time PCR positivity in the absence of a differential diagnosis should not be overlooked.

Liver involvement in urea cycle disorders: a review of the literature.

Urea cycle disorders (UCDs) are inborn errors of metabolism of the nitrogen detoxification pathway and encompass six principal enzymatic deficiencies. The aging of UCD patients leads to a better knowledge of the long-term natural history of the condition and to the reporting of previously unnoticed manifestations. Despite historical evidence of liver involvement in UCDs, little attention has been paid to this organ until recently. Hence, we reviewed the available scientific evidence on acute and chronic liver dysfunction and liver carcinogenesis in UCDs and discuss their pathophysiology. Overall, liver involvement, such as acute liver failure or steatotic-like disease, which may evolve toward cirrhosis, has been reported in all six main UCDs. Excessive glycogen storage is also a prominent histologic feature, and hypoglycemia has been reported in citrin deficiency. Hepatocarcinomas seem frequent in some UCDs, such as in citrin deficiency, and can sometimes occur in non-cirrhotic patients. UCDs may differ in liver involvement according to the enzymatic deficiency. Ornithine transcarbamylase deficiency may be associated more with acute liver failure and argininosuccinic aciduria with chronic liver failure and cirrhosis. Direct toxicity of metabolites, downstream metabolic deficiencies, impaired tricarboxylic acid cycle, oxidative stress, mitochondrial dysfunction, energy deficit, and putative toxicity of therapies combine in various ways to cause the different liver diseases reported.

Joint manifestations revealing inborn metabolic diseases in adults: a narrative review.

Inborn metabolic diseases (IMD) are rare conditions that can be diagnosed during adulthood. Patients with IMD may have joint symptoms and the challenge is to establish an early diagnosis in order to institute appropriate treatment and prevent irreversible damage. This review describes the joint manifestations of IMD that may be encountered in adults. The clinical settings considered were arthralgia and joint stiffness as well as arthritis. Unspecific arthralgias are often the first symptoms of hereditary hemochromatosis, chronic low back pain may reveal an intervertebral disc calcification in relation with alkaptonuria, and progressive joint stiffness may correspond to a mucopolysaccharidosis or mucolipidosis. Gaucher disease is initially revealed by painful acute attacks mimicking joint pain described as "bone crises". Some IMD may induce microcrystalline arthropathy. Beyond classical gout, there are also gouts in connection with purine metabolism disorders known as "enzymopathic gouts". Pyrophosphate arthropathy can also be part of the clinical spectrum of Gitelman syndrome or hypophosphatasia. Oxalate crystals arthritis can reveal a primary hyperoxaluria. Destructive arthritis may be indicative of Wilson's disease. Non-destructive arthritis may be seen in mevalonate kinase deficiency and familial hypercholesterolemia.

No evidence for systemic low-grade inflammation in adult patients with early-treated phenylketonuria: The INGRAPH study.

The question of an increased cardiovascular risk has been recently raised in adults with phenylketonuria (PKU). As low-grade systemic inflammation increases cardiovascular risk, the INGRAPH study aimed to evaluate low-grade inflammation in adult PKU patients compared to healthy controls and to determine the potential influence of Phe-controlled diet on inflammation. Twenty early-treated adult PKU patients, including a subgroup of 15 classical PKU patients, and 20 healthy volunteers were included. PKU patients and healthy subjects were matched on age, sex and body mass index class. Plasma concentrations of CRP, IFNg, IL1a, IL1b, IL2, IL6, IL10, and TNFα were measured in PKU patients and compared to controls. Plasma CRP was not different in the PKU group as compared to controls. No significant differences were observed between the two groups concerning plasma cytokines concentrations. Plasma CRP and cytokine profile were not different between "on diet" and "off diet" PKU patients. All these results were similar considering only the classical PKU subgroup. No differences were shown in plasma CRP and pro-inflammatory cytokines between adult PKU patients and healthy controls. Further studies are needed, including more patients and extensive characterization of systemic low-grade inflammation, as cardiovascular risk appears to be a new concern in adult PKU population.

Pleuropulmonary Manifestations of Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic (VEXAS) Syndrome.

BACKGROUND: The vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a newly identified autoinflammatory disorder related to somatic UBA1 mutations. Up to 72% of patients may show lung involvement. RESEARCH QUESTION: What are the pleuropulmonary manifestations in VEXAS syndrome? STUDY DESIGN AND METHODS: One hundred fourteen patients were included in the French cohort of VEXAS syndrome between November 2020 and May 2021. Each patient included in the study who had an available chest CT scan was discussed in an adjudication multidisciplinary team and classified as showing potentially pleuropulmonary-specific involvement of VEXAS syndrome or others. RESULTS: Fifty-one patients had a CT scan available for review and 45 patients (39%) showed pleuropulmonary abnormalities on chest CT scan that were considered related to VEXAS syndrome after adjudication. Most patients were men (95%) with a median age 67.0 years at the onset of symptoms. Among these 45 patients, 44% reported dyspnea and 40% reported cough. All 45 patients showed lung opacities on chest CT scan (including ground-glass opacities [87%], consolidations [49%], reticulation [38%], and septal lines [51%]) and 53% of patients showed pleural effusion. Most patients showed improvement with prednisone, but usually required > 20 mg/d. The main clinical and biological features as well the median survival did not differ between the 45 patients with pleuropulmonary involvement and the rest of the cohort, suggesting that the prevalence of pleuropulmonary involvement might have been underdiagnosed in the rest of the cohort. INTERPRETATION: Pulmonary manifestations are frequent in VEXAS syndrome, but rarely are at the forefront. The initial outcome is favorable with prednisone and does not seem to lead to pulmonary fibrosis.

Immunoglobulin A Vasculitis Following COVID-19: A French Multicenter Case Series.

OBJECTIVE: Immunoglobulin A vasculitis (IgAV) usually occurs following viral respiratory tract infection. In the context of the global coronavirus disease 2019 (COVID-19) pandemic, we describe a case series of patients who developed IgAV following SARS-CoV-2 infection. METHODS: This national multicenter retrospective study included patients with IgAV following SARS-CoV-2 infection from January 1, 2020, to January 1, 2022. Patients had histologically proven IgAV and reverse transcription PCR (RT-PCR)-proven SARS-CoV-2 infection. The interval between infection and vasculitis onset had to be < 4 weeks. RESULTS: We included 5 patients, 4 of whom were women with a mean age of 45 years. Four patients had paucisymptomatic infections and 1 required a 48-hour low-flow oxygen treatment. All 5 patients had purpuric skin involvement. Arthritis was observed in 2 patients, 3 had IgA glomerulonephritis, and 2 had digestive involvement. Three renal biopsies were performed and showed mesangial IgA deposits without any extracapillary proliferation. Median C-reactive protein was 180 (range 15.1-225) mg/L, median serum creatinine level was 65 (range 41-169) µmol/L, and 2 patients had a glomerular filtration rate < 60 mL/min. Four patients received first-line treatment with glucocorticoids. All patients had a favorable progression and 2 patients experienced minor skin relapses, one after COVID-19 vaccination. CONCLUSION: This series describes the emergence of IgAV closely following COVID-19; we were not able to eliminate an incidental link between these events. Their disease outcomes were favorable. In most of our patients, the SARS-CoV-2 infection was paucisymptomatic, and we recommend RT-PCR tests to look for COVID-19 in patients without any evident triggers for IgAV.

Does awake prone positioning prevent the use of mechanical respiratory support or death in COVID-19 patients on standard oxygen therapy hospitalised in general wards? A multicentre randomised controlled trial: the PROVID-19 protocol.

INTRODUCTION: COVID-19 is responsible of severe hypoxaemia and acute respiratory distress syndrome (ARDS). Prone positioning improves oxygenation and survival in sedated mechanically patients with ARDS not related to COVID-19. Awake prone positioning is a simple and safe technique which improves oxygenation in non-intubated COVID-19 patients. We hypothesised that early prone positioning in COVID-19 patients breathing spontaneously in medical wards could decrease the rates of intubation or need for noninvasive ventilation or death. METHODS AND ANALYSIS: PROVID-19 is an investigator-initiated, prospective, multicentre randomised, controlled, superiority trial comparing awake prone positioning to standard of care in hypoxaemic COVID-19 patients in 20 medical wards in France and Monaco. Patients are randomised to receive either awake prone position plus usual care or usual care alone with stratification on centres, body mass index and severity of hypoxaemia.The study objective is to compare the rate of treatment failure defined as a composite endpoint comprising the need for non-invasive ventilation (at two pressure levels) or for intubation or death, between the intervention group (awake prone position plus usual care) and the usual care (usual care alone) group at 28 days. ETHICS AND DISSEMINATION: The protocol and amendments have been approved by the ethics committees (Comité de protection des personnes Ouest VI, France, no 1279 HPS2 and Comité Consultatif d'Ethique en matière de Recherche Biomédicale, Monaco, no 2020.8894 AP/jv), and patients are included after written informed consent. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04363463.