Characteristics and outcome of ANCA-associated vasculitides induced by anti-thyroid drugs: a multicentre retrospective case-control study.

OBJECTIVE: Data on ANCA-associated vasculitis (AAV) induced by anti-thyroid drugs (ATD) are scarce. We aimed to describe the characteristics and outcome of these patients in comparison to primary AAV. METHODS: We performed a retrospective multicentre study including patients with ATD-induced AAV. We focused on ATD-induced microscopic polyangiitis (MPA) and compared them with primary MPA by matching each case with four controls by gender and year of diagnosis. RESULTS: Forty-five patients with ATD-induced AAV of whom 24 MPA were included. ANCA were positive in 44 patients (98%), including myeloperoxidase (MPO)-ANCA in 21 (47%), proteinase 3 (PR3)-ANCA in six (13%), and double positive MPO- and PR3-ANCA in 15 (33%). Main clinical manifestations were skin involvement (64%), arthralgia (51%) and glomerulonephritis (20%). ATD was discontinued in 98% of cases, allowing vasculitis remission in seven (16%). All the remaining patients achieved remission after glucocorticoids, in combination with rituximab in 11 (30%) or cyclophosphamide in four (11%). ATD were reintroduced in seven cases (16%) without any subsequent relapse. Compared with 96 matched primary MPA, ATD-induced MPA were younger at diagnosis (48 vs 65 years, P < 0.001), had more frequent cutaneous involvement (54 vs 25%, P = 0.007), but less frequent kidney (38 vs 73%, P = 0.02), and a lower risk of relapse (adjusted HR 0.07; 95% CI 0.01, 0.65, P = 0.019). CONCLUSION: ATD-induced AAV were mainly MPA with MPO-ANCA, but double MPO- and PR3-ANCA positivity was frequent. The most common manifestations were skin and musculoskeletal manifestations. ATD-induced MPA were less severe and showed a lower risk of relapse than primary MPA.

Severe Libman-Sacks endocarditis complicating antiphospholipid syndrome: a retrospective analysis of 23 operated cases.

OBJECTIVE: Data on severe heart valve disease (HVD), including Libman-Sacks endocarditis, associated with SLE and/or APS requiring valvular surgery are scarce. We thus conducted a retrospective study, aimed at describing and clarifying clinical, laboratory, echocardiographic, histopathological and evolutional features of SLE and/or APS patients with severe associated-HVD. METHODS: An observational retrospective multicentric analysis of 23 adults with SLE and/or APS and HVD between 1996 and 2019 and available histopathological report evaluating long-term follow-up. RESULTS: Twenty-three individuals (20 females, median age 37 [range 17-76] years) were included. All had APS (thrombotic in 22, with an arterial phenotype in 15 and with catastrophic APS [CAPS] in six), and 11 (47%) had SLE. Systemic underlying disease had been diagnosed prior to HVD in 12 (52%). In 10 patients (43%), HVD was complicated by cerebral stroke prior to surgery. Twenty patients (87%) had only one pathological valve, the mitral valve in 18 patients (78%). Valvular thickening (n = 19) and valvular regurgitation (n = 19) were the most frequently reported lesions. Fifteen (62%) patients underwent mechanical valve replacement, six (26%) conservative valve repair (five were later re-operated after a median time of 1 [0-4] year), and two (9%) underwent biological valve replacement. Nine patients (39%) presented early-onset post-operative complications, including three CAPS immediately after surgery and one death. After surgery, 18 patients (78%) had normal postoperative valvular function, but almost half of the patients (43%) had post-operative neurological sequelae (median follow-up of 6 [2-20] years). CONCLUSION: Severe HVD leading to surgery was strongly associated with thrombotic APS, especially arterial phenotypes. Half of the reported patients presented cerebral stroke complicating the HVD. Valvular surgery carried a significant risk of CAPS.

Cluster analysis unveils a severe persistent respiratory impairment phenotype 3-months after severe COVID-19.

BACKGROUND: The mid-term respiratory sequelae in survivors of severe COVID-19 appear highly heterogeneous. In addition, factors associated with respiratory sequelae are not known. In this monocentric prospective study, we performed a multidisciplinary assessment for respiratory and muscular impairment and psychological distress 3 months after severe COVID-19. We analysed factors associated with severe persistent respiratory impairment, amongst demographic, COVID-19 severity, and 3-month assessment. METHODS: Patients with severe SARS-CoV-2 pneumonia requiring ≥ 4L/min were included for a systematic 3-month visit, including respiratory assessment (symptoms, lung function, CT scan), muscular evaluation (body composition, physical function and activity, disability), psychopathological evaluation (anxiety, depression, post-traumatic stress disorder-PTSD) and quality of life. A cluster analysis was performed to identify subgroups of patients based on objective functional measurements: DLCO, total lung capacity and 6-min walking distance (6MWD). RESULTS: Sixty-two patients were analysed, 39% had dyspnea on exercise (mMRC ≥ 2), 72% had DLCO < 80%, 90% had CT-scan abnormalities; 40% had sarcopenia/pre-sarcopenia and 31% had symptoms of PTSD. Cluster analysis identified a group of patients (n = 18, 30.5%) with a severe persistent (SP) respiratory impairment (DLCO 48 ± 12%, 6MWD 299 ± 141 m). This SP cluster was characterized by older age, severe respiratory symptoms, but also sarcopenia/pre-sarcopenia, symptoms of PTSD and markedly impaired quality of life. It was not associated with initial COVID-19 severity or management. CONCLUSIONS AND CLINICAL IMPLICATION: We identified a phenotype of patients with severe persistent respiratory and muscular impairment and psychological distress 3 months after severe COVID-19. Our results highlight the need for multidisciplinary assessment and management after severe SARS-CoV-2 pneumonia. Trial registration The study was registered on ClinicalTrials.gov (May 6, 2020): NCT04376840.

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.

Phenotype and outcome of pulmonary arterial hypertension patients carrying a TBX4 mutation.

INTRODUCTION: TBX4 mutation causes small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with TBX4 mutations are largely unknown. METHODS: We report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a TBX4 mutation from the French pulmonary hypertension (PH) network. RESULTS: 20 patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 years (0-76 years) and a female to male ratio of three. Most of the patients (70%) were in New York Heart Association (NYHA) functional class III or IV with a severe haemodynamic impairment (median pulmonary vascular resistance (PVR) of 13.6 (6.2-41.8) Wood units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity of the lung for carbon monoxide (D LCO) was decreased in all patients. High-resolution computed tomography (HRCT) showed bronchial abnormalities, peri-bronchial cysts, mosaic distribution and mediastinal lymphadenopathies. PAH therapy was associated with significant clinical improvement. At follow-up (median 76 months), two patients had died and two had undergone lung transplantation. One-year, three-year and five-year event-free survival rates were 100%, 94% and 83%, respectively. Histologic examination of explanted lungs revealed alveolar growth abnormalities, major pulmonary vascular remodelling similar to that observed in idiopathic pulmonary arterial hypertension (IPAH) and accumulation of cholesterol crystals within the lung parenchyma. CONCLUSION: PAH due to TBX4 mutations may occur with or without skeletal abnormalities across a broad age range from birth to late adulthood. PAH is usually severe and associated with bronchial and parenchymal abnormalities.

Bioclinical Test to Predict Nephropathia Epidemica Severity at Hospital Admission.

We conducted a multicenter, retrospective cohort study of hospitalized patients with serologically proven nephropathia epidemica (NE) living in Ardennes Department, France, during 2000-2014 to develop a bioclinical test predictive of severe disease. Among 205 patients, 45 (22.0%) had severe NE. We found the following factors predictive of severe NE: nephrotoxic drug exposure (p = 0.005, point value 10); visual disorders (p = 0.02, point value 8); microscopic or macroscopic hematuria (p = 0.04, point value 7); leukocyte count >10 × 109 cells/L (p = 0.01, point value 9); and thrombocytopenia <90 × 109/L (p = 0.003, point value 11). When point values for each factor were summed, we found a score of <10 identified low-risk patients (3.3% had severe disease), and a score >20 identified high-risk patients (45.3% had severe disease). If validated in future studies, this test could be used to stratify patients by severity in research studies and in clinical practice.

Imbalance of the Vanin-1 Pathway in Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and visceral organs and vascular alterations. SSc pathophysiology involves systemic inflammation and oxidative stress. Because the vanin-1 gene (vnn1) encodes an enzyme with pantetheinase activity that converts vasculoprotective pantethine into profibrotic pantothenic acid and pro-oxidant cystamine, we tested this pathway in the pathophysiology of SSc. Activation of the vanin-1/pantetheinase pathway was investigated in wild-type BALB/c mice with hypochlorous acid (HOCl)-induced SSc by ELISA and Western blotting. We then evaluated the effects of the inactivation of vnn1 on the development of fibrosis, endothelial alterations, and immunological activation in mice with HOCl- and bleomycin-induced SSc. We then explored the vanin-1/pantetheinase pathway in a cohort of patients with SSc and in controls. In wild-type mice with HOCl-induced SSc, the vanin-1/pantetheinase pathway was dysregulated, with elevation of vanin-1 activity in skin and high levels of serum pantothenic acid. Inactivation of the vnn1 gene in vnn1-/- mice with HOCl-induced SSc prevented the development of characteristic features of the disease, including fibrosis, immunologic abnormalities, and endothelial dysfunction. Remarkably, patients with diffuse SSc also had increased expression of vanin-1 in skin and blood and elevated levels of serum pantothenic acid that correlated with the severity of the disease. Our data demonstrate that vanin-1/pantetheinase controls fibrosis, vasculopathy, autoimmunity, and oxidative stress in SSc. The levels of vanin-1 expression and pantothenic acid determine SSc severity and can be used as markers of disease severity. More importantly, inhibition of vanin-1 can open new therapeutic approaches in SSc.

Amelioration of systemic fibrosis in mice by angiotensin II receptor blockade.

OBJECTIVE: Systemic sclerosis (SSc) is characterized by microvascular damage, fibrosis of skin and visceral organs, and autoimmunity. Previous studies have shown that angiotensin II is involved in the synthesis of type I collagen. We investigated whether the blockade of angiotensin II receptor type I (AT1 ) by irbesartan reduces skin and lung fibrosis in 2 murine models of SSc. METHODS: SSc was induced by daily intradermal injection of HOCl into the backs of BALB/c mice (HOCl-induced SSc). Mice were treated daily with irbesartan by oral gavage. RESULTS: Irbesartan reduced dermal thickness, collagen concentration, Smad2/3, and α-smooth muscle actin expression, as well as fibroblast proliferation and H-Ras expression in the skin of mice with HOCl-induced SSc. Mice treated with irbesartan also displayed less lung fibrosis, less inflammation, and a lower concentration of collagen in the lungs than untreated mice. Exhaled nitric oxide, inducible nitric oxide synthase, and 3-nitrotyrosine expression in the lungs were decreased following irbesartan treatment. Moreover, irbesartan reduced the number and the proliferation of splenic B and T cells and the serum levels of anti-DNA topoisomerase I autoantibodies. CONCLUSION: Irbesartan, an AT1 antagonist, prevents fibrosis and inflammation and inhibits nitric oxide production in HOCl-induced models of systemic fibrosis. Our findings extend the indication of an AT1 antagonist to SSc patients with diffuse fibrosis, especially those with lung involvement.

Arsenic trioxide prevents murine sclerodermatous graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) follows allogeneic hematopoietic stem cell transplantation. It results from alloreactive processes induced by minor MHC incompatibilities triggered by activated APCs, such as plasmacytoid dendritic cells (pDCs), and leading to the activation of CD4 T cells. Therefore, we tested whether CD4(+) and pDCs, activated cells that produce high levels of reactive oxygen species, could be killed by arsenic trioxide (As(2)O(3)), a chemotherapeutic drug used in the treatment of acute promyelocytic leukemia. Indeed, As(2)O(3) exerts its cytotoxic effects by inducing a powerful oxidative stress that exceeds the lethal threshold. Sclerodermatous GVHD was induced in BALB/c mice by body irradiation, followed by B10.D2 bone marrow and spleen cell transplantation. Mice were simultaneously treated with daily i.p. injections of As(2)O(3). Transplanted mice displayed severe clinical symptoms, including diarrhea, alopecia, vasculitis, and fibrosis of the skin and visceral organs. The symptoms were dramatically abrogated in mice treated with As(2)O(3). These beneficial effects were mediated through the depletion of glutathione and the overproduction of H(2)O(2) that killed activated CD4(+) T cells and pDCs. The dramatic improvement provided by As(2)O(3) in the model of sclerodermatous GVHD that associates fibrosis with immune activation provides a rationale for the evaluation of As(2)O(3) in the management of patients affected by chronic GVHD.

Sunitinib inhibits the phosphorylation of platelet-derived growth factor receptor ß in the skin of mice with scleroderma-like features and prevents the development of the disease.

OBJECTIVE: Systemic sclerosis (SSc) is characterized by fibrosis of the skin and visceral organs, vascular dysfunction, and immunologic dysregulation. Platelet-derived growth factors (PDGFs) have been implicated in the development of fibrosis and dysregulation of vascular function. We investigated the effects of sunitinib and sorafenib, two tyrosine kinase inhibitors that interfere with PDGF signaling, in a mouse model of diffuse SSc. METHODS: SSc was induced in BALB/c mice by subcutaneous injections of HOCl daily for 6 weeks. Mice were randomized to treatment with sunitinib, sorafenib, or vehicle. The levels of native and phosphorylated PDGF receptor ß (PDGFRß) and vascular endothelial growth factor receptor (VEGFR) in the skin were assessed by Western blot and immunohistochemical analyses. Skin and lung fibrosis were evaluated by histologic and biochemical methods. Autoantibodies were detected by enzyme-linked immunosorbent assay, and spleen cell populations were analyzed by flow cytometry. RESULTS: Phosphorylation of PDGFRß and VEGFR was higher in fibrotic skin from HOCl-injected mice with SSc than from PBS-injected mice. Injections of HOCl induced cutaneous and lung fibrosis, increased the proliferation rate of fibroblasts in areas of fibrotic skin, increased splenic B cell and T cell counts, and increased anti-DNA topoisomerase I autoantibody levels in BALB/c mice. All of these features were reduced by sunitinib but not by sorafenib. Sunitinib significantly reduced the phosphorylation of both PDGF and VEGF receptors. CONCLUSION: Inhibition of the hyperactivated PDGF and VEGF pathways by sunitinib prevented the development of fibrosis in HOCl-induced murine SSc and may represent a new SSc treatment for testing in clinical trials.

Reactive oxygen species-mediated killing of activated fibroblasts by arsenic trioxide ameliorates fibrosis in a murine model of systemic sclerosis.

OBJECTIVE: In patients with systemic sclerosis (SSc), activated fibroblasts produce reactive oxygen species (ROS) that stimulate their proliferation and collagen synthesis. By analogy with tumor cells that undergo apoptosis upon cytotoxic treatment that increases ROS levels beyond a lethal threshold, we tested whether activated fibroblasts could be selectively killed by the cytotoxic molecule arsenic trioxide (As(2) O(3) ) in a murine model of SSc. METHODS: SSc was induced in BALB/c mice by daily intradermal injections of HOCl. Mice were simultaneously treated with daily intraperitoneal injections of As(2) O(3) . RESULTS: As(2) O(3) limited dermal thickness and inhibited collagen deposition, as assessed by histologic examination and measurement of mouse skin and lung collagen contents. As(2) O(3) abrogated vascular damage, as shown by serum vascular cell adhesion molecule 1 level, and inhibited the production of autoantibodies, interleukin-4 (IL-4), and IL-13 by activated T cells. These beneficial effects were mediated through ROS generation that selectively killed activated fibroblasts containing low levels of glutathione. CONCLUSION: Our findings indicate that treatment with As(2) O(3) dramatically improves skin and lung fibrosis in a mouse model of SSc, providing a rationale for the evaluation of As(2) O(3) treatment in patients with SSc.

Roth spots in a Rendu-Osler-Weber syndrome.

PURPOSE: To describe the molecular diagnosis and atypical ocular presentation of a patient who suffered for a Rendu-Osler-Weber syndrome associated with juvenile polyposis (JP) syndrome. METHODS: This is a case report of a patient that underwent fundus examen, brain Magnetic Resonance Imaging (MRI) and arteriography. Genetic testing was performed by next-generation-sequencing (NGS). RESULTS: A 35-year-old woman presented with right hemiplegia with right homonymous lateral hemianopia and homolateral complete sensory deficit. She also had Roth spots in her left fundus. Genetic testing revealed a pathogenic variation in the heterozygous state in the SMAD-4 gene (c.1245_1248del). CONCLUSION: Hereditary Hemorrhagic Telangiectasia (HTT) also known as Rendu-Osler-Weber syndrome is a rare autosomal dominant disease which reveals mostly with epistaxis and cutaneous telangiectasias. Our clinical case reports Roth spots in the context of HTT associated with juvenile polyposis syndrome. SMAD-4 mutation may explain the presence of a carotid-ophthalmic aneurysm which is not a lesion usually found in HTT.

Efficacy and Safety of Botulinum Toxin in Adults with Raynaud's Phenomenon Secondary to Systemic Sclerosis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study.

OBJECTIVE: To determine whether a single session of botulinum toxin type A (BTA) injections into both hands more effectively decreases the frequency of systemic sclerosis-associated Raynaud's phenomenon (SSc-RP) episodes than placebo. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group phase III trial in patients with SSc-RP assessed the effect of 50-unit BTA or placebo injections into the palms of both hands around each neurovascular bundle during 1 session in winter. The primary end point was the between-group difference in the median change in the number of RP episodes from baseline (day 0) to 4 weeks postinjection. Values between the groups were compared with the Wilcoxon rank-sum test. RESULTS: The intent-to-treat analysis included 46 BTA-treated patients and 44 placebo recipients. At 4 weeks after assigned treatment injections, the median number of daily RP episodes decreased comparably in the BTA and placebo groups (median change -1 episode/day [interquartile range (IQR) -1.5, 0 episodes/day] and -1 episode/day [IQR -2.5, 0 episodes/day], respectively) (P = 0.77 versus placebo). Moreover, change in Raynaud's Condition Score, quality of life assessed by Health Assessment Questionnaire disability index, and hand function assessed by shortened Disabilities of the Arm, Shoulder, and Hand (QuickDASH) and Cochin Hand Function Scale from baseline to follow-up weeks 4, 12, and 24 did not differ significantly between groups. The BTA group experienced transient hand muscle weakness significantly more frequently (P = 0.003). CONCLUSION: Neither the primary nor secondary end points were reached, and our results do not support any beneficial effect of palmar BTA injections to treat SSc-RP.

CovAID: Identification of factors associated with severe COVID-19 in patients with inflammatory rheumatism or autoimmune diseases.

Introduction: Autoimmune/inflammatory rheumatic diseases (AIRDs) patients might be at-risk of severe COVID-19. However, whether this is linked to the disease or to its treatment is difficult to determine. This study aimed to identify factors associated with occurrence of severe COVID-19 in AIRD patients and to evaluate whether having an AIRD was associated with increased risk of severe COVID-19 or death. Materials and methods: Two databases were analyzed: the EDS (Entrepôt des Données de Santé, Clinical Data Warehouse), including all patients followed in Paris university hospitals and the French multi-center COVID-19 cohort [French rheumatic and musculoskeletal diseases (RMD)]. First, in a combined analysis we compared patients with severe and non-severe COVID-19 to identify factors associated with severity. Then, we performed a propensity matched score case-control study within the EDS database to compare AIRD cases and non-AIRD controls. Results: Among 1,213 patients, 195 (16.1%) experienced severe COVID-19. In multivariate analysis, older age, interstitial lung disease (ILD), arterial hypertension, obesity, sarcoidosis, vasculitis, auto-inflammatory diseases, and treatment with corticosteroids or rituximab were associated with increased risk of severe COVID-19. Among 35,741 COVID-19 patients in EDS, 316 having AIRDs were compared to 1,264 Propensity score-matched controls. AIRD patients had a higher risk of severe COVID-19 [aOR = 1.43 (1.08-1.87), p = 0.01] but analysis restricted to rheumatoid arthritis and spondyloarthritis found no increased risk of severe COVID-19 [aOR = 1.11 (0.68-1.81)]. Conclusion: In this multicenter study, we confirmed that AIRD patients treated with rituximab or corticosteroids and/or having vasculitis, auto-inflammatory disease, and sarcoidosis had increased risk of severe COVID-19. Also, AIRD patients had, overall, an increased risk of severe COVID-19 compares general 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.

Eosinophilia during Hantavirus infection: a cohort study.

BACKGROUND: There are emerging eosinophil-related considerations concerning viral infections. The role of eosinophils has poorly been evaluated during Hantavirus infection. METHODS: The aim of this study was to determine the prevalence of eosinophilia (defined as an eosinophil count above 500 cells/mm3) during haemorrhagic fever with renal syndrome (HFRS) in a large cohort of patients, and to identify factors associated with eosinophilia. RESULTS: Among 387 patients hospitalized for HFRS, 98 (25.3%) had eosinophilia. By univariate analysis, eosinophilia was significantly associated with more severe thrombocytopenia, high C-reactive protein level, white blood cell count and neutrophil count and lower nephrotoxic drug intake. As there was a collinearity between white blood cell count and C-reactive protein level, only C-reactive protein level with platelet count and nephrotoxic drug intake were entered in the multivariable analysis. Elevated C-reactive protein concentrations remained independently associated with eosinophilia. CONCLUSION: Eosinophilia during HFRS affects one quarter of patients, and supports the role of eosinophils in antiviral immunity against hantavirus infection.

Incidence, associated factors, and effect on renal function of amoxicillin crystalluria in patients receiving high doses of intravenous amoxicillin (The CRISTAMOX Study): A cohort study.

Background: Amoxicillin crystalluria (AC), potentially responsible for acute kidney injury (AKI), is reported more and more frequently in patients treated with high doses of intravenous amoxicillin (HDIVA). The main objective of this study was to evaluate AC incidence in these patients. The secondary objectives were to identify factors associated with AC and to evaluate its impact on the risk of AKI. Methods: This multicentre, observational, cohort study was conducted between Mar 18, 2014 and Aug 16, 2019 in Dijon, Nancy, and Reims University Hospitals as well as Châlon-sur-Saône, Charleville-Mézières, and Troyes general hospitals in France. Adult patients (≥18 years) treated with HDIVA and having been tested for AC at least once during treatment were included. Clinical, biological, and therapeutic characteristics of the patients were collected. A univariable mixed logistic regression model assessed the factors associated with AC. A multivariable Cox model with AC as a time-dependent variable assessed the prognostic factors for AKI. ClinicalTrials.gov number: NCT02853292. Findings: Of the 112 included patients, 27 (24.1%, 95% CI [16.2-32.0]) developed at least one episode of AC within a mean of 5.1 days. The factors associated with its occurrence were the concomitant use of angiotensin converting enzyme (ACE) inhibitors (OR=4.6, 95% CI [2.2-9.3], p<0.0001) and the decrease of urinary pH (OR=2.1 for one pH point decrease, 95% CI [1.2-3.7], p=0.009). 20 patients (17.9%) presented with AKI, within a mean time of 10.9 days. The main factor associated with the occurrence of AKI was the occurrence of AC (aHR=7.4, 95% CI [2.5-22.2], p=0.0003). Interpretation: AC occurred in a quarter of patients treated with HDIVA and was highly prognostic of AKI. Funding: None.

New insights on chemically induced animal models of systemic sclerosis.

PURPOSE OF REVIEW: To discuss the most recent published studies on chemical-induced animal models of systemic sclerosis (SSc) and to precise the important signalling pathways that lead to the initiation and progression of the disease in these models. RECENT FINDINGS: Environmental factors undoubtedly contribute to the initiation and the development of SSc. Among those factors, bleomycin has been identified as a possible SSc-inducing substance in mice. The bleomycin model mimics the inflammatory changes observed in the early phase of the disease. This model has been extensively studied and has allowed identification of several key pathways activated in the human disease. More recently, a new chemical-induced model of scleroderma has been developed in mice using daily intradermal injections of a solution generating hypochlorous acid (HOCl)-model. This HOCl-model recapitulates the whole spectrum of the human disease, as fibrosis, inflammation, autoimmunity and vasculopathy can be observed in mice and brought new arguments for a major role of reactive oxygen species in the induction of local and systemic fibrosis. SUMMARY: Chemically induced models truly develop a SSc-like disease and argue for a crucial role of ROS in SSc.

Targeting the cannabinoid pathway limits the development of fibrosis and autoimmunity in a mouse model of systemic sclerosis.

Our aim was to evaluate the roles of the cannabinoid pathway in the induction and propagation of systemic sclerosis (SSc) in a mouse model of diffuse SSc induced by hypochlorite injections. BALB/c mice injected subcutaneously every day for 6 weeks with PBS or hypochlorite were treated intraperitoneally with either WIN-55,212, an agonist of the cannabinoid receptors 1 (CB1) and receptors 2 (CB2), with JWH-133, a selective agonist of CB2, or with PBS. Skin and lung fibrosis were then assessed by histological and biochemical methods, and the proliferation of fibroblasts purified from diseased skin was assessed by thymidine incorporation. Autoantibodies were detected by ELISA, and spleen cell populations were analyzed by flow cytometry. Experiments were also performed in mice deficient for CB2 receptors (Cnr2(-/-)). Injections of hypochlorite induced cutaneous and lung fibrosis as well as increased the proliferation rate of fibroblasts isolated from fibrotic skin, splenic B cell counts, and levels of anti-DNA topoisomerase-1 autoantibodies. Treatment with WIN-55,212 or with the selective CB2 agonist JWH-133 prevented the development of skin and lung fibrosis as well as reduced fibroblast proliferation and the development of autoantibodies. Experiments performed in CB2-deficient mice confirmed the influence of CB2 in the development of systemic fibrosis and autoimmunity. Therefore, we demonstrate that the CB2 receptor is a potential target for the treatment of SSc because it controls both skin fibroblast proliferation and the autoimmune reaction.