Search

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.What are the pleuropulmonary manifestations in VEXAS syndrome?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.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 required20 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.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.

Background and ObjectivesTo report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies.MethodsWe retrospectively included all patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα since 2017 from 2 French referral centers.ResultsWe identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score ≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies.DiscussionGFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome.

ObjectiveImmunoglobulin 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.MethodsThis 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.ResultsWe 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.ConclusionThis 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.

VEXAS syndrome (vacuoles in myeloid progenitors, E1 ubiquitin activating enzyme, X-linked, autoinflammatory manifestations and somatic) is an autoinflammatory condition caused by somatically acquired UBA1 mutations. Heiblig et al report on an international retrospective analysis of 30 patients with VEXAS syndrome treated with different Janus kinase (JAK) inhibitors, finding encouraging evidence supporting the use of the JAK1/2 inhibitor ruxolitinib with clinical remissions and reductions in steroid use seen in the majority of patients.

Background: Giant Cell Arteritis (GCA), is the most common primary vasculitis. It affects large vessels such as the aorta and its branches. According to Chapel Hill Consensus, GCA is one of the larger vessel vasculitis. The underlying mechanism involves inflammation of the large arteries. The most frequent presentation consists of headache, polymyalgia, and jaw claudication. GCA can put the visual prognosis at risk, and rapid diagnosis is compulsory. Cotton wool spots, due to focal inner retinal ischemia, are an early diagnostic ophthalmological sign. The most frequent presentation is a rapid, partial or complete blindness. However, atypical presentations, such as uveitis, especially in the anterior chamber, can delay diagnosis. Case Report: We report a 75-year-old woman with GCA who initially presented with anterior uveitis and without any other clinical sign. At the beginning, there was the only ophthalmic sign and systemic inflammation, the all exhaustive work-up including positron emission tomography (PET) scan was negative. The biology was fully normal without auto-immune profile (Angiotensin converting enzyme level, Interferon Gamma Release Assay, Syphilis serology, antinuclear antibody titer, Rheumatoid factor, CCP antibodies, and chest x-ray were normal. HLA B27 was negative). In the following weeks, she subsequently developed large vessel vasculitis with headache and more typical sign. She developed cotton wool spots linked to retinal arteriolar hypoperfusion. Anterior uveitis has been reported rarely in GCA and moreover, it is very uncommon at the early stages of GCA. Our case stresses that uveitis onset can precede large vessels vasculitis and typical symptoms of GCA. PET-scan is a useful tool for atypical GCA, but its sensitivity is not perfect, and its repetition can be helpful in selected cases such as that of this patient.

Summary Objectives To determine the impact of awareness sessions, proposed by the pharmaceutical team to the hospital physicians, on the reassessment of off-label non-hospital proton pump inhibitor prescriptions dedicated to hospitalized patients in the internal medicine department of a university hospital. Methods We conducted a retrospective and comparative cohort study of in-patients aged 65 years old and older with a prescription including a proton pump inhibitor. Patients who were admitted before the implementation of the awareness sessions were enrolled in the control group; others were enrolled in the awareness experimental group. The awareness sessions relating to the appropriate use of proton pump inhibitors involved a presentation about the national consensus guidelines, their side effects, the possible drug interactions with this therapeutic class, and recommendations about proton pump inhibitor discontinuation. Discussions took place around clinical cases during this multidisciplinary meeting. Results In total, 105 patients were included in the control group, and 52 in the awareness experimental group. In total, 10.8% of the non-hospital prescriptions were in accordance with the guidelines. The spontaneous reassessment of non-hospital proton pump inhibitors prescriptions was significantly higher in the experimental group (55.6%) compared to the control group (35.8%) (P = 0.02). At discharge, 66.7% of the off-label non-hospital proton pump inhibitor prescriptions were reassessed in the experimental group versus 28.4% in the control group P Conclusions This multidisciplinary team meetings on the appropriate use of proton pump inhibitors were proved effective to improve prescription conformity to guidelines in older patients.

There is currently no evidence of the possible benefit of plasma cell-targeting therapies (PCTT) in immunoglobulin A (IgA) monoclonal gammopathy (MG) associated with IgA vasculitis (IgAV). We report the outcome of different PCTT regimens in a cohort of MG-IgAV.We used a French network to retrospectively describe the outcome of MG-IgAV patients treated with PCTT.Five patients were included (mean age 65 years). All patients had severe baseline presentation including extensive necrotic purpura (n = 5), gastrointestinal involvement (n = 2), peripheral neuropathies (n = 2), and glomerulonephritis (n = 1). Two patients had IgA indolent multiple myeloma and three had IgA "MG of undetermined significance." Monotypic IgA deposition in the skin vessels wall was highlighted using an immunofluorescence assay. Cases of vasculitis in three patients (n = 3) were refractory to multiple line therapies, including cyclophosphamide (n = 3) or rituximab. Finally, PCTT including bortezomib plus cyclophosphamide and dexamethasone, bortezomib plus melphalan and prednisone, or bortezomib plus lenalidomide and dexamethasone were proposed, allowing complete remission in 4/5 patients without major adverse drug events.This study suggests that the MG-IgAV phenotype might be distinctive of usual IgAV (severe and refractory to conventional immunosuppressive regimens) and supports the benefit of PCTT. This study sheds new light on the overall biology of IgAV, strengthening the pathogenic role of the monoclonal IgA component in IgAV.

Objective We aimed to investigate whether anakinra, an interleukin-1receptor inhibitor, could improve outcome in moderate COVID-19 patients. Methods In this controlled, open-label trial, we enrolled adults with COVID-19 requiring oxygen. We randomly assigned patients to receive intravenous anakinra plus optimized standard of care (oSOC) vs. oSOC alone. The primary outcome was treatment success at day 14 defined as patient alive and not requiring mechanical ventilation or extracorporeal membrane oxygenation. Results Between 27th April and 6th October 2020, we enrolled 71 patients (240 patients planned to been enrolled): 37 were assigned to the anakinra group and 34 to oSOC group. The study ended prematurely by recommendation of the data and safety monitoring board due to safety concerns. On day 14, the proportion of treatment success was significantly lower in the anakinra group 70% (n = 26) vs. 91% (n = 31) in the oSOC group: risk difference—21 percentage points (95% CI, -39 to -2), odds ratio 0.23 (95% CI, 0.06 to 0.91), p = 0.027. After a 28-day follow-up, 9 patients in the anakinra group and 3 in the oSOC group had died. Overall survival at day 28 was 75% (95% CI, 62% to 91%) in the anakinra group versus 91% (95% CI, 82% to 100%) (p = 0.06) in the oSOC group. Serious adverse events occurred in 19 (51%) patients in the anakinra group and 18 (53%) in the oSOC group (p = 0·89). Conclusion This trial did not show efficacy of anakinra in patients with COVID-19. Furthermore, contrary to our hypothesis, we found that anakinra was inferior to oSOC in patients with moderate COVID-19 pneumonia.

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.

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.

IntroductionCOVID-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 analysisPROVID-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 disseminationThe 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 numberNCT04363463.

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.

BACKGROUND: 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. AIMS: Description of a cohort of patients with adult onset of UCDs. METHODS: 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). RESULTS: Seventy-one patients were included (68% female, 32% male). The diagnosis was made in the context of (i) a metabolic decompensation (42%), (ii) family history (55%), or (iii) 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. CONCLUSION: 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. This article is protected by copyright. All rights reserved.

ObjectiveImmunoglobulin A vasculitis (IgAV) and nephropathy (IgAN) share common immunological mechanisms. Liver cirrhosis is well known to be associated with IgAN. Here, we aimed to describe the presentation and outcome of IgAV patients with underlying cirrhosis.MethodsWe conducted a French nationwide retrospective study of adult patients presenting with both IgAV and cirrhosis. Baseline characteristics were compared to those of the 260 patients included in the French nationwide IgAV registry (IGAVAS).ResultsTwenty patients were included, and 7 (35%) were female. The mean ± SD age was 62.7 ± 11 years. At baseline, compared with IGAVAS patients, patients with underlying cirrhosis were older (62.7 ± 11 vs 50.1 ± 18, P < 0.01) and displayed more constitutional symptoms (weight loss 25% vs 8%, P = 0.03). Patients with underlying cirrhosis were also more likely to exhibit elevated serum IgA levels (5.6 g/L vs 3.6 g/L, P = 0.02). Cirrhosis and IgAV were diagnosed simultaneously in 12 patients (60%). Cirrhosis was mainly related to alcohol intake (n = 15, 75%), followed by nonalcoholic steato-hepatitis (n = 2), chronic viral hepatitis (n = 1), hemochromatosis (n = 1), and autoimmune hepatitis (n = 1). During follow-up with a median of 17 months (IQR 12–84), 10/13 (77%) exhibited IgAV remission at Month 3. One patient presented a minor relapse. Six patients died, but no deaths were related to IgAV.ConclusionWe report the first case series of IgAV patients with underlining cirrhosis, to our knowledge, which was mainly alcohol related. The liver disease did not seem to affect baseline vasculitis characteristics. Physicians should investigate the existence of liver cirrhosis at IgAV diagnosis, especially in the context of alcohol abuse.

Summary Background Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases. Methods In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609. Findings Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66–6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46–0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55–3·19, p=0·53). Interpretation Rituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases. Funding None.

Immune thrombocytopenia (ITP) is defined by a decreased platelet count (PC) leading to an increased risk of bleeding. Common hemorrhagic symptoms include bruising, purpura and petechiae, whereas se...

Background VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is due to a somatically acquired mutation of the E1-ubiquitin ligase UBA1, leading to the expression of a catalytically impaired isoform in myeloid cells. VEXAS syndrome combines severe auto-inflammatory manifestations and is frequently associated with myeloid neoplasia (MN). The outcome of VEXAS is poor, and most patients require high dose corticosteroids to reduce inflammation (Bourbon et al. Blood 2021). Therapeutic options besides steroids are currently limited in those patients. In this multicenter retrospective study, we report some clinical efficacy of JAK inhibitors (JAKi) in VEXAS patients. Patients We analyzed retrospectively 24 UBA1 mutated patients (Met41 or previously reported alternative splicing site) treated with JAKi (11 with ruxolitinib (RUXO), 11 with tofacitinib (TOFA), 1 with baricitinib, 1 with upadicitinib) in 7 French, 1 Portugese and 2 US centers. Complete clinical (CCR) and complete biological response (CBR) were defined as complete resolution of clinical symptoms and normalization of inflammation markers (C reactive protein, CRP) respectively. Partial clinical (PCR) and biological (PBR) response were defined by reduction of at least 50% of clinical or inflammation markers, respectively. Results All 24 patients were males with a median age at VEXAS diagnosis of 72 years [range 54-89]. Thirteen had documented myeloid neoplasia (MN) (1 CMML-0, 1 other MDS/MPN, 10 MDS). Clinical manifestations at VEXAS diagnosis include skin involvement (87.5%), arthritis or arthralgia (83.3%), vasculitis (37.5%), fever (75%), ocular manifestations (29.2%) and pulmonary infiltrates (41.6%). IPSS-R was very low/low/intermediate in 8/3/2 cases respectively. Median time between first VEXAS related clinical manifestations and JAKi onset was 2.45 years [0.15-5.45]. Prior to JAKi onset, patients had received a median of 2.5 immunosuppressive/immunomodulatory treatments [range 0-9]. After 1 month, 12/24 (50%) patients had achieved clinical and/or biological response. CCR and CBR was achieved in 7/11 (64%) and 6/11 (54%) patients treated with RUXO, and in 3/13 (23%) and 2/13 (15%) patients treated with other JAKi (figure A). After 3 months, CCR and CBR was 100% and 80% (10 evaluable patients) in the RUXO group as compared to 25% and 25 % in patients treated with other JAKi (8 evaluable patients) (p=0.0036 et 0.0055 respectively, figure B). RUXO efficacy was similar in patients with (n=9) or without (n=2) associated MN. In RUXO treated patients, median CRP and steroid dose reduction was 72.5% [range 21.5- 99.5] and 66.25% [range 0-75] respectively at 3 months. With a median follow-up of 4 months [range 1.4-12], only 1 RUXO treated patient had lost response, whereas median time to next of treatment was 3.4 months with other JAKi (figure C). Of the 13 patients with MN, 7 were RBC transfusion dependent at JAKi onset (6 with RUXO, 1 with other JAKi). Four of 6 patients treated with RUXO achieved RBC transfusion independence at 3 months, but not the patient treated with other JAKi. Regarding safety, severe adverse events were reported in 6 patients: 3 deep vein thrombosis, (2 with TOFA/1 with RUXO), 1 pneumonia (RUXO), 1 enterohemorrhagic E. Coli infection (RUXO), and 1 lethal legionellosis (TOFA)). Conclusion Ruxolitinib (and less often other JAK inhibitors used in this study) provides rapid response in most VEXAS patients, allowing in two third of the cases corticosteroid dose reduction/withdrawal and RBC transfusion independence in 4/6 patients with MN who were initially transfusion dependent. Those retrospective preliminary results, with limited follow up, must be interpreted with caution and will be updated at the meeting. The effect of RUXO on VEXAS patients with concomitant MN will soon be studied prospectively in a Groupe Francophone des Myélodysplasies (GFM) clinical study. Figure 1 Figure 1. Disclosures Galicier: Novartis Pharma Sas, Sanofi Aventis France: Consultancy; Lilly France, Baxalta France, Sanofi Aventis France Sas: Other: Payments as Speaker for Educational Program; Shire France SA, Janssen-Cilag, Pfizer Sas: Other: Invitation to Congress. Hirsch: Novartis Pharma: Consultancy; Daiichi Sankyo Oncology: Consultancy. Warrington: Eli Lilly: Research Funding; Kiniksa: Research Funding. Fenaux: Novartis: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria.

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.

Adult onset urea cycle disorders (UCD) may present with psychiatric symptoms, occasionally as the initial presentation. We aimed to describe the characteristics of patients presenting with a psychiatric adult-onset of UCDs, to discuss which signs could suggest this diagnosis in such a situation, and to determine which tests should be conducted. A survey of psychiatric symptoms occurring in teenagers or adults with UCD was conducted in 2010 among clinicians involved in the French society for the study of inborn errors of metabolism (SFEIM). Fourteen patients from 14 to 57 years old were reported. Agitation was reported in 10 cases, perseveration in 5, delirium in 4, and disinhibition in 3 cases. Three patients had pre-existing psychiatric symptoms. All patients had neurological symptoms associated with psychiatric symptoms, such as ataxia or dysmetria, psychomotor slowing, seizures, or hallucinations. Fluctuations of consciousness and coma were reported in 9 cases. Digestive symptoms were reported in 7 cases. 9 patients had a personal history suggestive of UCD. The differential diagnoses most frequently considered were exogenous intoxication, non-convulsive status epilepticus, and meningoencephalitis. Hyperammonemia (180–600 μmol/L) was found in all patients. The outcome was severe: mechanical ventilation was required in 10 patients, 5 patients died, and only 4 patients survived without sequelae. Adult onset UCDs can present with predominant psychiatric symptoms, associated with neurological involvement. These patients, as well as patients presenting with a suspicion of intoxication, must have UCD considered and ammonia measured without delay.

International audience; OBJECTIVE: The core outcome set for trials in systemic sclerosis (SSc) was developed in 2008 and comprises eleven domains and thirty-one measures, leading to the development of a composite index (CRISS). We aimed to assess the scope, and consistency of outcomes reported in trials of SSc, and the uptake of this core set and CRISS. METHODS: MEDLINE, Cochrane CENTRAL, Embase and clinicaltrials gov were searched to identify randomized trials published from 2000 to 29 April 2018 in adults with limited or diffuse SSc. Outcomes and measures were recorded for each trial, classified into domains and the frequency of outcomes before after publication of the publication of the core set calculated. RESULTS: From 152 trials, 4193 outcomes were classified into 84 domains. The three most common domains were health-related quality of life and function (59%, 130 measures), skin (47%, 59 measures) and pulmonary (45%, 168 measures). After the publication of the core outcome set, no trial reported the complete core set with adherence to each of the eleven domains ranging from 6.1% to 54.4% and adherence to each of the thirty-one measures ranging from 0 to 48.1%. The five measures required for CRISS were reported completely in 11% of trials. CONCLUSION: Despite recognition that uniform acquisition and reporting of outcomes would enable a better evaluation of proposed SSc therapeutics, the outcome domains and measures reported in randomized trials in systemic sclerosis remain very inconsistent, with little impact of the core outcome set. This article is protected by copyright. All rights reserved.

Urea cycle disorders (UCDs) are inborn errors of metabolism in which the clinical picture is mostly due to ammonia intoxication. UCD onset may be observed at any age. Acute decompensations of UCDs include neuro-psychiatric symptoms such as headache, confusion, convulsions, ataxia, agitation or delirium, as well as digestive symptoms, namely nausea and vomiting along with abdominal pain. Acute decompensations may lead to an irreversible coma in the absence of specific therapy. The first step is to measure promptly ammonemia in such patients, and start appropriate therapy on an emergency basis.

Introduction La maladie de Fabry est une maladie de surcharge lysosomale liee a l’X, responsable d’atteintes renales, cerebrales et cardiaques severes, pour laquelle des traitements efficaces sont disponibles. Le diagnostic des formes atypiques peut etre difficile mais marque un tournant de la prise en charge des patients. Observation Une insuffisance renale (proteinurie 1 g/L, creatininemie 110 μmol/L) etait decouverte en 2015 chez une patiente suivie pour des troubles du rythme rapportes a une cardiopathie hypertensive sur HTA diagnostiquee a 30 ans. Ses autres antecedents etaient une goutte, un syndrome d’apnees du sommeil, et une intolerance au glucose controlee sous regime seul. La PBR montrait des lesions de hyalinose segmentaire et focale (HSF), et un traitement medical par antiproteinuriques etait introduit. Malgre cela, l’evolution etait defavorable, avec une insuffisance renale terminale necessitant une bi-greffe en 2015. Du fait d’un arbre genealogique evocateur, une recherche de cause genetique d’HSF etait effectuee a l’hopital Necker, sur une puce NGS d’interet renal. Cette exploration permettait de decouvrir des mutations pathogenes sur le gene GLA, ainsi que sur le gene responsable de la maladie d’Alport COL 4A5. En dehors de l’HTA ancienne, la patiente ne presentait pas d’autre symptome faisant evoquer une maladie de Fabry ou d’Alport. Une relecture en microscopie electronique a transmission (MET) de la PBR initiale montrait une accumulation majeure de globotriaosylsphingosine (lyso-Gb3) dans les podocytes sans argument pour un syndrome d’Alport. La biochimie confirmait le diagnostic de maladie de Fabry, avec un abaissement de l’activite de la galactosidase acide et une augmentation du lyso-Gb3 plasmatique. Le diagnostic de maladie de Fabry etait alors retenu, et un traitement par enzymotherapie propose ainsi qu’un depistage familial. Discussion La maladie de Fabry est un trouble du metabolisme des glycosphingolipides due a des mutations perte de fonction du gene GLA situe sur le chromosome X et codant pour l’alpha-galactosidase A lysosomale. Elle a une prevalence estimee a 1/40 000 naissances en 2015. La perte d’activite de cette enzyme conduit a l’accumulation de globotriaosylceramide (Gb3) dans les lysosomes. Les femmes sont vectrices mais peuvent egalement avoir des atteintes severes comme dans notre observation selon la lyonisation. Les formes atypiques, notamment chez la femme, peuvent avoir une presentation ou manquent les signes peripheriques des formes classiques (cornee verticillee, angiokeratomes, anhydrose, acroparesthesies…). L’atteinte renale se manifeste par une proteinurie generalement inferieure a 3 g/j, une hematurie microscopique, une degradation de la fonction renale allant jusqu’a l’insuffisance renale terminale. Les mecanismes physiopathologiques sont multiples et ne sont pas totalement elucides. L’accumulation progressive de Gb3 dans les lysosomes entraine une perte de fonction des cellules qui les contiennent–podocytes, cellules epitheliales, cellules des tubules distaux et de l’anse de Henle- entrainant une glomerulosclerose, une atteinte vasculaire et une atteinte de l’interstitium. L’atteinte renale dans la maladie de Fabry peut se manifester histologiquement par une HSF dite secondaire par reduction nephronique. La PBR a un interet diagnostique quand la maladie est meconnue, pronostique et therapeutique permettant d’evaluer l’efficacite du traitement. Le diagnostic est confirme par la biochimie et la genetique. Comme notre observation le souligne, la microscopie optique peut etre insuffisante pour poser le diagnostic de maladie de Fabry et doit etre completee par la microscopie electronique qui montre alors des empilements des membranes denses separees par des zones plus claires realisant des structures en bulbe d’oignon ou corps zebres. Leur distribution dans les tissus depend du sexe du patient ainsi chez la femme la distribution de la surcharge dans les cellules est irreguliere. L’enzymotherapie peut permettre d’ameliorer les lesions renales mais peut etre inefficace si les lesions sont trop avancees. Conclusion La maladie de Fabry peut avoir des presentations atypiques, notamment chez la femme. La PBR peut permettre de faire le diagnostic, mais la sensibilite de la microscopie optique est insuffisante, et le recours systematique a la microscopie electronique devrait etre considere en cas de PBR. Le diagnostic de maladie de Fabry devrait etre envisage devant toute nephropathie inclassee. Le recours a la genetique devant un arbre genealogique evocateur permet a l’heure de la genomique de corriger des diagnostics.

Introduction Les cytopenies au cours de la maladie lupique peuvent etre multifactorielles, notamment auto-immunes et toxiques. Le recours au G-CSF est volontiers prescrit dans le cadre de neutropenie chez les patients atteints de LES et est en general bien tolere. Pour autant celui-ci peut etre a l’origine d’exacerbations de la maladie, et occasionner des poussees severes. Observation Nous rapportons le cas d’une patiente de 36 ans ayant un lupus hematologique et cutaneo-articulaire, sur un terrain de seropositivite VIH, et dont l’evolution avait ete emaillee d’une poussee renale de classe V en 2015. La patiente avait presente des episodes d’œdemes angioneurotiques corticosensibles, avec C1inh et kininoformation normale, et positivite des Ac anti-C1q, DNA, Sm, survenus sous Cellcept® en decembre 2017, lequel avait relaye par azathioprine, ayant permis une remission de la maladie auto immune, malgre la persistance d’une anemie. Debut juin 2018, apparition d’une pancytopenie avec agranulocytose a 0,4 G/L de PNN. Le traitement associe alors hydroxychloroquinine 400 mg/j, Eviplera®, prednisone 10 mg/j et azathioprine 100 mg/j pour une patiente de 80 kg. Les donnees de la pharmacovigilance et le myelogramme sont en faveur d’une toxicite de l’azathioprine qui est arrete le 08/06/2018, et relaye par du Tacrolimus®. Le 12 juin, une injection de lenograstim est realisee en traitement de la neutropenie avec une bonne reponse des neutrophiles. Deux jours plus tard, apparaissent des arthromyalgies d’aggravation progressive, accompagnees d’episodes de fievre et sueurs. Le Tacrolimus® est arrete en attente de la tacrolemie, qui revient en zone therapeutique a 5 mg/L, l’evolution est favorable et les arthromyalgies regressent progressivement en 3 jours. Cependant, la neutropenie recidive jusqu’a 0,4 G/L le 23 juin motivant une reprise des injections de Granocyte® du 23 au 25 juin. Dans la nuit du 24 au 25 juin, reapparaissent des arthromyalgies diffuses intenses, associees a un erytheme du visage, mis sur le compte d’un syndrome pseudogrippal au lenograstim, qui est arrete. Il n’y pas d’atteinte renale. L’hydroxychloroquinine et Eviplera® sont poursuivis, la posologie de prednisone augmentee a 15 mg. La patiente rentre a domicile avec un rendez-vous de suivi. Reapparition des arthromyalgies, puis survenue le 5 juillet d’un episode d’angio-œdeme larynge sans detresse respiratoire mais necessitant l’hospitalisation de la patiente en unite de surveillance continue et l’administration de methylprednisolone I.V. avec relais oral a 1 mg/kg, et une injection de Firazyr®, sans amelioration. Ainsi, malgre la realisation de 3 boli de 1000 mg de methylprednisolone, persistance de la symptomatologie d’angio-œdeme labial recidivant, justifiant le recours au cyclophosphamide selon le protocole Eurolupus. A 6 semaines de traitement, les manifestations cutaneo-articulaires sont controlees et une decroissance cortisonique est debutee. Un episode de leuconeutropenie transitoire sous cyclophosphamide a necessite le report d’une perfusion a S4 ; le G-CSF n’a pas ete utilise. Discussion Le delai de survenue des arthromyalgies, de l’atteinte cutanee a type d’erytheme malaire puis d’angio-œdeme resistant aux corticoides, est en faveur d’une exacerbation de la maladie lupique, pour laquelle les donnees chronologiques rendent imputable le lenograstim. L’arret de l’azathioprine a pu favoriser celle-ci, mais le relais par tacrolimus et le delai de survenue de cette poussee corticoresistante ainsi que les symptomes arthromyalgiques des la premiere injection plaident en faveur de la responsabilite du lenograstim. Par ailleurs la persistance de manifestations d’œdeme angioneurotique menacantes a necessite le recours au cyclophosphamide malgre l’absence d’atteinte d’organe « noble », chez une patiente en periode d’activite genitale. Le role causal du lenograstim dans des poussees lupiques a deja ete rapporte dans la litterature, donnant volontiers lieu a des poussees severes comme l’illustre notre observation. Nous supposons que la reconstitution immunitaire suite a la sortie d’agranulocytose et la stimulation non specifique du systeme immunitaire liee au lenograstim (augmentation des lignees granuleuses mais aussi lymphocytaire et monocytaire), favorise par le deficit en C1q chez cette patiente sont les causes physiopathologiques de la poussee ; en effet, le role des PNN en interaction avec les monocytes, macrophages et lymphocytes dans la physiopathologie du lupus est bien etabli. Conclusion La balance benefice-risque du G-CSF, pierre angulaire de la prise en charge des neutropenies, doit etre soigneusement pesee dans le cadre d’une maladie lupique, devant le risque d’induction de poussees severes.

Introduction La sitosterolemie est une maladie genetique rare due a une deregulation dans l’absorption de cholesterol resultant d’une accumulation de sterols d’origine vegetale. Elle peut s’associer des xanthomes, une anemie hemolytique stomatocytique, une thrombopenie (avec macroplaquettes), une (hepato) splenomegalie, parfois des arthrites, une fibrose retroperitoneale, une coronaropathie precoce (atherosclerose), une insuffisance hepatique, une hypercholesterolemie de degre variable. Quelques cas de cytopenies liees a une sitosterolemie sont rapportes dans la litterature. Nous rapportons le cas d’une patiente de 18 ans presentant une anemie hemolytique et une thrombopenie d’evolution tres favorable sous traitement adapte. Observation Une patiente âgee de 18 ans, aux antecedents d’anemie par carence martiale, de panaris et cellulite faciale ayant complique un abces dentaire, etait admise pour l’exploration de cytopenies. Il existait une consanguinite parentale. L’examen clinique montrait un IMC a 18 kg/m2, un ictere cutaneomuqueux et une hepatosplenomegalie. La patiente n’avait pas d’adenopathie peripherique. L’hemoglobine etait a 64 g/L avec un VGM a 79,3 fL et des reticulocytes plasmatiques a 368 G/L. Les plaquettes etaient a 89 G/L et les leucocytes a 3,9 G/L (PNN : 2,33 G/L, L : 0,2 G/L, Eo : 0,7 G/L, M : 1,2 G/L). Le bilan hepatique montrait des ALAT a 445 UI/L, des ASAT a 502 UI/L, des phosphatases alcalines a 328 UI/L et une gamma-GT a 309 UI/L. La bilirubine totale etait a 302 μmol/L (libre 162 μmol/L). Les LDH etaient a 687 UI/L (N 0,5). Le frottis sanguin montrait des stomatocytes et des macroplaquettes. Le test de Coombs etait negatif. Les vitamines B9 et B12 plasmatiques etaient normales. L’echographie abdominale montrait une fleche hepatique a 14 cm, une splenomegalie homogene une lithiase vesiculaire avec signe de Murphy et pas de dilatation des voies biliaires. Les explorations conventionnelles etaient negatives (recherche d’hemopathie, maladie de Gaucher…). La chromatographie des esters du cholesterol a montre des concentrations plasmatiques elevees de sitosterol et du campesterol, respectivement a 112 (N Conclusion La sitosterolemie (ou phytosterolemie) est une maladie rare, autosomique recessive, liee a des mutations des genes ABCG5 ou ABCG8. Le phenotype clinique de notre patiente etait incomplet. Le traitement consiste en la prise d’ezetimibe associee a l’eviction des phytosterol alimentaire. Nous rapportons le cas d’une patiente de 18 ans dont l’evolution favorable sous traitement, avec normalisation des cytopenies, est remarquable, grâce a une bonne observance.

Introduction L’acidose metabolique a trou anionique eleve est courante en pratique medicale. Elle est le plus souvent liee a l’acide lactique, aux corps cetoniques, a l’insuffisance renale ou a diverses intoxications. Certaines causes rares sont dues a l’accumulation d’acides organiques. Parmi celles-ci, nous decrivons une acidose pyroglutamique liee a une molecule tres frequemment utilisee. Observation Mme G, 67 ans, aux antecedents d’ACFA anticoagulee, HTA, asthme et ethylisme chronique, se presente aux urgences en fevrier pour un tableau de rectorragies et anemie, associe a un surdosage en AVK pour lequel elle recoit un traitement symptomatique. Des gaz du sang effectues revelent une acidose metabolique (pH 7,33 ; HCO3- 14 mmol/L ; PaCO2 mmHg ; trou anionique 26 mmol/L) sans cause recherchee. Depuis, elle se dit de plus en plus asthenique avec une anorexie (ne consomme que des yaourts) et des selles molles. Elle consomme regulierement du paracetamol a raison de 3 a 4 g/jour. En juillet, elle est adressee aux urgences pour une suspicion d’insuffisance respiratoire aigue. Le bilan retrouve un syndrome inflammatoire biologique ainsi qu’une acidose metabolique severe a trou anionique augmente (pH 7,19 ; PaCO2 14 mmHg ; bicarbonates 5,6 mmol/L ; TA 33 mmol/L). Les lactates sont normaux (1,7 mmol/L) ainsi que la chloremie (99 mmol/L) sans autre trouble ionique associe. La cetonemie est non-significative. Une diarrhee glairosanglante apparait parallelement, dont les prelevements sont positifs a Clostridium difficile, justifiant une antibiotherapie par Metronidazole. La patiente recoit une hyperhydratation IV dont du NaHCO3 1,4 %. Les explorations sont poursuivies, avec un dosage des anions indoses negatifs (ethanol, methanol, acide salicylique, ethylene glycol). La paracetamolemie faite a H36 est negative. Une chromatographie des acides organiques urinaires est des lors effectuee, confirmant un pic eleve d’acide pyroglutamique. Dans ce contexte, on evoque une acidose pyroglutamique induite par la prise repetee de paracetamol acutisee par la denutrition et l’episode infectieux. Le paracetamol est definitivement arrete. L’evolution clinique et biologique sans traitement specifique est par la suite lentement favorable permettant le retour au domicile. Discussion L’acide pyroglutamique (ou 5-oxoproline) est un acide organique, metabolite du cycle du gamma-glutamyl jouant un role dans le metabolisme du glutathion, molecule anti-oxydante impliquee dans de nombreux mecanismes metaboliques. Une diminution du glutathion a pour consequence une majoration de la 5-oxoproline par inhibition du retro-controle negatif (donc une activation) sur la gamma-glutamyl-transferase et donc la gamma-glutamylcysteine, elle-meme alors partiellement transformee en 5-oxoproline. L’acidose pyroglutamique est classiquement decrite chez les enfants [1] . Il s’agit alors d’une maladie metabolique hereditaire autosomique recessive par deficit en gluthation synthetase ou 5-oxoprolinase. Des cas acquis ont egalement ete decrits notamment lors de la prise de paracetamol [2] En effet, le paracetamol, meme a dose physiologique, peut entrainer une baisse du glutathion intracellulaire, en presence d’autres facteurs de risque comme la carence en glycine ou en cysteine (requise pour la formation du glutathion) que l’on observe dans des cas de malnutrition, ou comme l’epuisement chronique du stock de glutathion au cours de l’alcoolisme chronique ou dans les maladies hepatiques [2] . D’autres facteurs de risque sont decrits tels que les infections, l’utilisation de vigabatrine ou d’antibiotiques (flucloxacilline, netilmicine) [3] . Le sexe feminin est egalement associe a une augmentation du risque. Notre patiente avait donc de nombreux facteurs de risque : sexe, alcoolisme, malnutrition, abus de paracetamol, infection. Sur le plan therapeutique, le plus urgent est de cesser l’exposition au paracetamol et de traiter les facteurs de risque eventuels. L’administration de bicarbonates peut etre proposee. La prescription de N-acetyl-cysteine, par son role dans le metabolisme du glutathion, peut etre logiquement effectuee mais sans aucune preuve actuelle dans les acidoses pyroglutamiques acquises [1] . Conclusion En depit de son utilisation tres frequente, l’acidose pyroglutamique reste un effet secondaire meconnu du paracetamol.

Introduction Le « Fish odor syndrome » est une maladie metabolique rare responsable d’une odeur desagreable de poisson pourri liee a la presence de trimethylamine (TMA) dans les urines, la transpiration et la salive. Observation Une patiente de 45 ans etait adressee pour l’exploration d’une transpiration decrite comme « pestilentielle » a type d’odeur de « poisson pourri » apres l’ingestion de certains aliments, handicapant sa vie sociale depuis plus de 20 ans. Ses antecedents etaient marques par une hypothyroidie auto-immune et un vitiligo. L’examen clinique ne montrait pas d’organomegalie ou autres anomalies. Un test de charge en choline a montre un pic urinaire de trimethylamine (TMA) par spectro-RMN des urines, avec un ratio d’oxydation TMAO/(TMAO + TMA) a 21,2 % (N > 92 %). Le diagnostic etait confirme par la biologie moleculaire, avec la mise en evidence d’une heterozygotie composite c458C > T, p. Pro153Leu/c.118C > A, p.Leu40Met du gene codant la flavine mono-oxygenase 3 (FMO3). Un regime pauvre en choline etait prescrit, avec un bon resultat fonctionnel. Discussion Le fish odor syndrome est un symptome rare qui peut etre lie a une trimethylaminurie primaire ou secondaire. La trimethylaminurie primaire est due a une deficience en FMO3, comme dans le cas de notre patiente, de transmission autosomique recessive. Les trimethylaminuries secondaires sont decrites dans les defaillances hepatiques (hepatites virales, insuffisance hepatique) et renales, l’intoxication a la choline (traitement des maladies de Huntington et d’Alzheimer) et dans circonstances ou l’expression de FMO3 peut etre reduite de facon transitoire : petite enfance et phase premenstruelle. Le symptome malodorant peut etre extremement invalidant et conduire a un isolement social ou une depression. Le diagnostic doit imperativement etre confirme par la spectro-RMN des urines puis la genetique. Physiologiquement, la choline et ses precurseurs, contenus en grande majorite dans la viande, le poisson et les œufs sont transformes en TMA (malodorante) par le microbiote intestinal puis oxydes en TMA-N-oxyde (non odorant), par les enzymes hepatiques du complexe flavine mono-oxygenase FMO3. En cas de FMO3 deficiente, la TMA non oxydee reste preponderante. Le traitement repose sur l’exclusion des precurseurs de TMA, notamment la choline, associee a une supplementation en folates et en riboflavine, cofacteur de la FMO3. Une decontamination digestive sequentielle par antibiotiques peut etre utile. Conclusion Devant un phenomene de mauvaise odeur corporelle, le diagnostic de fish odor syndrome doit etre evoque. Comme cela est decrit dans notre observation, le traitement peut etre efficace et permettre aux patients de sortir de leur isolement social.

International audience; OBJECTIVE:Hypocomplementemic urticarial vasculitis (HUV) is an uncommon vasculitis of unknown etiology that is rarely described in the literature. We undertook this study to analyze the clinical spectrum and the therapeutic management of patients with HUV.METHODS:We conducted a French nationwide retrospective study that included 57 patients with chronic urticaria, histologic leukocytoclastic vasculitis, and hypocomplementemia. We assessed clinical and laboratory data and evaluated the patients' cutaneous and immunologic responses to therapy. We evaluated treatment efficacy by measuring the time to treatment failure.RESULTS:Urticarial lesions were typically more pruritic than painful and were associated with angioedema in 51% of patients, purpura in 35%, and livedo reticularis in 14%. Extracutaneous manifestations included constitutional symptoms (in 56% of patients) as well as musculoskeletal involvement (in 82%), ocular involvement (in 56%), pulmonary involvement (in 19%), gastrointestinal involvement (in 18%), and kidney involvement (in 14%). Patients with HUV typically presented with low C1q levels and normal C1 inhibitor levels, in association with anti-C1q antibodies in 55% of patients. Hydroxychloroquine or colchicine seemed to be as effective as corticosteroids as first-line therapy. In patients with relapsing and/or refractory disease, rates of cutaneous and immunologic response to therapy seemed to be higher with conventional immunosuppressive agents, in particular, azathioprine, mycophenolate mofetil, or cyclophosphamide, while a rituximab-based regimen tended to have higher efficacy. Finally, a cutaneous response to therapy was strongly associated with an immunologic response to therapy.CONCLUSION:HUV represents an uncommon systemic and relapsing vasculitis with various manifestations, mainly, musculoskeletal and ocular involvement associated with anti-C1q antibodies, which were found in approximately half of the patients. The best strategy for treating HUV has yet to be defined.

Objective: Obesity and diabetes mellitus increase the risk of chronic renal disease. However, whether body mass index (BMI) and metabolic disturbances are associated with renal dysfunction and affect similarly albuminuria and estimated glomerular filtration rate (eGFR) are less clear. Hence, the aim of this study was to describe these associations in the general French population. Methods: We realised a large cross-sectional study of 118,314 subjects aged ≥ 40 years undergoing a medical examination in 11 French regional health centers. Results: Renal dysfunction ((abnormal albuminuria (≥ 30 mg/g) and/or low eGFR ( 40: 7.35 [5.89-9.15]) had a greater risk of abnormal albuminuria than subjects with normal weight. In contrast, the relationship between BMI - or other metabolic disturbances- and low eGFR was continuous. Metabolic disturbances increased the risk of abnormal albuminuria to a greater extent than the risk of abnormal eGFR. High fatty liver index and high calculated risk of developing diabetes were risk factors for both abnormal albuminuria and low eGFR. Conclusion: There is a J-curve relationship between BMI and abnormal albuminuria, in contrast to the continuous association between other metabolic disturbances and abnormal eGFR. All metabolic disturbances are associated with abnormal albuminuria, but the association with abnormal eGFR is less clear, suggesting a stronger relationship with endothelial than renal dysfunction. Abnormal albuminuria and eGFR may precede the onset of diabetes.

Introduction Le syndrome de Marfan et l’homocystinurie classique ont des signes cliniques en commun mais une prise en charge et un pronostic bien differents. Observation Un homme âge de 44 ans etait vu en medecine interne pour lombalgies. Le patient etait suivi depuis 16 ans pour un syndrome de Marfan, diagnostique a l’âge de 30 ans sur une ectopie cristallinienne bilaterale et une morphologie evocatrice : le patient pesait 76 kg pour une taille de 1,90 m. Dans ses autres antecedents, on notait une lombosciatique S1 droite et une myopie bilaterale. Le patient rapportait des lombalgies anciennes de rythme mecanique et un defaut de concentration depuis l’enfance, responsable de difficultes scolaires puis professionnelles. Il avait un pectum exacavatum, un flessum des coudes, des pieds creux, des vergetures fessieres, des varicosites des membres inferieurs, mais pas de scoliose, d’hyperlaxite, ni d’arachnodactylie. Les radiographies du rachis lombaires etaient normales et le bilan biologique ne montrait pas de syndrome inflammatoire. Le diagnostic d’homocystinurie etait evoque et le dosage d’homocysteinemie revenait eleve a 150 μmol/L (N 21). Les dosages plasmatiques des vitamines B12 et B9 etaient normaux. L’analyse genetique montrait une mutation heterozygote du gene de la CBS : une mutation non-sens (c.572C > T) et une deletion ponctuelle (c.689delT). Un traitement par vitamine B6 etait introduit mais ne permettait pas de normaliser l’homocystinemie. Un regime hypoprotidique controle en methionine etait alors mis en route avec supplementation en acides amines. L’objectif principal etait de prevenir la survenue d’evenement thromboembolique chez ce patient indemne d’antecedent vasculaire. Discussion L’homocystinurie doit etre evoquee devant toute luxation du cristallin, ou aspect marfanoide puisque un traitement specifique permet de limiter la progression de cette maladie et de reduire le risque thromboembolique [1] , cause principale de morbi-mortalite chez ces patients. L’atteinte vasculaire arterielle ou veineuse peut manquer dans l’homocystinurie et cette maladie autosomique recessive, bien que moins frequente que le syndrome de Marfan (1/20 0000 naissances), doit donc etre recherchee devant des manifestation oculaires (luxation cristallin, myopie, glaucome), osseuses (osteoporose, arachnodactylie), neuropsychologiques (retard mental, troubles de la personnalite) et vasculaires (thrombose veineuse, infarctus du sujet jeune, accident vasculaire cerebral) evocatrices [2] . Dans notre observation, la plainte mnesique rapportee par le patient ne pouvait etre expliquee par le syndrome de Marfan. Dans l’homocystinurie classique, le defaut de CBS est responsable d’un defaut de degradation de l’homocysteine en cysteine sur la voie de la trans-sulfuration et d’une augmentation de la methionine. En cas de forme non sensible a la vitamine B6, une prise en charge nutritionnelle est necessaire avec mise en place d’un regime appauvri en methionine, l’administration de cofacteurs pour activer differentes voies metaboliques et la substitution en acides amines essentiels. Conclusion Ce cas original du fait de l’âge du patient illustre la presentation particuliere de l’homocystinurie par deficit en CBS qu’il faut savoir evoquer meme en l’absence d’atteinte vasculaire chez tout patient suspect de syndrome de Marfan. Le traitement specifique permet de reduire le risque de complications vasculaires.

Introduction Le rituximab est un anticorps therapeutique anti-CD20. Son champ d’application est en expansion, notamment en medecine interne ou il a par exemple demontre son efficacite dans les vascularites cryoglobulinemiques (CryoVas) [1] , [2] . Certains effets indesirables du rituximab sont desormais familiers mais l’expansion de son utilisation fait emerger des effets jusqu’alors inconnus. Nous presentons un cas de poussee paradoxale de cryoglobulinemie mixte suite a une perfusion de rituximab. Observation Une femme de 66 ans etait suivie depuis 2010 pour une maladie de Gougerot-Sjogren selon les criteres Europeens-Americains Consensuels associee a une cryoglobulinemie mixte de type II. Elle avait presente une premiere poussee cryoglobulinemique en avril 2014 avec atteinte cutanee et neurologique confirmee histologiquement, sans argument pour une evolution lymphomateuse. Un traitement d’attaque puis d’entretien par rituximab (4 perfusions de 375 mg/m2 hebdomadaire puis 500 mg en octobre 2014) ayant permis une remission et un sevrage cortisonique. Un purpura vasculaire isole etait reapparu en fevrier 2015. En avril 2015, 7 jours avant le traitement d’entretien a 12 mois, la patiente avait note une aggravation de son phenomene de raynaud, du purpura et l’apparition d’une mononeuropathie aigue du nerf median gauche (testing MRC 4/5). Biologiquement, lymphocytes CD19+ 21/mm3, creatinine 65 μmol/L, proteinurie 0,11 g/L, C3 0,77 g/L (N > 0,8), C4 indosable, facteur rhumatoide positif (7,2 UI/mL), cryoglobulinemie detectee a 2 reprises. Devant ce tableau de vascularite cryoglobulinemique, la perfusion de rituximab (500 mg) etait realisee le 8 avril. Des le lendemain, survenait une fievre concomitante de l’aggravation rapide du tableau cutane et de la mononeuropathie (MRC 3/5). Malgre la realisation de 3 boli de methylprednisolone (500 mg), apparaissait un tableau d’anasarque en lien avec un syndrome nephrotique impur (HTA, creatinine 150 μmol/L, albuminemie 26 g/L, rapport proteinurie/creatininurie 22 g/g). La ponction-biopsie renale confirmait une glomerulopathie membrano-proliferative cryoglobulinemique. L’evolution etait favorable apres 6 plasmaphereses : amelioration du deficit, regression du tableau d’anasarque, stabilisation de la fonction renale (creatinine a 110 μmol/L, proteinurie 0,88 g/g), et reascension du complement (C3 1,22 g/L, C4 0,02 g/L). Apres concertation avec le centre de reference et elimination d’une evolution lymphomateuse, un traitement d’induction par rituximab etait repris au decours immediat avec bonne tolerance. Conclusion L’association rituximab–corticosteroides, en passe de devenir le traitement de reference des vascularites cryoglobulinemiques [3] , peut neanmoins occasionner des complication serieuses. Une etude retrospective a rapporte 6 cas (27 %) de reactions systemiques paradoxales apres rituximab pour CryoVas VHC positives, dont 4 poussees cryoglobulinemiques severes. Comme dans notre observation, les facteurs associes etaient la dose elevee de rituximab, un taux eleve de cryoglobuline et un C4 bas. Le rituximab, etant une IgG1, est dans ce cas reconnu par l’IgM cryoglobulinemique a activite facteur rhumatoide, accelerant la cryoformation de complexes immuns a l’origine des lesions paradoxales. Cette observation souligne le polymorphisme des effets indesirables lies aux biotherapies, l’efficacite potentielle des plasmaphereses dans cette complication, et la possibilite de reaction paradoxale dans les cryoglobulunemies non VHC.

Introduction La vascularite urticarienne hypocomplementemique (VUH) est une entite rare, associant une urticaire recidivante, une hypocomplementemie, une vascularite leucocytoclasique et une atteinte systemique. Nous rapportons les caracteristiques cliniques et therapeutiques de patients presentant une VUH. Materiel et methode Cette etude nationale, francaise, multicentrique et transdisciplinaire a inclus 57 patients ayant une VUH diagnostiquee entre 1992 et 2013. Les criteres d’inclusions etaient la presence de lesions urticariennes recidivantes, une vascularite leucocytoclasique sur la biopsie cutanee et une hypocomplementemie definie par une baisse du C3 et/ou du C4. Resultats La VUH etait isolee (75 %) ou associee a une maladie systemique (25 %), principalement le lupus erythemateux systemique. Les lesions cutanees etaient typiquement des papules erythemateuses fixes, avec une evolution de plus de 24 h, plus souvent prurigineuses (53 %) que douloureuses, associees a un angio-œdeme (51 %), du purpura (35 %) ou un livedo (14 %). Les manifestations extracutanees incluaient une atteinte articulaire (arthralgies/arthrites, 82 %), oculaire (uveite, sclerite/episclerite, conjonctivite, 59 %), respiratoire (toux, dyspnee ou trouble ventilatoire obstructif, 22 %), digestive (16 %) et renale (14 %). Les patients avaient classiquement un C1q abaisse et un C1 inhibiteur normal, alors que les anticorps anti-C1q etaient positifs chez 55 % des patients testes. Sur le plan therapeutique, l’hydroxychloroquine (HCQ) et la colchicine avaient en premiere ligne une efficacite comparable aux corticoides. En cas d’atteinte severe ou refractaire, l’efficacite de la corticotherapie seule ou associee a des immunosuppresseurs comme l’azathioprine (AZA) ou le mycophenolate mofetil (MMF) etait comparable. Le rituximab (RTX) prescrit chez 8 patients semblait avoir une superiorite sur les reponses cutanees et immunologiques. Discussion Les VUH representent un spectre de vascularites systemiques rares et volontiers refractaires aux traitements, ayant des manifestations cliniques variees, principalement articulaires et oculaires. La baisse du C1q represente un marqueur plus specifique que la presence des anticorps antiC1q. L’HCQ et la colchicine constitueraient la premiere ligne therapeutique, alors que les corticoides, seuls ou associes a un immunosuppresseur, AZA, MMF et/ou RTX, representeraient une alternative therapeutique en cas d’atteinte severe et/ou refractaire. Conclusion Cette etude est la plus large serie decrivant les caracteristiques des patients atteints de VUH illustrant le spectre des manifestations cliniques et immunologiques ainsi que la complexite de la prise en charge therapeutique.

Introduction Les amyloses sont des maladies de depot de fibrilles proteiniques, se revelant par l’infiltration d’un ou plusieurs organes et realisant a terme un tableau de maladie systemique. Il existe une trentaine de proteines reconnues comme des precurseurs amyloides potentiels. Les atteintes nephrologiques, cutanees, intestinales, salivaires et cardiaques sont preferentielles, mais tous les organes peuvent etre impliques. Il existe egalement, dans de rares cas, des formes pseudo-tumorales, uniques ou multiples, alors revelees par des complications compressives. Observation Nous rapportons deux cas d’amylose pseudotumorale reveles par une compression medullaire. Cas n o 1 : un homme de 69 ans, hemodialyse depuis 1991 sur une polykystose renale et ayant une hemiplegie droite secondaire a un AVC, presentait en 2012 une paresie pyramidale gauche progressive, cotee a 1/5, d’aggravation recente. Une IRM du rachis cervical montrait une masse extramedullaire intra-rachidienne epidurale, prenant le contraste, s’etendant de C2 a C6. Une laminectomie decompressive avec exerese macroscopiquement complete de la masse epidurale posterieure etait realisee en semi-urgence. L’anatomopathologie retrouvait un depot amyloide a β2-microglobuline. Le taux serique de cette proteine etait a 6,9 mg/L (norme inferieure a 2,5 mg/L). Le diagnostic retenu etait celui d’une amylose pseudotumorale a β2-microglobuline. L’evolution clinique montrait une amelioration du deficit moteur cotee a 4/5 a deux mois de la chirurgie. Le patient etait decede de detresse respiratoire aigue en soins de suite un mois plus tard. Cas n o 2 : un homme de 81 ans etait adresse pour chutes en medecine interne en fevrier 2014. Il presentait un deficit sensitivo-moteur flasque et asymetrique des membres inferieurs. L’IRM medullaire montrait une masse tumorale centree sur T4, T5 et T6 avec fracture de T5, epidurite, et compression medullaire, ainsi que des nodules sur la queue de cheval, evocateurs de meningite carcinomateuse. La ponction lombaire etait acellulaire, avec une proteinorachie a 1,13 g/L (norme inferieure a 0,4 g/L). Une biopsie de la lesion montrait un materiel amyloide exempt de cellules pathologiques. Un pic monoclonal IgM kappa etait objective, et la biopsie osteomedullaire montrait un lymphome B d’allure lymphoplasmocytique avec une population plasmocytaire anormale suspecte de myelome associe. L’ensemble du tableau etait fortement evocateur d’amylose AL. Malheureusement, le patient etait decede des complications d’une grippe avant le typage de l’amylose et qu’un traitement medicochirurgical puisse etre entrepris. Discussion Nous rapportons ici deux cas d’amyloses pseudo-tumorales, a β2-microglobuline et AL, revelees par une compression medullaire. Si la majorite des amyloses pseudo-tumorales rapportees recemment est d’origine AL, notre premier cas illustre la possibilite d’amyloidomes compressifs autres–ici a β2-microglobuline. Il est possible que l’amelioration des parametres dialytiques et un acces plus precoce a la greffe renale diminuent l’incidence de l’amylose a β2-microglobuline, quoiqu’il n’y ait pas de donnees epidemiologiques dans la litterature. L’imagerie, dominee par l’IRM, permettrait d’orienter le diagnostic. En anatomopathologie, l’amylose est revelee par un aspect en birefringence jaune-vert en lumiere polarisee apres la coloration par le rouge Congo. Un typage de l’amylose est ensuite realise, oriente par la clinique. Dans les cas d’amylose avec compression medullaire, le traitement devrait etre dans un premier temps chirurgical pour ameliorer le pronostic fonctionnel, comme le montre notre premier cas. Il n’y a, dans la litterature, pas de cas rapportes ayant effectue un traitement par radiotherapie. Il est ensuite necessaire de realiser un bilan d’extension d’amylose, notamment dans la forme AL, a la recherche d’une infiltration systemique. Puis, un traitement specifique consistant a limiter le taux circulant de la proteine amyloidogene doit etre envisage : optimisation des parametres dialytiques et transplantation renale precoce chez le dialyse, traitement d’une eventuelle hemopathie sous-jacente dans l’amylose AL. Conclusion L’amyloidome est une forme rare d’amylose. Quoique de meilleur pronostic et rarement associe a une infiltration systemique, le diagnostic d’amylose pseudo-tumorale est a evoquer pour entreprendre un traitement medicochirurgical adapte. La compression medullaire en est un mode de revelation rare, mais greve d’un pronostic fonctionnel severe en cas de retard a la prise en charge neurochirurgicale.