Central nervous system vasculitis in VEXAS syndrome: A rare involvemen.

INTRODUCTION: VEXAS (Vacuoles, E1 Enzyme, X-linked, autoinflammatory, Somatic) syndrome is a recently described severe adult-onset autoinflammatory disorder mediated by X-linked gene UBA1 somatic mutations, responsible of recurrent fever, skin involvement, chondritis, macrocytic anemia and inflammatory syndrome. Neurological manifestations are rarely described, and predominantly involve peripheral nervous system (PNS) impairment. RESULTS: We report the first central nervous system (CNS) vasculitis in VEXAS syndrome, characterized by headache, cognitive dysfunction and focal signs (cerebellar ataxia). Magnetic resonance imaging (MRI) revealed multifocal white-matter lesions corresponding to recent ischemic strokes, combined with cortical hemorrhagic lesions and gadolinium enhancement of the distal wall vessels. Treatment with methylprednisone, ruxolitinib and tocilizumab led to clinical improvement and a decrease of the inflammatory syndrome. The patient died few months after due to infectious complications. CONCLUSION: CNS vasculitis, occurring as a manifestation of the systemic auto-inflammatory state of VEXAS syndrome, might be a rare but severe complication. We suggest that it be added to the list of inflammatory vasculopathies. More prospective studies are needed to optimize the treatment.

French National Diagnostic and Care Protocol for antiphospholipid syndrome in adults and children.

Antiphospholipid syndrome (APS) is a chronic autoimmune disease involving vascular thrombosis and/or obstetric morbidity and persistent antibodies to phospholipids or certain phospholipid-associated proteins. It is a rare condition in adults and even rarer in children. The diagnosis of APS can be facilitated by the use of classification criteria based on a combination of clinical and biological features. APS may be rapidly progressive with multiple, often synchronous thromboses, resulting in life-threatening multiple organ failure. This form is known as "catastrophic antiphospholipid syndrome" (CAPS). It may be primary or associated with systemic lupus erythematosus (associated APS) and in very rare cases with other systemic autoimmune diseases. General practitioners and paediatricians may encounter APS in patients with one or more vascular thromboses. Because APS is so rare and difficult to diagnosis (risk of overdiagnosis) any suspected case should be confirmed rapidly and sometimes urgently by an APS specialist. First-line treatment of thrombotic events in APS includes heparin followed by long-term anticoagulation with a VKA, usually warfarin. Except in the specific case of stroke, anticoagulants should be started as early as possible. Any temporary discontinuation of anticoagulants is associated with a high risk of thrombosis in APS. A reference/competence centre specialised in autoimmune diseases must be urgently consulted for the therapeutic management of CAPS.

Tocilizumab and COVID-19: Timing of administration assessment.

Recent evidence showed greater efficacy of tocilizumab (TCZ) in the subgroups of COVID-19 patients who presented with symptoms for less than 7 days and in those only receiving oxygen. We retrospectively analyzed a compassionate use cohort to determine the best timing for TCZ injection. We showed no association between the timing of injection after symptom onset and the efficacy of TCZ on mortality. We then investigated whether the oxygen level at the time of TCZ injection impacted the mortality rate. Our study finally suggested that TCZ could be less effective when oxygen requirement is >11L/min and we hypothesized that earlier administration could be associated with better outcome. However, randomized clinical trials are required to confirm this hypothesis.

[Behçet's-like syndrome and other dysimmunitary manifestations related to myelodysplastic syndromes with trisomy 8]. / Syndrome de pseudo-Behçet et autres manifestations dysimmunitaires associées aux syndromes myélodysplasiques avec trisomie 8.

Myelodysplastic syndromes (MDS) are clonal hematopoietic malignancies which are also characterised by immune dysregulation. The impaired immune response is mainly due to T lymphocytes (CD8 and T regulatory cells) with increased cell apoptosis. MDS could be associated in some cases with various clinical dysimmune features; however, only MDS with trisomy 8 is correlated with particular clinical phenotype. The latter is mainly Behçet's-like disease which includes orogenital aphtosis, skin features and severe ulcerative digestive disease of ileocaecal distribution. Other clinical manifestations, such as arthritis or neutrophilic dermatosis, have been also described in MDS patients with trisomy 8. The dysimmune manifestations, and among them the Behçet's-like disease, do not impact the overall survival or the risk of progression to acute myeloid leukemia. Immunosuppressive and immunomodulatory therapies, and among them TNF-α inhibitors, are usually ineffective to control the dysimmune manifestations. Targeting the underlying clonal disease with specific therapies, such as azacitidine, seems to be the best strategy to control these disorders, even in MDS patients with low-risk disease.

Syndrome de Cogan.

"Typical" Cogan's syndrome is defined as a non-syphilitic interstitial keratitis associated with audio-vestibular resembling Ménière's disease with a 2-year maximum delay between these 2 organ impairment. Cogan syndrome is classified as "atypical" in the absence of interstitial keratitis and the presence of other inflammatory eye manifestations, an audio-vestibular impairment different from typical Menière-like disease, or a delay longer than 2 years between eye and audio-vestibular manifestations. Constitutional signs and large-vessel vasculitis is also possible, mostly affecting the thoracic aorta. The presence of acute-phase reactants is common, but no specific laboratory tests are available. The prognosis is dominated by the audio-vestibular impairment and in particular the risk of deafness, while other complications especially vascular complications being rare. Treatment with glucocorticoids is usually necessary and the combination to other immunosuppressive therapies or biological-targeted drugs needs to be determined.

[Cancers in systemic sclerosis : risk factors, impact on survival and literature review]. / Survenue de cancers au cours de la sclérodermie systémique : facteurs de risque, impact sur la survie et revue de la littérature.

INTRODUCTION: Patients with systemic sclerosis (SSc) have an increased risk of malignancy. In this study, we aimed to analyze the prevalence of cancer, the risk factors and the impact on overall survival. PATIENTS AND METHODS: We analyzed clinical (history of cancer, toxic exposition, organ involvement), immunological and treatment data in a monocentric cohort of SSc patients followed between January 2004 and December 2017. RESULTS: Two hundred and ten patients with SSc were included. During the follow-up, twenty-one patients (10 %) were diagnosed with malignancies. The underlying malignancies were breast adenocarcinoma (n=6, 28%), lung cancer (n=6, 28%), colorectal (colic adenocarcinoma, carcinoid tumor of the appendix), ovarian and cervix uteri, melanoma, kidney and papillary thyroid carcinoma (one of each). The median time between the first visit and the diagnosis of cancer was 4 [2-10] years. The overall survival in SSc patients with cancer was not significantly different from patients without cancer, with median survival during the first quartile (75%) at 12 years for patients with cancer and 11.6 years for those without cancer (P=0.9). The history of renal scleroderma crisis (HR 10.99, IC95% [1.95-62.07]; P=0.006) and the presence of anti-topoisomerase I antibodies (HR 5.5, IC95% [1.40-21.67]; P=0.01) were associated with an increased risk of cancer, whereas the presence of gastroesophageal reflux was inversely associated with the cancer occurrence (HR 0.22, IC95% [0.056-0.867]; P=0.03). CONCLUSION: The history of renal scleroderma crisis and the positivity of anti-topoisomerase I antibodies were associated with an increased risk of cancer in SSc patients in this monocentric study.

[Polyarteritis nodosa, an alternative diagnosis of giant cell arteritis in cases of temporal arteritis]. / La périartérite noueuse, un diagnostic alternatif à l'artérite gigantocellulaire devant une artérite temporale.

INTRODUCTION: Weight loss, myalgias, neurologic manifestations and arterial hypertension are common features of polyarteritis nodosa (PAN) at diagnosis. Temporal arteritis is a rarer manifestation of PAN, more suggestive of giant cell arteritis (GCA). CASE: We report the case of a 77-year-old woman who presented with fatigue, weight loss, fever, neck pain, jaw claudication and cough, diagnosed with giant cell arteritis. Diagnosis was reconsidered in favour of a medium and small-sized vessels necrotizing vasculitis corresponding to PAN because of steroid dependence, mononeuritis and suggestive histological features. CONCLUSION: Although temporal arteritis is suggestive of GCA, other causes of temporal arteritis can be identified with temporal artery biopsy.

Survival and prognosis factors in systemic sclerosis: data of a French multicenter cohort, systematic review, and meta-analysis of the literature.

BACKGROUND: Data on survival and prognosis factors in incident cohorts are scarce in systemic sclerosis (SStc). To describe survival, standardized mortality ratio (SMR), and prognosis factors in systemic sclerosis (SSc), we analyzed a multicenter French cohort of incident patients and performed a systematic review of the literature and meta-analysis. METHODS: A multicenter, French cohort study was conducted between January 1, 2000, and December 31, 2013. Patients were followed-up until July 1, 2016. A systematic review of the literature was carried out in MEDLINE and EMBASE up to July 2017. Meta-analysis was performed using all available data on SMR and hazard ratios of prognosis factors. RESULTS: A total of 625 patients (493 females, 446 lcSSc) were included. During the study period, 104 deaths (16.6%) were recorded and 133 patients were lost to follow-up. Overall survival rates at 1, 3, 5, and 10 years from diagnosis were 98.0%, 92.5%, 85.9%, and 71.7% respectively in the French cohort. Overall SMR was 5.73 (95% CI 4.68-6.94). Age at diagnosis > 60 years, diffuse cutaneous SSc, scleroderma renal crisis, dyspnea, 6-min walking distance (6MWD), forced vital capacity < 70%, diffusing capacity of the lungs for carbon monoxide < 70%, pulmonary hypertension (PH), telangiectasia, valvular disease, malignancy, anemia, and CRP > 8 mg/l were associated with a poorer survival after adjustment. Eighteen studies (11,719 patients) were included in the SMR meta-analysis and 36 studies (26,187 patients) in the prognosis factor analysis. Pooled SMR was 3.45 (95%CI 3.03-3.94). Age at disease onset, male sex, African origin, diffuse cutaneous SSc, anti-Scl70 antibodies, cardiac and renal involvement, interstitial lung disease, PH, and malignancy were significantly associated with a worse prognosis. Anti-centromere antibodies were associated with a better survival. CONCLUSIONS: Overall, our study highlights a high mortality rate in SSc patients and confirms previously described prognosis factors related to skin extension and organ involvement while identifying additional prognosis factors such as autoantibody status, telangiectasia, 6MWD, and valvular disease.

[Hydroxychloroquine to obtain pregnancy without adverse obstetrical events in primary antiphospholipid syndrome: French phase II multicenter randomized trial, HYDROSAPL]. / Évaluation du bénéfice de l'utilisation d'hydroxychloroquine pour l'obtention d'une grossesse à terme non compliquée en cas de syndrome des antiphospholipides primaire : étude de phase II multicentrique randomisée en double insu versus placebo, HYDROSAPL.

Antiphospholipid syndrome is defined by the presence of thrombosis and/or obstetrical adverse events (≥3 recurrent early miscarriage or fetal death or a prematurity<34 weeks of gestation) associated with persistent antiphospholipid antibodies. The pregnancy outcome has been improved by the conventional treatment (aspirin 100mg/day with low molecular weight heparin [LMWH] from 30 to 75% of uncomplicated pregnancies. In PROMISSE study, 19% of pregnancies had at least one obstetrical adverse event despite treatment (maternal, fetal or neonatal complications) in relation with APS. In the European registry of babies born from APS mothers, maternal and foetal adverse events were observed in 13% of cases, with prematurity in 14% despite treatment. The presence of lupus erythematosus, a history of thrombosis, presence of lupus anticoagulant and APL triple positivity are considered as factors associated with unfavorable obstetrical outcome. Hydroxychloroquine (HCQ) has anti-inflammatory and anti-thrombotic properties. Studies in vitro have shown that HCQ is able to restore the placental expression of Annexin V, which has an anticoagulant effect and to prevent the placental injury induced by APL. HCQ used for lupus erythematosus decrease the thrombotic risk and its value for thrombotic APS has been raised in an open labelled French study. In European retrospective study, the addition of HCQ to conventional treatment improved refractory obstetrical APS. Its use during the pregnancy of patients with lupus erythematosus, the evidence of good safety during the pregnancy and follow-up of children born to mothers exposed to HCQ demonstrate an overall good safety profile for mothers and the fetus. This clinical trial is designed to assess the interest of the addition of hydroxychloroquine to conventional treatment in APS during the pregnancy.

[Systemic sclerosis: Efficacy of intravenous immunoglobulins in severe cardiac involvement?] / Sclérodermie systémique : efficacité des immunoglobulines intraveineuses pour l'atteinte cardiaque sévère ?

BACKGROUND: The heart involvement in systemic sclerosis is frequent and can touch various sites. The prognosis in the presence of heart disease is poor, but few data are available about its management. CASE: We report the case of 48 years old woman with systemic sclerosis which presented severe heart involvement. She has severe heart failure, supraventricular arrhythmias and symptomatic pericarditis, which required surgical intervention and immunosuppressive drugs (steroids with rituximab). Despite this treatment, she has persistent severe heart impaired function and intravenous immunoglobulins have been initiated. She experienced progressively the improvement of dyspnea, of heart systolic ejection fraction and decrease of Rodnan scale. CONCLUSION: Our case illustrates a severe heart involvement in systemic sclerosis which have been improved by intravenous immunoglobulins.

[Chronic histiocytic intervillositis: Diagnosis and management]. / Intervillites chroniques histiocytaires : bilan et prise en charge.

Chronic intervillositis is a rare condition, which is associated with severe obstetrical outcome and high recurrence rate. Obstetrical adverse events are intrauterine growth restriction, recurrent early miscarriages, intrauterine deaths and prematurity by placental insufficiency. The determination of the extension and the intensity of the chronic intervillositis are not currently standardized. High rates of recurrence have been described, but actually there is no reliable predictive biomarker. No treatment is currently validated, but the use of immunomodulatory drugs could be justified by the possible autoimmune or allo-immune origin. The treatment should be particularly discussed in patients with recurrent and severe obstetrical adverse events and in the presence of severe and massive histological lesions.

[Vasculitis of the hepatic artery: A case of a single-organ vasculitis]. / Vascularite de l'artère hépatique : à propos d'un cas d'atteinte d'organe isolée.

INTRODUCTION: Vasculitis usually have a systemic involvement. Rare cases of localized vasculitis have been described, but the exclusive involvement of the hepatic artery is exceptional. We report the case of a patient who developed a vasculitis of the right and left hepatic arteries. CASE REPORT: A 63-year-old woman presented with unexplained abdominal pain. A computed tomography of the abdomen was suggestive of vasculitis of the hepatic arteries, showing a sequence of stenosis and aneurysmal dilatations of the hepatic arteries. There were no other arterial involvement, in particular of the abdomen and the brain. No other systemic disease or infection was found. The outcome was favorable, with corticosteroids alone. DISCUSSION: The exclusive involvement of the hepatic artery is an exceptional form of localized vasculitis, with only one other case reported. This diagnosis could therefore be discussed, in the presence of unexplained hepatic hematoma or pain.

Mucosal-associated Invariant Cells are Deficient in Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease, characterized by fibrosis of the skin and other organs, vascular impairment and deficient immune responses. Mucosal-associated invariant T cells (MAIT) have been involved in various inflammatory and autoimmune diseases. The aims of this study were to determine the frequencies of MAIT cells in the blood of patients with systemic sclerosis (SSc) and to compare their distribution in different types of SSc. Blood samples from patients with SSc and healthy controls were examined by flow cytometer to analyse the frequencies of MAIT and γδ T cells. We demonstrate that in SSc the frequencies and absolute numbers of MAIT and γδ T cells are significantly reduced in comparison with healthy controls. MAIT and γδ T cells did not correlate with C-reactive protein, BNP, pulmonary involvement or median skin fibrosis scale, steroid amount or disease duration. In addition, MAIT and γδ T cells decrease did not stratify with gender, interstitial lung disease or active digital ulcers. Functional studies are necessary to determine the signification of MAIT cells decrease in systemic sclerosis.

[Pachymeningitis]. / Les pachyméningites.

Pachymeningitis is a fibrosing and inflammatory process, which involves the dura mater. Some pachymeningitis are cranial and induce headaches and cranial nerve palsies. Others are spinal and responsible for nerve roots or spinal cord compression. MRI shows contrast enhancement thickening of the dura mater. Etiologies are infectious (syphilis, tuberculosis, etc.) or inflammatory (sarcoidosis, granulomatosis with polyangiitis, IgG4-related disease, idiopathic). Corticosteroids are the main treatment. The use of immunosuppressive drugs or rituximab is yet to be determined and probably adapted to each etiology.

Cessation of oral anticoagulants in antiphospholipid syndrome.

Objective To study the outcome of patients with antiphospholipid syndrome (APS) after oral anticoagulant treatment cessation. Methods We performed a retrospective study of patients with APS experiencing cessation of oral anticoagulant and enrolled in a French multicentre observational cohort between January 2014 and January 2016. The main outcome was the occurrence of recurrent thrombotic event after oral anticoagulation cessation. Results Forty four APS patients interrupted oral anticoagulation. The median age was 43 (27-56) years. The median duration of anticoagulation was 21 (9-118) months. Main causes of oral anticoagulant treatment cessation were switch from vitamin K antagonists to aspirin in 15 patients, prolonged disappearance of antiphospholipid antibodies in ten, bleeding complications in nine and a poor therapeutic adherence in six. Eleven (25%) patients developed a recurrent thrombotic event after oral anticoagulation cessation, including three catastrophic APS and one death due to lower limb ischemia. Antihypertensive treatment required at time of oral anticoagulants cessation seems to be an important factor associated with recurrent thrombosis after oral anticoagulant cessation (15.2% in patients with no relapse versus 45.5% in patients with recurrent thrombosis, p = 0.038). Oral anticoagulant treatment was re-started in 18 (40.9%) patients. Conclusion The risk of a new thrombotic event in APS patients who stopped their anticoagulation is high, even in those who showed a long lasting disappearance of antiphospholipid antibodies. Except for the presence of treated hypertension, this study did not find a particular clinical or biological phenotype for APS patients who relapsed after anticoagulation cessation. Any stopping of anticoagulant in such patients should be done with caution.

[Obstetrical APS: Is there a place for additional treatment to aspirin-heparin combination?] / Le syndrome des antiphospholipides obstétrical : quelle est la place d'un traitement complémentaire à la combinaison aspirine et héparine ?

Obstetrical APS is defined by thrombosis and/or obstetrical morbidity associated with persistent antiphospholipid antibodies. The aspirin and low molecular weighted heparin combination dramatically improved obstetrical outcome in APS patients. Several factors could be associated with obstetrical prognosis, as previous history of thrombosis, associated SLE, the presence of lupus anticoagulant and triple positivity of antiphospholipid antibodies. Obstetrical APS with isolated recurrent miscarriages is mostly associated with isolated anticardiolipids antibodies and have better obstetrical outcome. The pregnancy loss despite aspirin and heparin combination define the refractory obstetrical APS, and the prevalence could be estimated to 20-39%. Several other treatments have been used in small and open labeled studies, as steroids, intravenous immunoglobulins, plasma exchanges and hydroxychloroquine to improve the obstetrical outcome. Some other drugs as eculizumab and statins could also have physiopathological rational, but studies are necessary to define the place of these various drugs.

[Autoimmune and inflammatory disorders associated with lymphoid hematological malignancies]. / Manifestations auto-immunes et inflammatoires des hémopathies lymphoïdes.

In this literature review, we reported autoimmune and inflammatory disorders associated with lymphoid hematological malignancies, including non-Hodgkin's lymphoma, Hodgkin's lymphoma and chronic lymphocytic leukemia. The different types of systemic involvement are classified by affected organ. We listed in this review the joint diseases, skin, neurologic, hematologic, renal, and vasculitis. We tried to determine whether there is a correlation between each autoimmune manifestation and a specific type of lymphoma or a particular feature that may support a paraneoplastic origin, if there is an impact on the prognosis of the hematological malignancy, and finally, we identified the different therapeutic strategies used in the literature.

[Insulin edema in hepatic glycogenosis]. / Œdème insulinique au cours d'une glycogénose hépatique.

INTRODUCTION: Hepatic glycogenosis is a rare syndrome, which includes poorly controlled diabetes mellitus, hepatomegaly, delayed puberty, and growth delay. Insulin edema is sometimes associated. CASE REPORT: An 18-year-old woman presented with diffuse edema, hepatomegaly, amenorrhea, uncontrolled diabetes, and elevated transaminases and cholestasis. Hepatic ultrasonography and abdominal computed tomographic scan confirmed the hepatomegaly. The liver biopsy showed a massive glycogenosis and the diagnosis of hepatic glycogenosis was confirmed. Too large doses of insulin were responsible of diffuse edema. Diabetes equilibration and diminution of insulin intakes allow correction of this disorder. CONCLUSION: Excess of insulin can lead to excessive hepatic glycogen storage by activation of glycogenosis enzymes. Biological manifestations consist on elevated liver enzymes and hyperlactatemia. There is a link between administration of high dose of insulin and edema. Hepatic glycogenosis should be suspected when diabetes is uncontrolled and be considered as a differential diagnosis of steatosis. It may be associated and revealed by insulin edema directly related to excessive insulin intakes.