Cyclophosphamide vs rituximab for eradicating inhibitors in acquired hemophilia A: A randomized trial in 108 patients.

BACKGROUND: Acquired hemophilia A (AHA) is a rare autoimmune disorder due to autoantibodies against Factor VIII, with a high mortality risk. Treatments aim to control bleeding and eradicate antibodies by immunosuppression. International recommendations rely on registers and international expert panels. METHODS: CREHA, an open-label randomized trial, compared the efficacy and safety of cyclophosphamide and rituximab in association with steroids in patients with newly diagnosed AHA. Participants were treated with 1 mg/kg prednisone daily and randomly assigned to receive either 1.5-2 mg/kg/day cyclophosphamide orally for 6 weeks, or 375 mg/m2 rituximab once weekly for 4 weeks. The primary endpoint was complete remission over 18 months. Secondary endpoints included time to achieve complete remission, relapse occurrence, mortality, infections and bleeding, and severe adverse events. RESULTS: Recruitment was interrupted because of new treatment recommendations after 108 patients included (58 cyclophosphamide, 50 rituximab). After 18 months, 39 cyclophosphamide patients (67.2 %) and 31 rituximab patients (62.0 %) were in complete remission (OR 1.26; 95 % CI, 0.57 to 2.78). In the poor prognosis group (FVIII < 1 IU/dL, inhibitor titer > 20 BU mL-1), significantly more remissions were observed with cyclophosphamide (22 patients, 78.6 %) than with rituximab (12 patients, 48.0 %; p = 0.02). Relapse rates, deaths, severe infections, and bleeding were similar in the 2 groups. In patients with severe infection, cumulative doses of steroids were significantly higher than in patients without infection (p = 0.03). CONCLUSION: Cyclophosphamide and rituximab showed similar efficacy and safety. As first line, cyclophosphamide seems preferable, especially in poor prognosis patients, as administered orally and less expensive. FUNDING: French Ministry of Health. CLINICALTRIALS: gov number: NCT01808911.

French national diagnostic and care protocol for Kawasaki disease.

Kawasaki disease (KD) is an acute vasculitis with a particular tropism for the coronary arteries. KD mainly affects male children between 6 months and 5 years of age. The diagnosis is clinical, based on the international American Heart Association criteria. It should be systematically considered in children with a fever, either of 5 days or more, or of 3 days if all other criteria are present. It is important to note that most children present with marked irritability and may have digestive signs. Although the biological inflammatory response is not specific, it is of great value for the diagnosis. Because of the difficulty of recognising incomplete or atypical forms of KD, and the need for urgent treatment, the child should be referred to a paediatric hospital as soon as the diagnosis is suspected. In the event of signs of heart failure (pallor, tachycardia, polypnea, sweating, hepatomegaly, unstable blood pressure), medical transfer to an intensive care unit (ICU) is essential. The standard treatment is an infusion of IVIG combined with aspirin (before 10 days of fever, and for a minimum of 6 weeks), which reduces the risk of coronary aneurysms. In case of coronary involvement, antiplatelet therapy can be maintained for life. In case of a giant aneurysm, anticoagulant treatment is added to the antiplatelet agent. The prognosis of KD is generally good and most children recover without sequelae. The prognosis in children with initial coronary involvement depends on the progression of the cardiac anomalies, which are monitored during careful specialised cardiological follow-up.

[Hereditary angioedema and its new treatments: An update]. / Mise au point sur les angiœdèmes héréditaires et leurs nouvelles thérapeutiques.

Hereditary angioedema, with or without deficient C1 inhibitor level or function, is a rare disease characterized by recurrent attacks of noninflammatory subcutaneous and/or submucosal edema. It may be life-threatening and substantially affects quality of life. Attacks may be spontaneous or induced, in a setting of emotional stress, by infections or physical trauma, in particular. As the key mediator is bradykinin, this angioedema does not respond to the usual treatments of mast cell-mediated angioedema (antihistamines, corticosteroids, adrenaline), which is much more frequent. Therapeutic management of hereditary angioedema first consists in treating severe attacks with a selective B2 bradykinin receptor antagonist or a C1 inhibitor concentrate. The latter or an attenuated androgen (danazol) can be used for short-term prophylaxis. Therapeutic solutions conventionally proposed for long-term prophylaxis (danazol, antifibrinolytics [tranexamic acid], C1 inhibitor concentrate) vary in efficacy and/or pose problems of safety or ease of use. Kallikrein inhibitors (subcutaneous lanadelumab, oral berotralstat) recently made available as disease-modifying treatment constitute an important advance in long-term prophylaxis of hereditary angioedema attacks. The advent of these new drugs is accompanied by a new ambition for patients: optimize control of the disease and thereby minimize its impact on quality of life.

Why are people still dying of drug-susceptible TB in Paris in the 21st century?

BACKGROUND: Although the burden of TB is lower in France than in low-income countries, patients continue to die from TB in Paris. Our goal was to describe TB-related deaths and to identify associated risk factors.METHODS: We conducted a retrospective cohort study in two hospitals in Paris between 2013 and 2018. All patients with drug-susceptible TB were included and followed until end of treatment. The primary outcome was death. We performed univariate and multivariate analysis using Cox proportional hazard model.RESULTS: Of the 523 patients included, 362 were men (median age 37 years), of whom 24 patients died (4.5%). The final survival model concluded that age (HR 1.1 for each additional year), not living in one´s own accommodation (HR 5.9), being born in France (HR 8.0), being alcoholic (HR 4.2), having a history of cancer (HR 7.1) or meningeal or miliary TB (HR 8.2) were associated with a higher risk of death.CONCLUSION: The rate of TB-associated death is unacceptably high for a curable disease. To note, patients born in France were much more at risk of death than immigrants. We believe raising awareness among healthcare professionals is a potentially easy and efficient lever for improving care.

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.

[Periodic fever syndrome associated with mutations in the TNF type 1 receptor gene: A differential diagnosis of familial Mediterranean fever that should not be overlooked in patients of Mediterranean origin]. / Le syndrome de fièvre prolongée associée aux mutations du gène du récepteur au TNF de type 1 : un diagnostic différentiel de la fièvre méditerranéenne familiale à ne pas méconnaître chez les patients d'origine méditerranéenne.

INTRODUCTION: Tumor Necrosis Factor Type 1 Receptor Associated Periodic Syndrome (TRAPS) is a rare autosomal dominant autosomal autoinflammatory disease associated with mutations in the TNF type 1 receptor gene (TNFRSF1A). It is characterized by relatively long recurrent febrile seizures with an average duration of 7 days accompanied by arthralgia, myalgia, and usually a rash. In a patient of Mediterranean origin with recurrent fever, familial Mediterranean fever is the first diagnosis to be suspected by argument of frequency. METHODS: A retrospective observational study was conducted on patients from Mediterranean origin followed for TRAPS and included in the "Juvenile Inflammatory Rheumatism" (JIR) observational cohort in the national French autoinflammatory center. The age of onset of symptoms, age of diagnosis, number of years of wandering and treatments received were collected for each index case. RESULTS: Nine patients from 6 families of Mediterranean origin were included. A molecular diagnosis confirmed TRAPS in all patients. The median age at diagnosis was 26 years, the mean number of years of wandering was 17 years. The diagnosis of FMF was made first in all patients. AA amyloidosis revealed TRAPS in 2 patients. Colchicine was started without any efficacy in all cases. Five patients were treated with interleukin-1 inhibitory biotherapy with 100% efficacy. CONCLUSION: In a patient of Mediterranean origin presenting with recurrent febrile abdominal pain of AA amyloidosis, the first diagnosis to be suspected is FMF. Long relapses, dominant transmission, a non-Mediterranean relative, and the ineffectiveness of colchicine should evoke TRAPS.

[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.

[Acquired angioedema due to C1-inhibitor deficiency: CREAK recommendations for diagnosis and treatment]. / Angiœdèmes par déficit acquis en C1-inhibiteur : recommandations du CREAK pour le diagnostic et la prise en charge.

Acquired angioedema with C1-inhibitor deficiency is a rare and peculiar entity belonging to the spectrum of bradykinin angioedemas. It usually occurs in subjects over 60 years old, and is mostly associated with a B-cell lymphoid hemopathy or a monoclonal gammopathy. The diagnosis relies on at least one angioedema episode, lasting more than 24 h, and on the decrease of functional C1-inhibitor. Low C1q is observed in 90% of patients, and an anti C1-inhibitor antibody is found in 50% of patients. The treatment of severe attacks relies on icatibant or C1-inhibitor perfusions. Long term prophylaxis in patients with frequent attacks requires treatment of the associated hemopathy if so. In case of idiopathic angioedema, tranexamic acid and danazol may be used, provided that there is-no thrombophilia; as well as rituximab as second-line treatment. Inhibitors of kallikrein still need to be evaluated in this therapeutic indication.

[Association between psychiatric comorbidities and hospital length of stay in post-emergency internal medicine patients]. / Association des comorbidités psychiatriques avec la durée de séjour des patients en médecine interne d'aval des urgences.

INTRODUCTION: Patients with psychiatric disorders suffer from a higher rate of somatic disorders than those without psychiatric disorder, often inappropriately managed. Our study aimed to describe patients with psychiatric comorbidity in post-emergency internal medicine units and to compare their length of hospital stay to patients without psychiatric disease. METHODS: This French cross sectional study used the data warehouse of the greater Paris hospitals. It included, all patients hospitalized through the emergency department in 9 internal medicine departments during the year 2017. Psychiatric disorders and the burden of somatic disorders (Charlson score) were determined through diagnostic coding. Charlson score and hospital length of stay were compared between patients with and without psychiatric comorbidity. RESULTS: In total, 8981 hospital stays (8001 patients) were included, 1867 (21%) with psychiatric comorbidity. After adjusting for age, gender, hospital and main diagnosis, the Charlson score was on average 0.68 higher in the psychiatric comorbidity group (P<0.001) and the length of hospital stay was 30% higher after further adjustment on the Charlson score (P<0.001). These differences were consistent for each main diagnosis. CONCLUSION: Patients with psychiatric comorbidity are frequent in post-emergency internal medicine wards. They experience longer hospital stays, only partly related with a higher burden of somatic disorders. Special attention should be paid to this vulnerable population.

Angioedema associated with thrombolysis for ischemic stroke: analysis of a case-control study.

BACKGROUND: Bradykinin-mediated angioedema (AE) is a complication associated with thrombolysis for acute ischemic stroke. Risk factors are unknown and management is discussed. OBJECTIVES: To clarify risk factors associated with bradykinin-mediated AE after thrombolysis for acute ischemic stroke. METHODS: In a case-control study conducted at a French reference centre for bradykinin angiœdema, patients with thrombolysis for acute ischemic stroke and a diagnosis of bradykinin-mediated angiœdema, were compared to controls treated with thrombolysis treatment without angiœdema. RESULTS: Fifty-three thrombolysis-related AE were matched to 106 control subjects. The sites of attacks following thrombolysis for ischemic stroke mainly included tongue (34/53, 64%) and lips (26/53, 49%). The upper airways were involved in 37 (70%) cases. Three patients required mechanical ventilation. Patients with bradykinin-mediated angiœdema were more frequently women [33 (62%) vs. 44 (42%); P = 0.01], had higher frequency of prior ischemic stroke [12 (23%) vs. 9 (8%); P = 0.01], hypertension [46 (87%) vs. 70 (66%); P = 0.005], were more frequently treated with angiotensin-converting enzyme inhibitor [37 (70%) vs. 28 (26%); P < 0.001] and were more frequently hospitalized in intensive care medicine [ICU; 11 (21%) vs. 5 (5%); P = 0.004]. In multivariate analysis, factors associated with thrombolysis-related AE were female sex [odds ratio (OR), 3.04; 95% confident interval (CI), 1.32-7.01; P = 0.009] and treatment with angiotensin-converting enzyme inhibitors [(OR), 6.08; 95% (CI), 2.17-17.07; P < 0.001]. CONCLUSIONS: This case-control study points out angiotensin-converting enzyme inhibitors and female sex as risk factors of bradykinin AE associated with thrombolysis for ischemic stroke.

[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.

Repeated attacks of type III hereditary angioedema with factor XII mutation during pregnancy.

In type III hereditary angioedema (HAE type III), the phenotype is the same as type I and type II disease, but the level and function of C1-esterase inhibitor (C1-INH) is normal. Hereditary angioedema type III has been described as an oestrogen-sensitive form because it can be triggered or aggravated by exposure to high oestrogen levels as seen during pregnancy, especially when associated with Factor XII mutation. This case report describes the evolution and management of repeated angioedema attacks during pregnancy in a woman with HAE, with normal levels and function of C1-INH (type III); and a mis-sense mutation of factor XII. The physiopathology and genetic features, the unpredictability of clinical manifestations and the management during pregnancy and delivery are discussed.

[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.