[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.

[Profiles of autoimmune myositis with or without pulmonary involvement: A retrospective single-center study of 40 patients]. / Profils des myosites auto-immunes avec ou sans atteinte pulmonaire : une étude monocentrique rétrospective de 40 patients.

INTRODUCTION: Idiopathic inflammatory myopathies (IMM) are rare diseases with clinico-biological heterogeneity. Pulmonary involvement is frequent and associated with some distinctive manifestations. The aim of this study was to describe the clinico-biological profile of patients with autoimmune myositis with and without pulmonary involvement. METHODS: This retrospective descriptive study included patients with idiopathic inflammatory myopathies and a positive antibody test performed at Grenoble Alpes University Hospital between 2010 and 2020. RESULTS: Forty patients were included, the majority were women. The anti-Jo1 autoantibody was the most frequently found (37.5%). The prevalence of pulmonary involvement was 70%. Mechanics' hands and Raynaud's syndrome were the extra-respiratory signs significantly more present in the group with lung involvement (P <0.05), in contrast to creatine kinase levels which were lower in this group (P <0.05). Glucocorticoids and rituximab were significantly more often used in the group with lung involvement (P <0.05). The 5-year survival rate was 76.2% in patients with lung involvement and 100% in patients without lung involvement (P=0.50). CONCLUSION: We report a high prevalence of lung involvement probably explained by the presence of many patients with anti-synthetase syndrome. Our study highlights a lower severity of muscle involvement in myositis patients with lung disease, which deserves to be confirmed in a larger study.

[Place of internal medicine specialists in inpatient unprogrammed care of adult patients in France: A survey of in training and senior internal medicine specialists]. / Place des internistes dans la prise en charge hospitalière de la médecine adulte non programmée : enquête auprès des internistes en formation et en exercice.

INTRODUCTION: French internal medicine specialists are trained in clinical immunology and rare diseases as well as frequent ones. The latest activity is rarely highlighted by practitioners themselves and their representative authorities. Frequent diseases care in French hospitals are also the tasks of physicians without internal medicine specialty, mostly trained in general medicine, who practice in departments carrying various names. METHODS: We conducted a survey to estimate the part of frequent diseases' care and unplanned hospital medicine in the practice of specialists and residents in internal medicine in France, and its designation, through two surveys released by the "Collège National Professionnel de Médecine Interne" (for the internal medicine specialists), and the "Amicale des Jeunes Internists" (for the internal medicine residents). RESULTS: A total of 180 and 247 responses were obtained among the residents and the specialists, respectively, representing 31.3% and 24.8% of the internal medicine specialist's workforce. The most suitable qualifier for frequent diseases' care and unplanned hospital medicine, primarily post-emergency, was "general hospital medicine" for 48.9% of the residents and "general internal medicine" for 35.6% of the specialists. Unplanned hospital medicine was considered to represent a large part of the internal medicine activity by 66.7% and 64.7% of residents and specialists, respectively. A 50% and more hourly part of the activity devoted to it was reported by 71.4% of the residents and 76.1% of the specialists. General hospital medicine was reported to be distinct from internal medicine-clinical immunology by 46.1% of the residents and 47.4% of the specialists. CONCLUSION: French internists devote a large part of their activities to frequent diseases' care and unscheduled medicine, the name of which was not consensual. However, their work could not be summarized to it, often involving a specific activity named internal medicine - clinical immunology.

[Cerebral venous thrombosis revealing neurosyphilis]. / Une thrombose veineuse cérébrale révélant une neurosyphilis.

INTRODUCTION: Syphilis is a bacterial infection which is increasing in France. Neurosyphilis is a rare manifestation of syphilis, mainly involving the meninges and the blood vessels. It is a rare cause of cerebral vascular stroke. Venous thrombosis of syphilitic origin is rarely described. OBSERVATION: We reported a case of a fifty-year-old patient hospitalized for bilateral non-painful decreased visual acuity with headache. The CT scan showed cerebral venous thrombosis from the right lateral sinus to the jugular gulf. Patient presented a bilateral papillar oedema on the ocular fundus. Lumbar puncture showed lymphocytic meningitis with blood and CSF serology suggestive of neurosyphilis. The patient received antibiotic therapy with penicillin G for 14days with curative anticoagulation for six months. The evolution was favorable. CONCLUSION: Cerebral venous thrombosis in neurosyphilis is a poorly described entity. This case report confirms the status of great simulator of syphilis. In the context of its worldwide recrudescence, syphilis must be evoked in front of an unexplained neurological disorder.

Fatal hymenoptera venom anaphylaxis by undetected clonal mast cell disorder: A better identification of high risk patients is needed.

Hymenoptera venom anaphylaxis is the most frequent cause of anaphylaxis and responsible for about 20% of all fatal anaphylaxis cases in adults. We report two cases of fatal hymenoptera venom anaphylaxis with undiagnosed underlying mastocytosis and review the risk factors for severe or fatal hymenoptera venom anaphylaxis, as well as the specificities of its association with mastocytosis. As hymenoptera venom allergic patients with underlying clonal mast cell disorder generally lack typical skin lesions of mastocytosis, its diagnosis can easily be missed, underscoring the importance and need for diagnostic strategies in order to correctly identify these patients. Predominant cardiovascular symptoms in the absence of urticaria or angioedema following an insect sting are suggestive of underlying clonal mast cell disorder, and should be distinguished from panic attack or vasovagal syncope. Similarly, an unexplained syncope or an "idiopathic" anaphylaxis might reveal mastocytosis or hereditary alpha-tryptasemia. Acute and basal serum tryptase measurements should always be integrated in the diagnostic work-up of an insect sting reaction or unexplained syncope or shock of any origin.

Variability of disease activity in patients with hereditary angioedema type 1/2: longitudinal data from the Icatibant Outcome Survey.

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE-1/2) is a chronic and debilitating disease. The unpredictable clinical course represents a significant patient burden. OBJECTIVE: To analyse longitudinal registry data from the Icatibant Outcome Survey (IOS) in order to characterize temporal changes in disease activity in patients with HAE-1/2. METHODS: Icatibant Outcome Survey (NCT01034969) is an international observational registry monitoring the clinical outcomes of patients eligible for icatibant treatment. The current analyses are based on data collected between July 2009 and July 2019. Retrospective data for attacks recorded in the 12 months prior to IOS enrolment and for each 12-month period up to 7 years were analysed. RESULTS: Included patients reported angioedema attacks without long-term prophylaxis (LTP; n = 315) and with LTP (n = 292) use at the time of attack onset. Androgens were the most frequently used LTP option (80.8%). At the population level, regardless of LTP use, most patients (52-80%) reporting <5 attacks in Year 1 continued experiencing this rate; similarly, many patients (25-76%) who reported high attack frequency continued reporting ≥10 attacks/year. However, year on year, 31-51% of patients experienced notable changes (increase/decrease of ≥5 attacks) in annual attack frequency. Of patients who reported an absolute change of ≥10 attacks from Year 1 to 2, 17-50% continued to experience a change of this magnitude in subsequent years. CONCLUSION: At the population level, attack frequency was generally consistent over 7 years. At the small group level, 28.8-34.5% of patients reported a change in attack frequency of ≥5 attacks from Year 1 to Year 2; up to half of these patients continued to experience this magnitude of variation in disease activity in later years, reflecting high intra-patient variability.

[Assessment of the Internal Medicine Multidisciplinary Team meetings at the Grenoble University Hospital]. / Évaluation des réunions de concertation pluridisciplinaire de médecine interne au CHU Grenoble Alpes.

INTRODUCTION: Multidisciplinary team (MDT) meetings purpose is to optimize the disease management regarding state of science. While cancer MDT has proven its effectiveness, this is not yet the case with internal medicine MDT. METHODS: We performed a descriptive monocentric retrospective study. Data were collected from 247 MDT meeting reports which took place at the Grenoble University Hospital over a 5 years period. We investigated the data related to patient, MDT features, and decision-making process and reporting. Discussions were classified as diagnostic and/or therapeutic. RESULTS: Three specialties, among which at least internal medicine, attended to meetings. While 12% of cases were considered as "complex", a specialist opinion was required in 18% of diagnostic discussions. With regards to therapeutic discussions, 35% were supported by guidelines, 50% of therapeutic implementation involved innovating and expensive drugs, with off-label prescription in 75% of them. The decision-making process was described in 6% of the reports. Treatment recommendations were actually implemented in 72% of the patients. CONCLUSION: MDT meetings in Internal medicine meets a real need of physicians, in the ultimate interest of the patient. A prospective analysis would be interesting for a better definition of the evaluation criteria of these MDT meetings, meeting the physicians' needs, in patient management best interest. Prospective analyses are needed to better define MDT meetings assessment criteria.

[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.

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.

Monitoring of visual field over 6 months after active ocular toxoplasmosis.

PURPOSE: To prospectively report the perimetric defects during a 6-month follow-up (FU) in patients with initially active ocular toxoplasmosis (OT). METHODS: Twenty-four patients were studied, including 11 eyes with chorioretinal toxoplasmosis proven with a positive aqueous humor sample and 13 eyes with a biologically unproven, chorioretinal lesion. Automated 24-2 SITA-Standard visual fields were performed at baseline, at the first, and sixth months of FU. A composite clinical severity score was calculated from visual acuity (VA), severity of vitreitis, chorioretinal lesion size, location of the lesion in zone 1, the presence of an initial macular or papillary edema, and long-term scarring. This provided a relative cutoff level of severity. Nine eyes out of the 24 eyes were considered severe (3 unproven and 6 proven OT). RESULTS: Initial and final visual field parameters (mean deviation [MD] and pattern standard deviation [PSD]) were significantly correlated (r = 0.873; p < 0.001, and r = 0.890; p < 0.001, respectively). During FU, only foveal threshold [FT] was correlated with VA at baseline (r = 0.48; p = 0.01) and at the 6-month FU visit (r = 0.547; p = 0.004). The MD initial predictive value of clinical severity was 0.739 according to the ROC curve. At baseline, severe and nonsevere OT exhibited no significant difference in term of MD (p = 0.06) and PSD (p = 0.1). During the FU, taking into account all the data, MD, PSD, visual function index [VFI], and FT were associated with the severity of toxoplasmosis (p = 0.018, 0.05, 0.016, and 0.02, respectively): the unproven group had a faster recovery of MD during FU (p = 0.05). CONCLUSION: Visual field parameters better reflected the chorioretinal destruction related to the toxoplasmosis lesion and the functional repercussions than VA alone. Interestingly, MD at presentation could be a discriminating factor of severity in active OT, and each visual field parameter follow-up could be a support to manage patients with active OT, especially in the severe group.

Omalizumab in patients with chronic spontaneous urticaria nonresponsive to H1-antihistamine treatment: results of the phase IV open-label SUNRISE study.

BACKGROUND: Omalizumab is approved as an add-on therapy for the treatment of chronic spontaneous urticaria (CSU) in patients with inadequate response to H1-antihistamine treatment. The urticaria control test (UCT) is a reliable, concise tool developed as an alternative to the 7-day urticaria activity score (UAS7) - the standard for CSU disease activity assessment. OBJECTIVES: This prospective, open-label, phase IV study evaluated the efficacy and safety of omalizumab in French adult patients with CSU nonresponsive to H1-antihistamine treatment. MATERIALS AND METHODS: Patients [n = 136; stratified 1 : 2 (with angio-oedema : without angioedema)] received omalizumab 300 mg subcutaneously every 4 weeks for 12 weeks. Study assessments included UCT, UAS7, angio-oedema activity score and d-dimer levels (exploratory objective). RESULTS: At Week 12, 74·6% of the patients achieved disease control [UCT score ≥ 12 (primary endpoint)] and 67·7% of patients showed well-controlled disease (UAS7 ≤ 6). There was a strong negative correlation between UCT score and UAS7 at Week 12 (Spearman's correlation coefficient -0·839). Mean plasma d-dimer concentration was elevated at baseline (1002·1 ng mL-1 ) and decreased notably at Week 8 (455 ng mL-1 ). Among the nine patients with a very high baseline d-dimer concentration (> 3000 ng mL-1 ), eight were responders (UAS7 ≤ 6) at Week 12. CONCLUSIONS: Omalizumab was efficacious in patients with CSU nonresponsive to H1-antihistamines. The UCT was a reliable tool for disease assessment and the scores correlated well with UAS7. This study does not support the usefulness of d-dimer to monitor long-term disease prognosis in adult urticaria; however, it may indicate patients who respond to omalizumab.

[Neurologic disorders and Hepatitis E: Review of literature]. / Trouble neurologique et hépatite E : revue de la littérature.

INTRODUCTION: Hepatitis E is an emerging, worldwide disease. It is often asymptomatic. Nevertheless, in few cases, clinical manifestation such as neurological disorder could be present. The aim of this article is to realize a literature review of the neurological symptoms associated with hepatitis E. METHODS: We searched the Pubmed database using the term "hepatitis E", "neurological disorder AND hepatitis E". RESULTS: One hundred and thirty cases have been described between 2000 and 2017. The majority of cases were associated with the genotype 3 and were reported in Europe or in Asia. It preferentially affected immunocompetent (93%) men with a median age of 52 years. The main neurologic disorders were Guillain-Barré syndrome (54 cases), Parsonage-Turner syndrome (35 cases), multiplex mononeuropathy (6 cases), meningitis and meningoencephalitis (9 cases). The diagnosis was done with HEV IgM serology in most cases (98%). Aminotranferases increase and cholestasis were found in 88% and 82% respectively. The outcome varied according to the neurological syndrome. Antiviral or immunomodulatory therapies did not seem to improve symptoms. CONCLUSION: Hepatitis E seems to be associated with acute, wide neurological disorders. These data should be confirmed with a long term prospective study.

[Amoebosis: May sexual transmission be an underestimated way of contamination?] / Amibiase : au cours de rapports sexuels, un mode de transmission sous-estimé ?

INTRODUCTION: Amoebiasis is a cosmopolitan disease and the third most deadly of parasitic diseases. Entamoeba histolytica is the only one to be pathogenic. Its transmission is not only related to the faecal peril but also sexual, with cases described among men who have sex with men. A case of unusual sexual transmission is described in this article, aiming to discuss the impact of these ways of transmitting amoebiasis on patient management. CASE REPORT: We describe the case of an amebic liver abscess in a 27-years-old man who did not travel in endemic areas. After patient interrogation, it seems that the contamination mode was sexual, related to a heterosexual relationship with a new female partner 4 months before the diagnosis. HIV and hepatitis B serologies were negative. CONCLUSION: The diagnosis of amoebiasis should be suspected in case of dysentery or liver abscess even if there is no history of travel in endemic areas or of sexual intercourse between men.

Evaluation of avoralstat, an oral kallikrein inhibitor, in a Phase 3 hereditary angioedema prophylaxis trial: The OPuS-2 study.

BACKGROUND: Effective inhibition of plasma kallikrein may have significant benefits for patients with hereditary angioedema due to deficiency of C1 inhibitor (C1-INH-HAE) by reducing the frequency of angioedema attacks. Avoralstat is a small molecule inhibitor of plasma kallikrein. This study (OPuS-2) evaluated the efficacy and safety of prophylactic avoralstat 300 or 500 mg compared with placebo. METHODS: OPuS-2 was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were administered avoralstat 300 mg, avoralstat 500 mg, or placebo orally 3 times per day for 12 weeks. The primary efficacy endpoint was the angioedema attack rate based on adjudicator-confirmed attacks. RESULTS: A total of 110 subjects were randomized and dosed. The least squares (LS) mean attack rates per week were 0.589, 0.675, and 0.593 for subjects receiving avoralstat 500 mg, avoralstat 300 mg, and placebo, respectively. Overall, 1 subject in each of the avoralstat groups and no subjects in the placebo group were attack-free during the 84-day treatment period. The LS mean duration of all confirmed attacks was 25.4, 29.4, and 31.4 hours for the avoralstat 500 mg, avoralstat 300 mg, and placebo groups, respectively. Using the Angioedema Quality of Life Questionnaire (AE-QoL), improved QoL was observed for the avoralstat 500 mg group compared with placebo. Avoralstat was generally safe and well tolerated. CONCLUSIONS: Although this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1-INH-HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo.

The Icatibant Outcome Survey: experience of hereditary angioedema management from six European countries.

BACKGROUND: Hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE) is a rare, potentially fatal, bradykinin-mediated disease. Icatibant is a bradykinin B2 receptor antagonist originally approved in 2008 in the European Union and 2011 in the United States as an acute therapy option for HAE attacks in adults. OBJECTIVE: To compare demographics, disease characteristics and treatment outcomes of icatibant-treated HAE attacks in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey across six European countries: Austria, France, Germany, Italy, Spain and the UK. METHODS: The Icatibant Outcome Survey [IOS; Shire, Zug, Switzerland (NCT01034969)] is an international observational study monitoring the safety and effectiveness of icatibant. Descriptive, retrospective analyses compared IOS country data derived during July 2009-April 2015. RESULTS: Overall, 481 patients with C1-INH-HAE provided demographic data. A significant difference across countries in age at onset (P = 0.003) and baseline attack frequency (P < 0.001) was found although no significant differences were found with respect to gender (majority female; P = 0.109), age at diagnosis (P = 0.182) or delay in diagnosis (P = 0.059). Icatibant was used to treat 1893 attacks in 325 patients with majority self-administration in all countries. Overall, significant differences (all P < 0.001) were found across countries in time to treatment [median 1.8 h; median range: 0.0 (Germany-Austria) to 4.4 (France) h], time to resolution [median 6.5 h; median range: 3 (Germany-Austria) to 12 (France) h] and attack duration [median 10.5 h; median range: 3.1 (Germany-Austria) to 18.5 (France) h]. CONCLUSION: These data form the first European cross-country comparison of disease characteristics and icatibant use in patients with C1-INH-HAE who are enrolled in IOS. International variation in icatibant practice and treatment outcomes across the six European countries assessed highlight the need to further investigate the range of country-specific parameters driving regional variations in icatibant use.

Analysis of autofluorescence pattern in birdshot chorioretinopathy.

PURPOSE: To characterize and correlate the different patterns of fundus autofluorescence (FAF) in patients with birdshot chorioretinopathy (BSCR), with functional and anatomical parameters. METHODS: Twenty-one BSCR patients were prospectively studied in 2013 and 2014. Each patient underwent visual acuity (VA) and visual field (SITA standard 30.2) testing as well as fluorescein and indocyanine green angiography, spectral-domain optical coherence tomography (SD-OCT) B scan, enhanced depth imaging (EDI), and fundus autofluorescence (FAF) imaging. The disease was classified as active, chronic, or quiescent. RESULTS: The patients' mean age was 60.3 ± 9.2 years and 60% were female. Disease duration was 5.7 ± 3.7 years. Autofluorescence imaging showed punctiform hyper-FAF spots in 23 out of the 29 eyes (79%), which was significantly associated with a greater visual field mean deviation (-7 ± 7 versus -3 ± 2 dB, p = 0.04). Hypo-FAF was defined as peripapillary (n = 25; 86.2%), macular (n = 10; 34.5%), lichenoid (n = 17; 58.6%), and/or diffuse (n = 13; 44.8%). Lichenoid hypo-FAF was significantly associated with worse VA (0.18 ± 0.24 vs. 0.05 ± 0.07 LogMAR, p = 0.04). Macular hypo-FAF was associated with a history of macular edema (62.5%; p = 0.06). Diffuse hypo-FAF was observed more frequently (p = 0.01) in chronic disease (66.7%) than in active (0%) or quiescent disease (27.3%). CONCLUSIONS: Autofluorescence analysis in BRSC patients contributes to evaluating disease activity and could be useful to guide follow-up and treatment.