Pericardiectomy and Mechanical Mitro-Aortic Valve Replacement in a Young Patient With Erdheim-Chester Disease.

Erdheim-Chester disease is a rare histiocytosis that primarily affects the skeletal system, but cardiovascular manifestations occur in 75% of cases and are associated with a poor prognosis. Given the small number of cases, the evolution and management of the disease are uncertain. Therefore, it is important to report and share Erdheim-Chester cases. This report presents the case of a young patient with constrictive pericarditis and mitral valve regurgitation resulting from Erdheim-Chester disease.

[Sjögren's syndrom: clinical, diagnostic and therapeutic innovations]. / Syndrome de Sjögren : nouveautés cliniques, diagnostiques et thérapeutiques.

Sjögren's syndrome (SS) is a systemic autoimmune disease affecting the lacrimal and salivary glands. In up to one third of patients, SS may be complicated by potentially severe extra-glandular visceral involvement, which can be life-threatening. Diagnosis is often difficult based on a combination of clinical and biological evidence. The development of new imaging techniques can now help the clinician in his diagnostic approach. Long considered incurable, new medical and surgical treatments are being studied and are potentially promising. Paramedical management and regular physical activity are also essential and contribute to the improvement of patients' fatigue. The objective of this article is to review the main clinical manifestations as well as the diagnostic and therapeutic novelties developed in recent years.

Le syndrome de Sjögren (SS) est une maladie autoimmune systémique touchant les glandes lacrymales et salivaires. Chez près d'un tiers des patients, il peut se compliquer d'atteintes extraglandulaires potentiellement sévères. Le diagnostic, reposant sur un faisceau d'arguments clinicobiologiques, est souvent difficile. Le développement des nouvelles techniques d'imagerie peut aujourd'hui aider le clinicien dans sa démarche diagnostique. Longtemps considéré comme incurable, de nouveaux traitements médicochirurgicaux sont en cours d'étude et potentiellement prometteurs. Une prise en charge paramédicale avec une activité physique régulière est également essentielle. L'objectif de cet article est de revoir les manifestations cliniques ainsi que les nouveautés diagnostiques et thérapeutiques développées ces dernières années.

[VEXAS syndrome : when do we have to consider it ?] / Syndrome VEXAS : quand y penser ?

VEXAS syndrome was recently discovered in patients who developed late in adulthood an inflammatory syndrome with fever, cytopenias, dysplastic bone marrow, cutaneous and pulmonary neutrophilic inflammation, arthritis, chondritis, or vasculitis. It is the result of an inactivating somatic mutation affecting methionine codon 41 of the UBA1 gene which encodes an ubiquitin activating enzyme (E1). Systemic corticosteroids generally reduce symptoms, while other immunosuppressive drugs only have limited long-term effects. Azacitidine is a promising treatment, but further studies are warranted. Here, we describe 2 new cases including one associated with pyoderma gangrenosum and cryoglobulinemia.

Le syndrome VEXAS (Vacuoles, E1 Enzyme, X-Linked, Auto- Inflammatory, Somatic Syndrome) a été récemment découvert chez des patients développant tardivement à l'âge adulte un syndrome inflammatoire associé à de la fièvre, des cytopénies, une moelle osseuse dysplasique, une inflammation neutrophilique cutanée et pulmonaire, des arthrites, des chondrites ou des vasculites. Il est le résultat d'une mutation somatique inactivatrice affectant le codon méthionine 41 du gène UBA1 qui encode une enzyme E1 activant l'ubiquitine. Les corticostéroïdes systémiques permettent généralement de diminuer les symptômes alors que les autres immunosuppresseurs ont un effet limité à long terme. L'azacitidine est l'un des traitements ayant démontré une efficacité, cependant de nouvelles études sont souhaitables. Nous décrivons ici 2 cas dont l'un est associé à un pyoderma gangrenosum et une cryoglobulinémie.

[Idiopathic recurrent pericarditis: review of the literature and the Geneva experience]. / Péricardite récurrente idiopathique : revue de littérature et expérience genevoise.

The notion of idiopathic recurrent pericarditis (IRP) appeared in the scientific literature in the 1930s. In 1955, W. Dressler published a case series of IRP in which treatment of cortisone and salicylates (i.e. Aspirin) was effective. About 30 years later, De La Serna et al. in 1987 and Guindo et al. in 1990, reported a beneficial effect of colchicine. In recent years, several clinical studies have helped to i mprove the management of this disease. In this present literature review of IRP, we will focus on the definition, differential diagnoses, pathophysiological hypotheses and available treatments. We will also discuss the clinical experience at the division of clinical immunology at the University Hospitals of Geneva.

La notion de péricardite récurrente idiopathique (PRI) apparaît dans la littérature scientifique dans les années 1930. En 1955, Dressler publie une série de cas de PRI où les traitements de cortisone et les salicylates (c'est-à-dire l'aspirine) semblent être efficaces. Environ 30 ans plus tard, De La Serna et coll., en 1987, et Guindo et coll., en 1990, évoquent un effet bénéfique de la colchicine. Depuis le développement clinique moderne, plusieurs études ont permis de faire évoluer la prise en charge de cette entité. Dans cette revue de littérature de la PRI, nous nous intéressons à la définition, aux diagnostics différentiels, aux hypothèses physiopathologiques ainsi qu'aux traitements disponibles. Nous parlons également de l'expérience clinique de cette pathologie au sein de notre Service d'immunologie clinique aux HUG.

Short-term glucocorticoid-related side effects and adverse reactions: a narrative review and practical approach.

Glucocorticoids are the mainstay treatment of a variety of inflammatory and autoimmune disorders. Unfortunately, metabolic side effects, drug interactions and adverse reactions commonly lead to glucocorticoid-related side effects, thereby compromising their intended anti-inflammatory and immunosuppressive effects. The goal of this review is to help clinicians to monitor the broad spectrum of side effects of short-term systemic glucocorticoid administration, defined as glucocorticoid treatment shorter than 30 days. We review the various systems affected, with a focus on metabolic conditions and hyperglycaemia management.

Sarcoidosis - a multisystem disease.

Sarcoidosis is a systemic inflammatory disease, characterised by granuloma formation upon an unknown trigger in genetically predisposed individuals. The inflammation is characterised by an activation of both the innate immune system, with macrophages differentiating into epitheloid cells and dendritic cells, and the adaptive immune system, particularly T helper (Th) 1 and Th17 cells. Since all organs can be affected to varying extents, clinical presentation is often diverse. Most commonly, the lungs, lymph nodes, skin and eyes are involved, whereas cardiac, renal and neurological manifestations are less common but associated with higher morbidity. Depending on the clinical symptoms, a detailed evaluation including thorough clinical examination, imaging and laboratory tests should explore all possible organ involvements. In some patients, fatigue manifests as a para-sarcoidosis symptom impacting quality of life, even if sarcoidosis is in remission. Some acute syndromic presentations, such as Löfgren's syndrome, have a good prognosis and are commonly self-limiting. If possible, a topical treatment, for example for cutaneous sarcoidosis or bronchial involvement, should be applied. Treatment of severe cases with persisting disease activity necessitates long-term immunosuppressive drugs, with glucocorticoids as the first-line option. Steroid-sparing and second-line drugs include methotrexate, azathioprine, mycophenolate mofetil and immunomodulators such hydroxychloroquine, with the latter being first-line therapy in cutaneous sarcoidosis. Tumour necrosis factor-alpha inhibitors (particularly adalimumab and infliximab) are used as third-line agents but are administered earlier in cases of persistent disease activity, severe organ-involvement or intolerance to conventional drugs. Treatment decisions should be based on a multidisciplinary approach, depending on organ involvement and treatment tolerability. Para-sarcoidosis manifestations, particularly fatigue, should also be carefully addressed, where the patient could also be enrolled in multidimensional rehabilitation programmes. With various organ involvement and different phenotypes, larger studies including real-world data from registries are necessary to evaluate different sarcoidosis endotypes and preferential treatment pathways.

Novel Multidisciplinary Salivary Gland Society (MSGS) Questionnaire: An International Consensus.

OBJECTIVES: First, establishment and validation of a novel questionnaire documenting the burden of xerostomia and sialadenitis symptoms, including quality of life. Second, to compare two versions regarding the answering scale (proposed developed answers Q3 vs. 0-10 visual analogue scale Q10) of our newly developed questionnaire, in order to evaluate their comprehension by patients and their reproducibility in time. STUDY DESIGN: The study is a systematic review regarding the evaluation of the existing questionnaire and a cohort study regarding the validation of our new MSGS questionnaire. MATERIALS AND METHODS: A Multidisciplinary Salivary Gland Society (MSGS) questionnaire consisting of 20 questions and two scoring systems was developed to quantify symptoms of dry mouth and sialadenitis. Validation of the questionnaire was carried out on 199 patients with salivary pathologies (digestive, nasal, or age-related xerostomia, post radiation therapy, post radioiodine therapy, Sjögren's syndrome, IgG4 disease, recurrent juvenile parotitis, stones, and strictures) and a control group of 66 healthy volunteers. The coherence of the questionnaire's items, its reliability to distinguish patients from healthy volunteers, its comparison with unstimulated sialometry, and the time to fill both versions were assessed. RESULTS: The novel MSGS questionnaire showed good internal coherence of the items, indicating its pertinence: the scale reliability coefficients amounted to a Cronbach's alpha of 0.92 for Q10 and 0.90 for Q3. The time to complete Q3 and Q10 amounted, respectively, to 5.23 min (±2.3 min) and 5.65 min (±2.64 min) for patients and to 3.94 min (±3.94 min) and 3.75 min (±2.11 min) for healthy volunteers. The difference between Q3 and Q10 was not significant. CONCLUSION: We present a novel self-administered questionnaire quantifying xerostomia and non-tumoral salivary gland pathologies. We recommend the use of the Q10 version, as its scale type is well known in the literature and it translation for international use will be more accurate. Laryngoscope, 132:322-331, 2022.

The RAI-6 Questionnaire: A New Screening Questionnaire to Monitor Complications of Radioiodine Treatment.

Objective: The aim of this study is to develop a simple and efficient screening questionnaire to be able to routinely monitor potential radioiodine therapy-induced complications. Materials and Methods: A new radioiodine 6 (RAI-6) questionnaire containing six questions adressing salivary, ocular, and nasal symptoms as well as quality of life was developed. Validation of the RAI-6 questionnaire was assessed with a group of fifty-four patients diagnosed with differentiated thyroid carcinoma treated post-operatively with radioiodine therapy, and in a group of fifty healthy volunteers. The patient's group was subdivided into subgroups according to the radioiodine dose received: 23 patients received less or 30 mCi, 28 patients received 100 mCi, and three patients received between 200 and 300 mCi. We asked the patients to complete the RAI-6 questionnaire in a retrospective manner, regarding their situation before radioiodine therapy and regarding their actual symptoms after radioiodine therapy. The time needed to complete the RAI-6 was also assessed both in patients and in healthy volunteers. Results: The mean post radioiodine treatment RAI-6 score were significantly higher than the mean pre radioiodine RAI-6 scores (p < 0.001) and the scores of healthy participants (p < 0.001). The mean total RAI-6 scores increased significantly with increasing radioiodine dose. A total mean RAI-6 score of each question was also analysed and revealed that ocular and nasal discomfort as well as quality of life were the items which affected the patients most after radioiodine treatment. The mean time to fill the RAI-6 questionnaire was 2 min for patients and 49 s for healthy volunteers. Conclusion: The RAI-6 represents a new questionnaire which is easy and quick to complete. This simple screening tool can be recommended for general clinical practise and further epidemiological research.

Prevalence of large vessel vasculitis in ANCA-associated vasculitis: a retrospective cohort study.

ANCA-associated vasculitis (AAV) in general involves small blood vessels and includes granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA). Although reported in a few studies, the prevalence of large vessel vasculitis (LVV) in patients with AAV remains to be further explored. The goal of the present study was to assess the prevalence of LVV in a cohort of patients with AAV and to characterize this population. We conducted a ten-year retrospective study of a single-center cohort of AAV, including 101 patients with GPA (n = 58), EGPA (n = 28), MPA (n = 15), and compared the groups with or without associated LVV. LVV was diagnosed in five patients, two with aortitis and three with temporal arteritis, corresponding to a total prevalence of 5.0% [95% CI 1.6-11.2%]. This value was significantly higher than the estimated prevalence of LVV in the normal Swiss population (OR 234.9 95% CI 91.18-605.2, p < 0.001). All five patients had GPA, whereas no cases with EGPA or MPA were identified. Anti-PR3 antibodies were detected in four out of five patients, anti-MPO in one patient. Since LVV can occur in a significant proportion of patients with GPA, evaluation for LVV may be considered systematically in the diagnostic workup of AAV.

[Small fiber neuropathy in systemic autoimmune diseases]. / Neuropathie des petites fibres dans les maladies autoimmunes systémiques.

Small fiber neuropathy (SFN) causes damage to small-calibre nerve fibers (unmyelinated C fibers and myelinated A-delta fibers). The symptoms of SFN usually are sensitive including paresthesia, dysesthesia or burning pain, and protopathic deficits, sometimes associated with dysautonomia. The causes of SFN can be classified in six main groups: idiopathic, toxic, metabolic, immunological, infectious and hereditary. In this article, we present the diagnostic approach to SFN, the most common autoimmune aetiologies, as well as elements of their therapeutic management.

La neuropathie des petites fibres (NPF) implique une atteinte des fibres nerveuses de petit calibre : les fibres C non myélinisées et les fibres A-delta myélinisées. Elle se manifeste principalement par des troubles sensitifs : paresthésies, dysesthésies ou douleurs neuropathiques (brûlures) et déficits protopathiques, associés à des symptômes dysautonomiques. Les étiologies possibles des NPF sont variées : idiopathiques, toxiques, métaboliques, immunologiques, infectieuses et héréditaires. Nous présentons dans cet article la démarche diagnostique des NPF, les étiologies autoimmunes les plus fréquemment associées aux NPF, ainsi que des éléments de prise en charge thérapeutique.

Three cases of BRAF mutation negative Erdheim-Chester disease with a challenging distinction from IgG4-related disease.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare non-Langerhans histiocytosis with slow progression over the years that is particularly difficult to diagnose. CASES: Here we report three cases of ECD without BRAF mutation presenting with a renal mass, hairy kidney appearance, and a rather benign course, for which the diagnosis of ECD was delayed, characterized by multiple investigations and unsuccessful treatments attempts. In two cases the distinction from IgG4-related disease required multiple investigations and reevaluation of the clinical, radiological, histological, and immunological characteristics. CONCLUSION: A correct diagnosis of ECD may take several years and often requires revisiting previous hypotheses. Reassessment of histological slides and more modern complementary exams such as PET-CT or BRAF and MAPK-ERK mutation analysis can help to confirm the diagnosis of ECD and to select effective therapy.

Comparison of Clinical Characteristics and Magnetic Resonance Imaging of Salivary Glands With Magnetic Resonance Sialography in Sjögren's Syndrome.

OBJECTIVES/HYPOTHESIS: To compare the results of magnetic resonance imaging with magnetic resonance sialography (MRSIAL) and the clinical and laboratory characteristics in a well-characterized cohort of patients with primary or secondary Sjögren's syndrome (SS) meeting the American-European Consensus Group criteria. STUDY DESIGN: Retrospective, observational, monocentric study. METHODS: Thirty-six patients (81% female, mean age = 48 ± 35 years) with primary or secondary SS who underwent MRSIAL were included in the study. RESULTS: MRSIAL revealed characteristic radiological signs in the parotid, sublingual, and submandibular salivary glands in 35/36 patients (97%). Patients presenting with anti-Sjögren's syndrome-related antigen A (SSA) autoantibodies showed more often fatty infiltration, a "pepper-and-salt" appearance, ductal stenosis, and/or ductal dilation of the parotid gland (88%, 88%, and 72% respectively) than patients negative for anti-SSA (12%, 4%, and 28% respectively). MRSIAL demonstrated signs characteristic of SS in all 11 patients with negative minor salivary gland biopsy. For 15 patients undergoing ultrasound examination only, 11 (73%) had SS findings, but all 15 had SS findings on MRSIAL. Two cases of parotid lymphoma were detected by MRSIAL (6%). CONCLUSIONS: MRSIAL is a reliable technique to detect glandular anomalies in patients with SS, and seems to provide a valuable aid in the diagnosis of SS. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E83-E89, 2021.

[ENT and head and neck manifestations of the IgG4-related disease]. / Atteintes de la sphère ORL et cervicofaciale dans la maladie à IgG4.

IgG4-related disease is a rare multi-organic inflammatory disease that frequently involves the ENT and head and neck areas. In these cases, salivary gland and lacrimal gland involvement is very common and includes enlargement, infiltration, and formation of pseudotumours. Diagnosis of IgG4 related disease remains a challenge and relies on several clinical, serological, radiological and histopathological criteria to differentiate from other diseases with similar clinical presentation. Histology reveals IgG4 positive lymphoplasmocytic infiltrates, storiform fibrosis and obliterative phlebitis. Glucocorticoids are the first line of treatment and can be combined with other immunosuppressants. The prognosis is favorable if treatment is initiated early. Recurrences are common. Delay in diagnosis can have severe multi-organic consequences.

Rare et encore peu connue, la maladie à immunoglobuline G4 (IgG4) est multiorganique et se manifeste fréquemment dans la sphère oto-rhino-laryngologique et cervico-faciale. Dans ces cas, les glandes lacrymales et salivaires sont les plus fréquemment touchées, présentant des tuméfactions, infiltrations et pseudotumeurs. Le diagnostic reste un défi ; il repose sur des critères cliniques, sérologiques, radiologiques et histopathologies qui visent à la distinguer des nombreuses maladies de présentations cliniques similaires. À l'histologie, on retrouve un infiltrat lymphoplasmocytaire riche en plasmocytes IgG4+, une fibrose storiforme et des phlébites oblitérantes. Les glucocorticoïdes sont la première ligne de traitement et peuvent être associés à d'autres immunosuppresseurs. Le pronostic est favorable si le traitement est initié rapidement. Les récidives sont courantes. Un retard diagnostique peut avoir des conséquences multiorganiques sévères.

Anti-CD20 rituximab IgG1, IgG3, and IgG4 but not IgG2 subclass trigger Ca2+ mobilization and cytotoxicity in human NK cells.

NK cell-mediated Ab-dependent cellular cytotoxicity (ADCC) is increasingly recognized to play an important role in cancer immunotherapy, transplant rejection, and autoimmunity. However, several aspects of the molecular interactions of IgG subclasses with the Fc-gamma receptor IIIA (FcγRIIIA)/CD16a expressed on NK cells remain unknown. The aim of the current study was to further analyze the role of IgG subclasses and FCGR3A V158F single nucleotide polymorphism (SNP) on Ca2+ signaling and NK cell-mediated ADCC against Daudi target cells in vitro. NK cells were isolated from donors with different FCGR3A SNP. The affinity of rituximab IgG subclasses to CD20 expressed on Daudi cells showed similar dissociation constant as tested by flow cytometry. Induction of Ca2+ signaling, degranulation, intracellular cytokine production, and ADCC was demonstrated for IgG1 and IgG3, to a lesser degree also for IgG4, but not for IgG2. Compared to NK cells carrying the low-affinity (FF) variant for the FCGR3A V158F SNP, binding of IgG1 and IgG3 to NK cells carrying the high-affinity (VV) and VF SNP variants was two- to threefold higher. Variations of FCGR3A SNP among the eight tested donors (1 VV, 3FF, and 4VF) revealed no significant differences of Ca2+ signaling and degranulation; however, ADCC was somewhat weaker in donors with the low-affinity FF variation. In conclusion, this is the first study correlating Ca2+ signaling and NK cell-mediated ADCC triggered by the four IgG subclasses with the FCGR3A V158F SNP. Our findings indicate important differences in the interactions of IgG subclasses with FcγRIIIA/CD16a but no major impact of FCGR3A SNP and may therefore help to better correlate the functional properties of particular engineered therapeutic antibodies in vitro with individual differences of their clinical efficacy.

[Myocarditis in 2020]. / La myocardite en 2020.

Myocarditis is an inflammatory disease of the myocardium caused by various etiologies with a dominance of viral infections and potential post-infectious autoimmunity. The clinical presentation ranges from chest pain to severe complications including cardiogenic shock, ventricular arrhythmias, and progression to dilated cardiomyopathy. The diagnostic approach is challenging and includes several investigations, such as an ECG, an echocardiography, troponin testing and the exclusion of coronary artery disease. Although endomyocardial biopsy remains the gold standard, cardiovascular magnetic resonance is now the most valuable tool to accurately characterize myocardial tissue inflammation. The management is mainly symptomatic and consists in early detection and treatment of complications including heart failure and arrhythmias.

La myocardite est une inflammation du muscle cardiaque dont les étiologies sont variées, avec une prédominance d'atteinte infectieuse virale et d'une autoimmunité postinfectieuse. Le spectre clinique varie de la douleur thoracique aux complications comme le choc cardiogénique, les arythmies malignes et la cardiomyopathie dilatée. La démarche diagnostique est un défi pour le clinicien et comprend un ECG, un bilan biologique, une échocardiographie, ainsi que l'exclusion d'une maladie coronarienne. La biopsie myocardique reste le gold standard, mais l'imagerie par résonance magnétique est actuellement l'examen de référence pour caractériser avec précision le tissu myocardique inflammatoire. La prise en charge est essentiellement symptomatique et consiste à dépister et traiter précocement les complications comme l'insuffisance cardiaque et les arythmies.

Prolongation of rat-to-mouse islets xenograft survival by co-transplantation of autologous IL-10 differentiated murine tolerogenic dendritic cells.

BACKGROUND: Tolerogenic dendritic cells (DCs) represent a promising approach to promote transplantation tolerance. In this study, the potential of autologous bone marrow (BM)-derived murine DC to protect rat-to-mouse islets xenografts was analyzed. METHODS: Tolerogenic DCs were generated by differentiating BM cells in the presence of granulocyte-macrophage colony-stimulating factor and interleukin 10 (IL-10, IL-10 DC). The phenotype of IL-10 DC was characterized in vitro by expression of costimulatory/inhibitory molecules (flow cytometry) and cytokines (Luminex and ELISA), their function by phagocytosis and T-cell stimulation assays. To study transplant tolerance in vivo, rat islets were transplanted alone or in combination with autologous murine IL-10 DC under the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice. Xenograft survival was evaluated by monitoring glycemia, cellular infiltration of xenografts by microscopy and flow cytometry 10 days post-transplantation. RESULTS: Compared with control DC, IL-10 DC exhibited lower levels of major histocompatibility complex class II, costimulatory molecules (CD40, CD86, CD205), lower production of pro-inflammatory cytokines (IL-12p70, TNF, IL-6), and higher production of IL-10. Phagocytosis of xenogeneic rat splenocytes was not impaired in IL-10 DC, whereas stimulation of T-cell proliferation was reduced in the presence of IL-10 DC. Xenograft survival of rat islets in diabetic mice co-transplanted with autologous murine IL-10 DC was significantly prolonged from 12 to 21 days, without additional immunosuppressive treatment. Overall, infiltration of xenografts by T cells and myeloid cells was not different in IL-10 DC recipient mice, but enriched for CD8+ T cells and myeloid cells with suppressor-associated phenotype. CONCLUSIONS: Autologous IL-10-differentiated DC with tolerogenic properties prolong rat-to-mouse islets xenograft survival, potentially by locally inducing immune regulatory cells, indicating their potential for regulatory immune cell therapy in xenotransplantation.