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.

[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.

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.

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.

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.

Efficacy of Omalizumab in Mastocytosis: Allusive Indication Obtained from a Prospective, Double-Blind, Multicenter Study (XOLMA Study).

BACKGROUND: Patients with mastocytosis often suffer from a variety of symptoms caused by mast cell mediators where treatments remain difficult, showing various success rates. Omalizumab, a monoclonal anti-IgE antibody, has been postulated to have a positive impact on mastocytosis-associated symptoms such as flush, vertigo, gastrointestinal problems, or anaphylaxis. OBJECTIVE: To investigate the efficacy and safety of omalizumab in systemic mastocytosis. METHODS: Patients with histologically proven mastocytosis were investigated in a multicenter prospective double-blind placebo-controlled trial to receive either omalizumab or placebo, dosed according to IgE and body weight. The primary endpoint was change in the AFIRMM activity score after 6 months of treatment. Different laboratory parameters were analyzed. RESULTS: Sixteen patients were analyzed: 7 to omalizumab and 9 to placebo (mean age 47.7 ± 13.8 vs. 45.4 ± 8.8 years; 66.6 vs. 85.7% were female; mean disease duration 10.0 ± 5.1 vs. 4.5 ± 2.9 years, respectively). After 6 months the median AFIRMM score decreased 50% from 52.0 to 26.0 in the omalizumab group versus 104.0-102.0 in the placebo group (p = 0.286); however, the difference was not significant (p = 0.941). Secondary endpoints, including the number of allergic reactions, changes in major complaints, wheal-and-flare reaction due to mechanical irritation (Darier's sign), and frequency of the use of mastocytosis-specific drugs improved in the omalizumab group, but not significantly. Adverse events like urticaria, bronchospasm, and anaphylactic shock showed no significant difference between the groups. No severe adverse events occurred. FcεRI (Fc-epsilon receptor) expression on basophils decreased after receiving omalizumab versus placebo. CONCLUSION: Omalizumab was safe and showed a tendency to improve mastocytosis-related symptoms, in particular diarrhea, dizziness, flush, and anaphylactic reactions, including the AFIRMM score and secondary endpoints; however, the difference was not significant. Due to the small study size and difference at baseline between the study groups, further studies are required to confirm our findings.

Thyroid Rosai-Dorfman disease with infiltration of IgG4-bearing plasma cells associated with multiple small pulmonary cysts.

BACKGROUND: Rosai-Dorfman disease (RDD) is a rare histiocytosis which involves principally lymph nodes. Thyroid involvement in RDD is a very rare situation, and lung involvement is even rarer. CASE PRESENTATION: We report the case of a 46-year-old woman presenting a painless mass in the right side of the neck and subacute dyspnoea. Computerised tomography (CT) scans of the neck and thorax showed a large thyroid mass causing tracheal stenosis and multiple cystic lesions in both lungs. Subtotal thyroidectomy with a tracheal segment resection and histological analysis confirmed the diagnosis of nodal and extranodal (thyroid, tracheal and probably lung) Rosai-Dorfman disease (RDD) with the presence of increased numbers of IgG4-bearing plasma cells. Clinical, functional and radiological follow up 4 years after surgery without medical treatment did not show any disease progression. CONCLUSIONS: This case report indicates a benign course of nodal RDD with thyroid and tracheal infiltration following surgical resection, association of typical histological signs of RDD (emperipolesis) with IgG4-related disease features, and that lung cysts might be a manifestation of RDD.

CLIPPERS and its mimics: evaluation of new criteria for the diagnosis of CLIPPERS.

OBJECTIVE: To evaluate the accuracy of the recently proposed diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). METHODS: We enrolled 42 patients with hindbrain punctate and/or linear enhancements (<3 mm in diameter) and tested the CLIPPERS criteria. RESULTS: After a median follow-up of 50 months (IQR 25-82), 13 out of 42 patients were CLIPPERS-mimics: systemic and central nervous system lymphomas (n=7), primary central nervous system angiitis (n=4) and autoimmune gliopathies (n=2). The sensitivity and specificity of the CLIPPERS criteria were 93% and 69%, respectively. Nodular enhancement ( ≥ 3 mm in diameter), considered as a red flag in CLIPPERS criteria, was present in 4 out of 13 CLIPPERS-mimics but also in 2 out of 29 patients with CLIPPERS, explaining the lack of sensitivity. Four out of 13 CLIPPERS-mimics who initially met the CLIPPERS criteria displayed red flags at the second attack with a median time of 5.5 months (min 3, max 18), explaining the lack of specificity. One of these four patients had antimyelin oligodendrocyte glycoprotein antibodies, and the three remaining patients relapsed despite a daily dose of prednisone/prednisolone ≥ 30 mg and a biopsy targeting atypical enhancing lesions revealed a lymphoma. CONCLUSIONS: Our study highlights that (1) nodular enhancement should be considered more as an unusual finding than a red flag excluding the diagnosis of CLIPPERS; (2) red flags may occur up to 18 months after disease onset; (3) as opposed to CLIPPERS-mimics, no relapse occurs when the daily dose of prednisone/prednisolone is ≥ 30 mg; and (4) brain biopsy should target an atypical enhancing lesion when non-invasive investigations remain inconclusive.

Small-Molecule Immunosuppressive Drugs and Therapeutic Immunoglobulins Differentially Inhibit NK Cell Effector Functions in vitro.

Small-molecule immunosuppressive drugs (ISD) prevent graft rejection mainly by inhibiting T lymphocytes. Therapeutic immunoglobulins (IVIg) are used for substitution, antibody-mediated rejection (AbMR) and HLA-sensitized recipients by targeting distinct cell types. Since the effect of ISD and IVIg on natural killer (NK) cells remains somewhat controversial in the current literature, the aim of this comparative study was to investigate healthy donor's human NK cell functions after exposure to ISD and IVIg, and to comprehensively review the current literature. NK cells were incubated overnight with IL2/IL12 and different doses and combinations of ISD and IVIg. Proliferation was evaluated by 3[H]-thymidine incorporation; phenotype, degranulation and interferon gamma (IFNγ) production by flow cytometry and ELISA; direct NK cytotoxicity by standard 51[Cr]-release and non-radioactive DELFIA assays using K562 as stimulator and target cells; porcine endothelial cells coated with human anti-pig antibodies were used as targets in antibody-dependent cellular cytotoxicity (ADCC) assays. We found that CD69, CD25, CD54, and NKG2D were downregulated by ISD. Proliferation was inhibited by methylprednisolone (MePRD), mycophenolic acid (MPA), and everolimus (EVE). MePRD and MPA reduced degranulation, MPA only of CD56bright NK cells. MePRD and IVIg inhibited direct cytotoxicity and ADCC. Combinations of ISD demonstrated cumulative inhibitory effects. IFNγ production was inhibited by MePRD and ISD combinations, but not by IVIg. In conclusion, IVIg, ISD and combinations thereof differentially inhibit NK cell functions. The most potent drug with an effect on all NK functions was MePRD. The fact that MePRD and IVIg significantly block NK cytotoxicity, especially ADCC, has major implications for AbMR as well as therapeutic strategies targeting cancer and immune cells with monoclonal antibodies.

Release of pig leukocytes and reduced human NK cell recruitment during ex vivo perfusion of HLA-E/human CD46 double-transgenic pig limbs with human blood.

BACKGROUND: In pig-to-human xenotransplantation, interactions between human natural killer (NK) cells and porcine endothelial cells (pEC) are characterized by recruitment and cytotoxicity. Protection from xenogeneic NK cytotoxicity can be achieved in vitro by the expression of the non-classical human leukocyte antigen-E (HLA-E) on pEC. Thus, the aim of this study was to analyze NK cell responses to vascularized xenografts using an ex vivo perfusion system of pig limbs with human blood. METHODS: Six pig forelimbs per group, respectively, stemming from either wild-type (wt) or HLA-E/hCD46 double-transgenic (tg) animals, were perfused ex vivo with heparinized human blood for 12 hours. Blood samples were collected at defined time intervals, cell numbers counted, and peripheral blood mononuclear cells analyzed for phenotype by flow cytometry. Muscle biopsies were analyzed for NK cell infiltration. In vitro NK cytotoxicity assays were performed using pEC derived from wt and tg animals as target cells. RESULTS: Ex vivo, a strong reduction in circulating human CD45 leukocytes was observed after 60 minutes of xenoperfusion in both wt and tg limb groups. NK cell numbers dropped significantly. Within the first 10 minutes, the decrease in NK cells was more significant in the wt limb perfusions as compared to tg limbs. Immunohistology of biopsies taken after 12 hours showed less NK cell tissue infiltration in the tg limbs. In vitro, NK cytotoxicity against hCD46 single tg pEC and wt pEC was similar, while lysis of double tg HLA-E/hCD46 pEC was significantly reduced. Finally, circulating cells of pig origin were observed during the ex vivo xenoperfusions. These cells expressed phenotypes mainly of monocytes, B and T lymphocytes, NK cells, as well as some activated endothelial cells. CONCLUSIONS: Ex vivo perfusion of pig forelimbs using whole human blood represents a powerful tool to study humoral and early cell-mediated rejection mechanisms of vascularized pig-to-human xenotransplantation, although there are several limitations of the model. Here, we show that (i) transgenic expression of HLA-E/hCD46 in pig limbs provides partial protection from human NK cell-mediated xeno responses and (ii) the emergence of a pig cell population during xenoperfusions with implications for the immunogenicity of xenografts.

Spirometry and provocation tests for vocal fold dysfunction diagnosis: a retrospective case series.

AIMS: Vocal cord dysfunction (VCD) is characterised by paradoxical inspiratory laryngeal motion and is often misdiagnosed as asthma. Definitive diagnosis of VCD is difficult, because laryngoscopy is positive only during symptomatic episodes or upon provocation with exercise or inhaled irritants. The aims of the study were to better characterise the symptomatology of patients with VCD and to evaluate the potential usefulness of less-invasive diagnostic tools, namely provocation tests and spirometry. METHODS: Retrospective case series of 84 patients with a typical clinical history of VCD, in whom at least one of the three following diagnostic tests were performed: laryngoscopy, provocation testing, or spirometry. RESULTS: The mean age of the patients was 51 years and 74% were women. The principal comorbidities were rhinosinusitis (60%), gastro-oesophageal reflux disease (56%) and atopy (54%). Diagnosis of VCD was confirmed in 73/84 cases (87%), by laryngoscopy (8%), spirometry (84%) and/or provocation tests (68%). CONCLUSIONS: VCD remains an underdiagnosed condition. A negative finding on laryngoscopy can lead to false negative diagnosis if it is done when the patient is asymptomatic. Here we show that a clinical suspicion of VCD, evoked by medical history, can be confirmed in many cases by less invasive diagnostic tools such as spirometry and provocation tests. Future well-conducted prospective case-control studies are needed to draw firmer conclusions and to improve the diagnostic accuracy of this condition.  .

TAFRO Syndrome in Caucasians: A Case Report and Review of the Literature.

BACKGROUND: TAFRO syndrome has been reported in Japan among human herpesvirus 8 (HHV-8)-negative/idiopathic multicentric Castleman's disease (iMCD) patients. To date, the majority of iMCD patients with TAFRO syndrome originate from Japan. CASE PRESENTATION: Herein, we report a 67-year-old HIV/HHV-8-negative Caucasian iMCD patient diagnosed with TAFRO. He presented with marked systemic inflammation, bicytopenia, terminal renal insufficiency, diffuse lymphadenopathies, and anasarca. Lymph node and bone marrow biopsies revealed atrophic germinal centers variably hyalinized and megakaryocytic hyperplasia with mild myelofibrosis. Several other biopsies performed in kidneys, liver, gastrointestinal tract, prostate, and lungs revealed unspecific chronic inflammation. The patient had a complete response to corticosteroids, tocilizumab, and rituximab. He relapsed twice following discontinuation of rituximab. When reviewing the literature, we found seven other Caucasian cases with TAFRO syndrome. There were no significant differences with those described by the Japanese cohort except for the higher frequency of kidney failure and auto-antibodies in Western patients. CONCLUSION: This case illustrates that patients with TAFRO syndrome can develop non-specific inflammation in several tissue sites. Furthermore, this case and our review of the literature demonstrate that TAFRO syndrome can affect Caucasian and Japanese patients highlighting the importance of evaluating for this syndrome independently of ethnic background.

Multipotent mesenchymal stromal cells enhance insulin secretion from human islets via N-cadherin interaction and prolong function of transplanted encapsulated islets in mice.

BACKGROUND: Multipotent mesenchymal stromal cells (MSC) enhance viability and function of islets of Langerhans. We aimed to examine the interactions between human MSC and human islets of Langerhans that influence the function of islets. METHODS: Human MSC and human islets (or pseudoislets, obtained after digestion and reaggregation of islet cells) were cocultured with or without cellular contact and glucose-stimulated insulin secretion assays were performed to assess cell function. The expression of several adhesion molecules, notably ICAM-1 and N-cadherin on islets and MSC, was investigated by qPCR. The role of N-cadherin was analyzed by adding an anti-N-cadherin antibody in islets cultured with or without MSC for 24 h followed by insulin measurements in static incubation assays. Islets and MSC were coencapsulated in new hydrogel microspheres composed of calcium alginate and covalently crosslinked polyethylene glycol. Encapsulated cells were transplanted intraperitoneally in streptozotocin-induced diabetic mice and glycemia was monitored. Islet function was evaluated by the intraperitoneal glucose tolerance test. RESULTS: In vitro, free islets and pseudoislets cocultured in contact with MSC showed a significantly increased insulin secretion when compared to islets or pseudoislets cultured alone or cocultured without cell-to-cell contact with MSC (p < 0.05). The expression of ICAM-1 and N-cadherin was present on islets and MSC. Blocking N-cadherin prevented the enhanced insulin secretion by islets cultured in contact with MSC whereas it did not affect insulin secretion by islets cultured alone. Upon transplantation in diabetic mice, islets microencapsulated together with MSC showed significantly prolonged normoglycemia when compared with islets alone (median 69 and 39 days, respectively, p < 0.01). The intraperitoneal glucose tolerance test revealed an improved glycemic response in mice treated with islets microencapsulated together with MSC compared to mice transplanted with islets alone (p < 0.001). CONCLUSIONS: MSC improve survival and function of islets of Langerhans by cell-to-cell contact mediated by the adhesion molecule N-cadherin.

[Erdheim-Chester disease : a differential diagnosis of retroperitoneal fibrosis]. / La maladie d'Erdheim Chester : un diagnostic différentiel de fibrose rétropéritonéale.

Erdheim-Chester disease is a rare multisystemic non-Langerhans histiocytosis with about 500 reported cases. Typical features include retroperitoneal and perirenal fibrosis (hairy kidney), periaortitis with a coated aorta, osteosclerosis of the lower limbs, and sometimes exophthalmia or diabetes insipidus. Histology is the cornerstone for diagnosis showing an infiltrate with foamy histiocytes and occasional multinucleated giant cells (Touton cells). There is no standard treatment regimen, current options include corticosteroids, interferon alpha, systemic chemotherapy, and radiation therapy ; however, a better understanding of the pathophysiological mechanisms has allowed the emergence of novel targeted treatments such as vemurafenib, imatinib, and anakinra.

La maladie d'Erdheim-Chester, une histiocytose non langerhansienne, caractérisée par une atteinte multisystémique, est rare avec environ 500 cas décrits. Les manifestations typiques sont une fibrose rétropéritonéale et périrénale (reins chevelus), une périaortite avec engainement circulaire (manchon aortique), une ostéosclérose des membres inférieurs et parfois une exophtalmie ou un diabète insipide. L'histologie montre un infiltrat d'histiocytes spumeux et parfois de cellules géantes polynucléées (cellules de Touton). Il n'y a pas de traitement standard et les options actuelles comprennent les corticoïdes, l'interféron alpha, la chimiothérapie et la radiothérapie ; cependant, une meilleure compréhension des phénomènes physiopathologiques a permis l'émergence de traitements ciblés comme l'anakinra, l'imatinib et le vémurafénib.

[Segmental arterial mediolysis : a differential diagnosis of vasculitis]. / Médiolyse artérielle segmentaire : un diagnostic différentiel de vasculite.

Segmental arterial mediolysis (SAM) is a rare non-atherosclerotic, non-inflammatory disease of unknown aetiology mostly affecting medium-sized arteries of the splanchnic circulation. Histologically, SAM is characterized by vacuolization and lysis of the arterial media leading to dissection, stenosis/occlusion or aneurysms. Symptoms vary from unspecific abdominal pain to hemorrhagic shock due to vessel rupture. The clinical and radiological presentation can mimic vasculitis, fibromuscular dysplasia or collagen vascular diseases. SAM is often self-limited and may be managed conservatively with adequate blood pressure control in the majority of cases. However, if arterial dissections or aneurysmal ruptures are present, endovascular or surgical treatment should be considered urgently.

La médiolyse artérielle segmentaire (SAM) est une maladie rare, non athérosclérotique et non inflammatoire, d'étiologie inconnue qui atteint les artères de calibre moyen, principalement de la circulation splanchnique. Histologiquement, la SAM est caractérisée par une vacuolisation et une lyse au niveau de la média qui peut aboutir à une dissection, à une sténo-occlusion, ou à un anévrisme. Les symptômes varient, allant d'une douleur abdominale jusqu'au choc hémorragique. La présentation clinique et radiologique peut mimer une vasculite, une dysplasie fibromusculaire ou les maladies héréditaires du collagène. La SAM est souvent spontanément résolutive, et peut être traitée conservativement avec contrôle de la tension artérielle. Une dissection artérielle ou une rupture d'anévrisme nécessitent une prise en charge endovasculaire ou chirurgicale en urgence.