Involvement of the JAK-STAT pathway in the molecular landscape of tyrosine kinase fusion-negative hypereosinophilic syndromes: A nationwide CEREO study.

We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion-negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HEUS used as controls; p < .001). Thirty-five patients (54%) had at least one mutation involving the JAK-STAT pathway, including STAT5B (n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Other previously undescribed somatic mutations were also found in JAK2, JAK1, STAT5B, and STAT5A, including three patients who shared the same STAT5A V707fs mutation and features consistent with primary polycythemia. Nearly all JAK-STAT mutations were preceded by (or associated with) myelodysplasia-related gene mutations, especially in RNA-splicing genes or chromatin modifiers. In multivariate analysis, neurologic involvement (hazard ratio [HR] 4.95 [1.87-13.13]; p = .001), anemia (HR 5.50 [2.24-13.49]; p < .001), and the presence of a high-risk mutation (as per the molecular international prognosis scoring system: HR 6.87 [2.39-19.72]; p < .001) were independently associated with impaired overall survival. While corticosteroids were ineffective in all treated JAK-STAT-mutated patients, ruxolitinib showed positive hematological responses including in STAT5A-mutated patients. These findings emphasize the usefulness of NGS for the workup of tyrosine kinase fusion-negative HE/HES patients and support the use of JAK inhibitors in this setting. Updated classifications could consider patients with JAK-STAT mutations and eosinophilia as a new "gene mutated-entity" that could be differentiated from CEL, NOS, and idiopathic HES.

Giant cell arteritis associated with scalp, tongue or lip necrosis: A French multicenter case control study.

BACKGROUND: Scalp, tongue and/or lip necrosis are rare complications of GCA. OBJECTIVES: To describe characteristics and outcome of patients with giant cell arteritis (GCA) -related scalp, tongue and/or lip necrosis. METHODS: A retrospective nationwide multicenter study included 20 GCA patients with scalp, tongue, and/or lip necrosis diagnosed between 1998 and 2021 and 80 GCA control patients matched for age, sex and management period. Logistic regression analyses were conducted to identify baseline characteristics associated with scalp, tongue and/or lip necrosis. RESULTS: Compared to controls, patients with scalp, tongue and/or lip necrosis showed significantly more cranial manifestations (headache, p=0.045; scalp tenderness, p=0.006; jaw claudication, p=0.02). No differences were observed between both groups regarding the occurrence of visual symptoms or large vessel involvement. At diagnosis, GCA patients with necrosis more likely received IV methylprednisolone infusions and higher doses of oral prednisone. There were no differences regarding vascular complications during follow up. Compared to controls, survival was decreased in GCA patients with necrosis (p=0.003). In a multivariable logistic regression model, scalp tenderness [odds ratio (OR) 4.81(95 % CI: 1.57, 14.79), p = 0.006] and cognitive disorder [OR 6.42 (95 % CI: 1.01, 40.60), p=0.048] were identified as factors associated to scalp, tongue, and/or lip necrosis. CONCLUSION: Our results suggest that scalp, tongue, and/or lip necrosis is associated to higher mortality in GCA patients. Scalp tenderness and cognitive disorder were significant factors associated to this very rare complication of GCA.

[Influenza A: H1N1 post-viral membranoproliferative glomerulonephritis occurring in aggressive systemic mastocytosis: Case report and literature review]. / Glomérulonéphrite membrano-proliférative post-grippale chez un patient atteint de mastocytose systémique agressive : observation commentée et revue de la littérature.

Systemic mastocytosis is characterised by tissular infiltration and a cytokine storm due to mast cells excessive proliferation and activation. Herein, we report an extraordinary case of AH1N1 influenza post-viral glomerulonephritis occurring in the course of an aggressive systemic mastocytosis with an associated hematological neoplasm. Because of a multisystemic involvement including the liver and lungs, we treated mastocytosis with midostaurin (multiple inhibitor of kinase protein), anti H1/H2 blockers and dexamethasone as first line treatment. One month later and despite vaccination, he developed a severe acute lung injury with respiratory distress due to AH1N1 influenza in association with the nephrotic syndrome. Kidney biopsy disclosed a membranoproliferative glomerulonephritis that was successfully treated with mycophenolate mofetil. Only a few cases of influenza post-viral or post-vaccination glomerulonephritis are documented in the medical literature. This is an exceptional association of uncommon conditions occurring within only a few months in the same patient.

Glial Fibrillary Acidic Protein Autoimmunity: A French Cohort Study.

BACKGROUND AND OBJECTIVES: To report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies. METHODS: We retrospectively included all patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα since 2017 from 2 French referral centers. RESULTS: We identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score ≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies. DISCUSSION: GFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome.

Cardiac involvement in adult-onset Still's disease: Manifestations, treatments and outcomes in a retrospective study of 28 patients.

OBJECTIVE: Adult-onset Still's disease (AOSD) is a rare inflammatory disease that may be life-threatening if complicated by cardiac problems. We performed a retrospective multicenter study to describe the manifestations, treatments and outcomes of cardiac involvement in AOSD. METHODS: We reviewed the medical databases of eight centers. All AOSD patients identified as fulfilling Yamagushi's or Fautrel's criteria were included in the study. Cardiac involvement, clinical manifestations, laboratory features, the course of the disease and treatments were evaluated. RESULTS: We included 96 AOSD patients in this study: 28 (29%) had documented cardiac involvement (AOSD + C group) and 68 (71%) had no cardiac involvement (control group). Cardiac complications were observed at diagnosis in 89% of cases. It were pericarditis (n = 17), tamponade (n = 5), myocarditis (n = 5) and non-infectious endocarditis (n = 1). Levels of leukocytes, neutrophils and C-reactive protein were significantly higher (p = 0.02, p = 0.02 and p = 0.002, respectively in the AOSD + C group than in the control group. Admission to intensive care, and the use of biotherapy were more frequent during follow-up in the AOSD + C group than the control group (p = 0.0001 and p = 0.03 respectively). Cardiac involvement was associated with refractory form in multivariate analyzed (p = 0.01). Corticosteroids were effective with or without methotrexate in 71% of patients but not in severe involvement as myocarditis or tamponade. CONCLUSION: Cardiac complications are frequent, inaugural, can be life-threatening and predictive of a refractory course in patients with AOSD. Systematic cardiac screening should be proposed at diagnosis and biotherapy early use should be considered especially in myocarditis.

Acute cardiac failure secondary to senile systemic amyloidosis.

Hereditary or senile transthyretin (TTR) cardiac amyloidosis is a rare and underestimated cause of heart failure in old patients. New diagnostic methods, particularly cardiac MRI and proteomic analysis, have been recently developed that enable both earlier identification and development of specific treatments.We report a case of cardiac amyloidosis revealed through late-onset heart failure.