Difficult-to-treat primary immune thrombocytopenia in adults: Prevalence and burden. Results from the CARMEN-France registry.

The aim of this study was to assess the prevalence and the burden of difficult-to-treat primary ITP (pITP), defined by the need for another ITP treatment after romiplostim and eltrombopag. Adult patients were selected in the prospective, real-world CARMEN-France registry up to December 2021. Out of 821 adult patients with pITP, 29 had difficult-to-treat ITP (3.5%; 95% confidence interval [CI]: 2.3%-4.8% in total; 7.6%; 95% CI: 4.9%-10.2% of patients needing ≥2nd line treatment). The 3-year cumulative incidence of bleeding, infection and thrombosis was 100%, 24.1% and 13.8% respectively. The median cumulative duration of hospital stays was 31 days (median follow-up: 30.3 months).

Cluster analysis of clinical manifestations assigns systemic lupus erythematosus-phenotype subgroups: A multicentre study on 440 patients.

OBJECTIVE: Systemic lupus erythematous (SLE) is a heterogenous disease characterised by a large panel of autoantibodies and a wide spectrum of clinical signs and symptoms that engender different outcomes. We aimed to identify distinct, homogeneous SLE patients' phenotypes. METHODS: This retrospective study enrolled SLE patients meeting the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria, enrolled in the French multicentre "APS (antiphospholipid syndrome) and SLE" Registry. Based on 29 variables selected to cover a broad range of clinical and laboratory (excluding autoantibodies) SLE manifestations, unsupervised multiple correspondence analysis followed by hierarchical ascendent-clustering analysis assigned different phenotypes. RESULTS: We included 440 patients, mostly women (94.3%). Median age at SLE diagnosis was 24 (IQR 19-32) years. Cluster analysis yielded three distinct subgroups based on cumulative clinical manifestations, not autoantibody pattern. Cluster 1 (n=91) comprised mostly Caucasian patients, with APS-associated clinical and biological manifestations, e.g., livedo, seizure, thrombocytopaenia and haemolytic anaemia. Cluster 2 (n=221), the largest, included patients with mild clinical manifestations, mainly articular, more frequently associated with Sjögren's syndrome and with less frequent autoantibody-positivity. Cluster 3 (n=128) consisted of patients with the largest panel of SLE-specific clinical manifestations (cutaneous, articular, proliferative nephritis, pleural, cardiac and haematological), the most frequent autoantibody-positivity, low complement levels, and more often of Asian and sub-Saharan African origin. CONCLUSION: This unsupervised clustering method distinguished three distinct SLE patient subgroups, highlighting SLE heterogeneity.

Human epicardial adipose tissue contains innate and adaptive lymphoid cells and a higher proportion of innate type 2 lymphoid cells compared to other adipose tissues.

IMPORTANCE: Epicardial adipose tissue (EAT) is a biologically active organ surrounding myocardium and coronary arteries that has been associated with coronary artery disease (CAD) and atrial fibrillation. Previous work has shown that EAT exhibits beige features. OBJECTIVE: Our objective was to determine whether the stromal vascular fraction of the human EAT contains innate or adaptive lymphoid cells compared to thoracic subcutaneous (thSAT), visceral abdominal (VAT) and subcutaneous abdominal (abSAT). PARTICIPANTS: New pangenomic microarray analysis was performed on previous transcriptomic dataset using significance analysis of microarray and ingenuity pathway analysis (n=41) to identify specific immune signature and its link with browning genes. EAT, thSAT, VAT and abSAT samples from explanted patients with severe cardiomyopathies and multi-organ donor patients (n=17) were used for flow cytometry (FC) immunophenotyping assay. Patients were on average 55±16 years-old; 47% had hypertension and 6% CAD. Phenotypic adaptive and innate immune profiles were performed using a TBNK panel and a specific ILC1-2-3 panel including CD127, CD117, CRTH2 (CD294) and activation markers such as CD25 and CD69. RESULTS: Transcriptomic analysis showed a significant positive correlation between the TH2 immune pathway (IL-4, IL-5, IL-13, IL-25, IL-33) and browning genes (UCP-1, PRDM16, TMEM26, CITED1, TBX1) in EAT versus thSAT (R=0.82, P<0.0001). Regarding adaptive immune cells, a preponderance of CD8T cells, a contingent of CD4T cells, and a few B cells were observed in all ATs (P<0.0001). In innate lymphoid cells (ILCs), an increase was observed in visceral ATs (i.e. EAT; VAT 35±8ILCs/g of tissue) compared to their subcutaneous counterpart (i.e. thSAT+abSAT: 8±3 ILCs/g of AT, P=0.002), with a difference in the proportion of the 3 subtypes of ILCs (ILC1>ILC3>ILC2). In addition, we observed an increase in EAT-ILC2 compared to other ATs and almost all these EAT-ILC2 expressed CD69 and/or CD25 activation markers (99.75±0.16%; P<0.0001). We also observed more NKs in EAT and VAT (1520±71 cells/g of AT) than in SATs (562±17 cells/g of AT); P=0.01. CONCLUSION: This is the first study to provide a comparison between innate and adaptive lymphoid cells in human epicardial versus abdominal or thoracic adipose tissues. Further studies are ongoing to decipher whether these cells could be involved in EAT beiging. TRIAL REGISTRATION: CODECOH No. DC-2021-4518 The French agency of biomedicine PFS21-005.

Human epicardial fat has a beige profile and contains higher type 2 innate lymphoid cells than subcutaneous fat.

OBJECTIVE: Epicardial adipose tissue (EAT) is a visceral fat that has been associated with coronary artery disease and atrial fibrillation. Previous work has revealed that EAT exhibits beige features. METHODS: First, a new pan-genomic microarray analysis was performed on previously collected paired human EAT and thoracic subcutaneous AT (thSAT) from the EPICAR study (n = 31) to decipher a specific immune signature and its link with browning genes. Then, adaptive (T and B cells) and innate lymphoid cell (ILC1, ILC2, and ILC3) immunophenotyping assay panels, including CD127, CD117, and prostaglandin D2 receptor 2, were performed on prospectively collected paired human multiorgan donors (n = 18; INTERFACE study). RESULTS: In the EPICAR study, a positive correlation between the T helper cell subtype Th2 immune pathway and browning genes was found in EAT versus thSAT (r = 0.82; p < 0.0001). In the INTERFACE study, this correlation was also observed (r = 0.31; p = 0.017), and a preponderance of CD4+T cells, CD8+T cells, and a few B cells was observed in all ATs (p < 0.0001). An increase in ILCs was observed in visceral AT (VAT) (i.e., EAT + VAT; 30 ± 5 ILCs per gram of AT) compared with subcutaneous counterparts (i.e., thSAT + abdominal SAT; 8 ± 2 ILCs per gram of AT; p = 0.001), with ILC1 being the most frequent (ILC1 > ILC3 > ILC2). Numbers of ILCs per gram of AT correlated with several Th2 or browning genes (IL-13, TNF receptor superfamily member 9 [TNFRSF9], and alkaline phosphatase, biomineralization associated [ALPL]). Interestingly, a specific increase in EAT-ILC2 compared with other ATs was observed, including a significant proportion expressing CD69 and/or CD25 activation markers (97.9% ± 1.2%; p < 0.0001). Finally, more natural killer cells were observed in EAT + VAT than in thSAT + abdominal SAT (p = 0.01). Exclusion of patients with coronary artery disease in the EPICAR and INTERFACE studies did not modify the main findings. Gene expression phenotyping confirmed specific upregulation of Th2 pathway and browning genes (IL-33 and uncoupling protein 1 [UCP-1]) in EAT. CONCLUSIONS: This is the first study, to our knowledge, to provide a comparison between innate and adaptive lymphoid cells in human EAT. Further studies are ongoing to decipher whether these cells could be involved in EAT beiging.

Ophthalmic vascular manifestations in eosinophil-associated diseases: a comprehensive analysis of 57 patients from the CEREO and EESG networks and a literature review.

Introduction: Eosinophils have widespread procoagulant effects. In daily practice, eosinophil-related cardiovascular toxicity consists of endomyocardial damage, eosinophilic vasculitis and arterial or venous thrombosis. Here we aim to report on the clinical features and treatment outcomes of patients with unexplained ophthalmic vascular manifestations and eosinophilia. Methods: We conducted a retrospective, multicenter, observational study and a literature review of patients with eosinophilia (≥0.5 x109/L) and concomitant ophthalmic vascular manifestations independent of the underlying eosinophilic disease but with no alternative cause for ophthalmic manifestations. Results: Fifty-seven patients were included (20 from the observational study and 37 from the literature review). Ophthalmic vascular features were the initial manifestation of eosinophil-related disease in 34 (59%) patients and consisted of 29 central retinal artery occlusions, six branch retinal artery occlusions, five central retinal vein occlusions, two branch retinal vein occlusions, seven retinal vasculitides, two retinal vasospasms, 12 Purtscher's retinopathies, 13 anterior ischemic optic neuropathies and two posterior ischemic optic neuropathies. The median [IQR] absolute eosinophil count at onset of ophthalmic vascular manifestations was 3.5 [1.7-7.8] x109/L. Underlying eosinophil-related diseases included eosinophilic granulomatosis with polyangiitis (n=32), clonal hypereosinophilic syndrome (HES) (n=1), idiopathic HES (n=13), lymphocytic HES (n=2), adverse drug reactions (n=3), parasitosis (n=2), polyarteritis nodosa (n=1), IgG4-related disease (n=1), eosinophilic fasciitis (n=1) and primary sclerosing cholangitis (n=1). Other extra-ophthalmologic arterial or venous thromboses related to eosinophilia were reported in four (7%) and nine (16%) patients, respectively. Visual prognosis was poor: only eight (10%) patients achieved full recovery of ophthalmologic symptoms. After a median follow-up of 10.5 [1-18] months, one patient (3%) had a recurrence of an ophthalmic vascular manifestation, and three patients (10%) had a recurrence of other vascular symptoms (deep vein thrombosis in two and pulmonary embolism in one patient). At the time of recurrence, absolute eosinophil counts were above 0.5 x109/L in all cases (n=4). Discussion: This study broadens the spectrum of vascular manifestations associated with hypereosinophilia by adding ophthalmic vascular manifestations. In patients with ophthalmological vascular manifestations and hypereosinophilia, aggressive treatment of the underlying pathology (and normalization of blood count) should be implemented.