Systemic sclerosis (SSc) is a systemic disease characterized by a great clinical and immunological heterogeneity whose pathophysiology is still being unraveled. Recently, innate immunity has been proposed to participate to the pathogenesis of SSc. In this study, we investigated the release of neutrophil extracellular traps (NETs) according to patient phenotype. Polymorphonuclear neutrophils (PMN) from 34 SSc patients and 26 healthy controls were stimulated by serum from SSc or healthy subject. NETs were visualized using epifluorescence microscope after DNA, myeloperoxidase, and Histone H3 tagging. Area of NETs were quantified using an original macro running in ImageJ^® software. PMN from SSc patients were significantly more prone to releasing NETs than control PMN after autologous stimulation. PMN from patients with severe vascular complications (pulmonary arterial hypertension, digital ulcers) produced more NETs than PMN from other SSc patients and their aberrant NET production appeared to be sustained over time. In patients with pulmonary interstitial disease or extensive cutaneous fibrosis, NET production was high at an early stage of the disease before progressively decreasing. Both serum factors and PMN activation status were involved in the enhanced production of NETs in SSc. Consequently, neutrophils and especially NETosis represent new physiopathological and therapeutic fields in SSc.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular dysplasia characterized by mucocutaneous telangiectasia and visceral arteriovenous malformations. Hepatic involvement with vascular malformations may lead to portal hypertension, biliary ischemia, and high-output cardiac failure. There is no curative treatment for the disease. Liver transplantation is indicated for life-threatening complications, but it carries significant risk due to surgery and immunosuppressive treatment. Some case reports or small open studies suggest that bevacizumab, a recombinant humanized anti-VEGF monoclonal antibody, should be efficient in limiting bleeding and in reducing liver disease in HHT.We report a case of a 63-year-old woman with HHT presenting with ischemic cholangiopathy. Liver transplant was indicated, but given a previous encouraging report showing a regression of biliary disease with bevacizumab in 3 patients with HHT this drug was proposed. No significant efficacy but a severe adverse effect was observed after 3 months: bilateral pulmonary embolisms, thrombosis in the right atrial cavity, and thrombosis of the right hepatic vein were evidenced. Bevacizumab was stopped; anticoagulant started. Four months later, the patient received a transplanted liver. She feels well 1 year later.This case report intends to provide the information for clinicians to consider the use of bevacizumab in HHT. Whereas several uncontrolled series and case reports have suggested the efficacy of this drug in reducing bleeding and liver disease, no severe side effects were mentioned to date. For the first time in HHT we report a life-threatening side effect of this drug and no efficacy. Moreover, systemic thrombosis, the observed complication, may preclude transplantation. To date, caution seems still indispensable when considering the use of bevacizumab in HHT.

Pyoderma gangrenosum (PG), like other neutrophilic dermatosis, may be associated with a variety of systemic disorders including inflammatory bowel diseases, rheumatoid arthritis, and hematologic disorders. Conversely, the association between PG and systemic lupus erythematosus (SLE) has rarely been reported. We report here 2 cases of this association. The first case involves a 32-year-old woman who developed, 1 year after SLE diagnosis, 3 painful nodular lesions of PG on her face, and cervical area. The second case was observed in a 37-year-old woman referred for ulcerative nodular papules of PG on her legs, whereas she had been diagnosed with SLE 10 years before. SLE was inactive in the first case, whereas PG occurred during a lupus flare up in the second one. We found 23 previous cases of SLE and PG in the literature with most cases (12/20) occurring during a lupus flare. Although rare, this association may be supported by common innate immunity dysregulation and abnormal neutrophil activation. PG and other neutrophilic diseases reported in patients with SLE may be added to the large clinical spectrum of cutaneous lesions observed in SLE.

Introduction Systemic sclerosis (SSc) is a rare autoimmune disease currently classified into two subgroups based on skin extension. The aim of this study was to determine in a large cohort whether the determination of autoantibody (AAb) profile among a full antinuclear AAbs panel including nine specificities had a higher impact than skin phenotype on stratifying the risk of organ involvement and mortality in SSc. Methods Data for patients with SSc followed in seven French university hospitals were retrospectively analysed in terms of skin phenotype, AAbs (anti-topoisomerase I (ATA), anticentromere (ACA), anti-RNA polymerase III (anti-RNAPIII), anti-U1RNP, anti-U3RNP, anti-Pm/Scl, anti-Ku, anti-Th/To, anti-NOR90), organ involvement and mortality. Multivariate analyses were performed to identify independent factors associated with organ involvement and mortality. Results We included 1605 patients with SSc (367 with diffuse cutaneous SSc). On multivariate analysis, ATAs were associated with interstitial lung disease and mortality (OR=3.27 (95% CI 2.42 to 4.42); HR=1.9 (95% CI 1.01 to 3.58)), anti-RNAPIII with scleroderma renal crisis and mortality (OR=7.05 (95% CI 2.98 to 16.72); HR=2.35 (95% CI 1.12 to 4.93)), anti-U1RNP with arthritis (OR=3.79 (95% CI 2.16 to 6.67)), anti-Pm/Scl and anti-Ku with myositis (OR=7.09 (95% CI 3.87 to 12.98) and 7.99 (95% CI 2.41 to 26.46)). The skin phenotype was not associated with survival or organ involvement on multivariate analysis without stepwise selection. Conclusion This study unravels, by contrast with skin phenotype, a strong association between AAbs specificities, organ involvement and outcome in SSc and suggests that patients’ classification based on only skin extension is not sufficient for defining prognosis and phenotype.

Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant acquired hematopoietic stem cell disease, which can be revealed by hemolytic anemia, thromboembolism, or bonemarrow failure. Thrombosis can occur at any site, but coronary thrombosis is extremely rare. Controlled trials have demonstrated that eculizimab, an inhibitor of the terminal complement cascade, was able to reduce both hemolysis and thrombosis, but its efficacy in cases of PNH with coronary thrombosis is unknown. We report herein the unusual case of a 73-year-old patient presenting with recurrent coronary syndromes without associated stenosis, fever, marked inflammatory syndrome, and anemia, leading to a delayed diagnosis of PNH. Eculizumab allowed the resolution of fever and inflammation, and prevented further thromboembolism. This case emphasizes the importance of performing aflow cytometry test for PNH in front of unusual or unexplained recurrent thromboses. Thromboses, as observed in our case, may be associated with fever and marked inflammation. This case also provides useful information on eculizumab ability to prevent further thromboembolism in PNH patients with a medical history of arterial thrombosis.