Pathophysiologic implications of elevated prevalence of hereditary alpha-tryptasemia in all mastocytosis subtypes.

BACKGROUND: Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal. OBJECTIVE: We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT. METHODS: Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases. RESULTS: We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαT+ patients were more likely to have anaphylactic reactions and less likely to have cutaneous lesions than HαT- patients (43.0% vs 24.4%, P = .006; 57.7% vs 75.6%, respectively, P = .006). In the pooled analysis, the prevalence of HαT was higher in advSM (11.5%) than in control cohorts (5.2%, P = .01). CONCLUSION: Here we confirm the increase incidence of anaphylaxis in HαT+ mastocytosis patients. The increased prevalence of HαT in all subtypes of systemic mastocytosis (including advSM) is suggestive of pathophysiologic involvement.

Serious infections in patients with VEXAS syndrome: data from the French VEXAS registry.

INTRODUCTION: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an acquired autoinflammatory monogenic disease with a poor prognosis whose determinants are not well understood. We aimed to describe serious infectious complications and their potential risk factors. METHODS: Retrospective multicentre study including patients with VEXAS syndrome from the French VEXAS Registry. Episodes of serious infections were described, and their risk factors were analysed using multivariable Cox proportional hazards models. RESULTS: Seventy-four patients with 133 serious infections were included. The most common sites of infection were lung (59%), skin (10%) and urinary tract (9%). Microbiological confirmation was obtained in 76%: 52% bacterial, 30% viral, 15% fungal and 3% mycobacterial. Among the pulmonary infections, the main pathogens were SARS-CoV-2 (28%), Legionella pneumophila (21%) and Pneumocystis jirovecii (19%). Sixteen per cent of severe infections occurred without any immunosuppressive treatment and with a daily glucocorticoid dose ≤10 mg. In multivariate analysis, age >75 years (HR (95% CI) 1.81 (1.02 to 3.24)), p.Met41Val mutation (2.29 (1.10 to 5.10)) and arthralgia (2.14 (1.18 to 3.52)) were associated with the risk of serious infections. JAK inhibitors were most associated with serious infections (3.84 (1.89 to 7.81)) compared with biologics and azacitidine. After a median follow-up of 4.4 (2.5-7.7) years, 27 (36%) patients died, including 15 (56%) due to serious infections. CONCLUSION: VEXAS syndrome is associated with a high incidence of serious infections, especially in older patients carrying the p.Met41Val mutation and treated with JAK inhibitors. The high frequency of atypical infections, especially in patients without treatment, may indicate an intrinsic immunodeficiency.

Histological characterization of liver involvement in systemic mastocytosis.

BACKGROUND AND AIMS: Systemic mastocytosis (SM) is characterized by the accumulation of atypical mast cells (MCs) in organs. Liver histology of SM has been marginally described and accurate histological classification is critical, given the consequences of aggressive SM diagnosis. We aimed to describe the histological features associated with liver SM using updated tools. METHODS: Using the database of the French Reference Centre for Mastocytosis, we retrospectively identified patients with a liver biopsy (LB) and a diagnosis of SM. All LB procedures were performed according to the local physician in charge and centrally reviewed by an expert pathologist. RESULTS: A total of 28 patients were included: 6 had indolent SM, 9 had aggressive SM, and 13 had SM with an associated hematologic neoplasm. Twenty-five (89%) patients presented hepatomegaly, and 19 (68%) had portal hypertension. The LB frequently showed slight sinusoid dilatation (82%). Fibrosis was observed in 3/6 indolent SM and in almost all advanced SM cases (21/22), but none of them showed cirrhosis. A high MC burden (>50 MCs/high-power field) was correlated with elevated blood alkaline phosphatase levels (p = .030). The presence of portal hypertension was associated with a higher mean fibrosis grade (1.6 vs. 0.8 in its absence; p = .026). In advanced SM, the presence of nodular regenerative hyperplasia (NRH) was associated with decreased overall survival (9.5 vs. 46.3 months, p = .002). CONCLUSIONS: MC infiltration induced polymorphic hepatic lesions and the degree of fibrosis is associated with portal hypertension. NRH identifies a poor prognosis subgroup of patients with advanced SM. Assessing liver histology can aid in SM prognostic evaluation.

Efficacy and safety of mammalian target of rapamycin inhibitors in systemic mastocytosis: A nationwide French pilot study.

Systemic mastocytosis (SM) corresponds to a rare and heterogeneous spectrum of diseases characterized by the accumulation of atypical mast cells (MCs). Advanced mastocytosis (Adv-SM) is associated with poor survival; in contrast, patients with non-advanced SM (non-Adv-SM) usually have a normal life expectancy but may experience poor quality of life. Despite recent therapeutic progress including tyrosine kinase inhibitors, new treatment options are needed for refractory and/or intolerant patients with both severely symptomatic and Adv-SM. In vitro, the mTOR pathway is activated in MCs from patients bearing the KIT D816V mutation. Furthermore, rapamycin induces the apoptosis of KIT D816V MCs selectively. In this nationwide study, we report the outcomes of patients diagnosed with SM and treated with a mammalian target of rapamycin inhibitor (imTOR) within the French National Reference Center for mastocytosis (CEREMAST). All patients registered were relapsing, treatment-refractory, or ineligible for other cytoreductive therapy. Non-Adv-SM patients received imTOR as a monotherapy (rapamycin/everolimus), and Adv-SM patients received imTOR as a monotherapy or in combination with cytarabine. The objective response rate (ORR) in non-Adv-SM was 60% (partial response in 40% and major response in 20%), including reductions in skin involvement, mediator release symptoms, and serum tryptase. In the Adv-SM group, the ORR was 20% (including one major response and one partial response, both in patients with a KIT D816V mutation), which enabled a successful bridge to allogeneic stem cell transplantation in one patient. Our results suggest that imTOR treatment has potential benefits in patients with SM harboring a KIT D816V mutation.

Chronological interplay, clinical features, and treatments among patients with cancer and primary Sjögren's syndrome.

OBJECTIVE: While the incidence and type of blood malignancies are well documented amid primary Sjögren's syndrome patients (pSS), data focusing on solid neoplasms are more conflicting. We aimed to describe clinical, pathological, and immunological characteristics of pSS patients with cancers, along with the chronological interplay between the two conditions. METHODS: Outcomes concerning both pSS and cancer were retrospectively collected from Montpellier University Hospital (tertiary center) between 2019 and 2020. pSS characteristics were compared to a control group of pSS patients without cancer. RESULTS: A total of 165 patients with pSS were included: 55 patients with cancer (52 female, mean age 58.4 ± 10.4 years at pSS diagnosis; mean follow-up 10.5 ± 10.1 years, 12 patients had multiple cancers) and 110 controls without cancer. Characteristics of pSS patients with cancers were different from controls mostly for lymphoma prognosis factors. Among the 70 cancers, we recorded 55 solid neoplasms (whom 27 breast cancers and 8 lung cancers, and 82% of adenocarcinomas), with no evidence of disease at the end of follow-up in 85% of them. Among the 15 recorded blood malignancies, ten were lymphomas with an excellent prognosis. Regarding chronological interplay between cancer and pSS, most cancers (43%) were diagnosed close (± 5 years) to pSS diagnosis. Breast cancers were diagnosed before or close to pSS diagnosis (mean delay - 1.8 ± 13.0 years), at an early stage, with only two relapses (no cancer-related death), while lung cancers were diagnosed late after. CONCLUSIONS: The tight chronological interplay between breast cancer and pSS and the intriguing pathological and immunological pattern of pSS in these patients suggest a hypothesis of immune control of cancer.

Prevalence of anti-neutrophil cytoplasmic antibody-associated vasculitis in the south of France, using the capture-recapture method.

OBJECTIVES: This study aimed to estimate the prevalence of ANCA-associated vasculitis (AAV), ie granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), in Southern France in 2018, and evaluate differences among Europeans and non-Europeans. METHODS: This population-based, cross-sectional study used four sources (hospitals, community-based physicians, laboratories, National Health Insurance) to identify adults ≥ 15 years diagnosed with GPA, MPA or EGPA, living in Hérault and Gard in 2018. Cases were defined using the ACR/EULAR classification criteria, and if necessary, the European Medicines Agency algorithm. Prevalence estimates were standardised to the world population and capture-recapture analysis was used to assess the comprehensiveness of the estimation. The influence of geographical origin was evaluated. RESULTS: 202 patients were selected, with 86 cases of GPA (42.6%), 85 cases of MPA (42.1%), and 31 cases of EGPA (15.3%). The standardised prevalence estimates per million inhabitants for 2018 were: 103 (95%CI 84 - 125) for AAV, 48 (95%CI 35 - 64) for GPA, 39 (95%CI 28 - 53) for MPA and 16 (95%CI 9 - 26) for EGPA, 36 (95%CI 25 - 50) for anti-PR3 positive AAV, 46 (95%CI 34 - 61) for anti-MPO positive AAV, and 16 (95%CI 9 - 26) for ANCA-negative AAV. The global estimation of comprehensiveness by capture-recapture analysis was 80.5%. The number of AAV cases was higher for non-European residents (P=0.001), particularly for MPA (P<0.0001). CONCLUSION: We provide a new estimate of AAV prevalence in France and show a higher prevalence of MPA in non-European patients.

Immune-mediated diseases involving central and peripheral nervous systems.

BACKGROUND AND PURPOSE: In addition to combined central and peripheral demyelination, other immune diseases could involve both the central nervous system (CNS) and peripheral nervous system (PNS). METHODS: To identify immune-mediated diseases responsible for symptomatic combined central/peripheral nervous system involvement (ICCPs), we conducted a multicentric retrospective study and assessed clinical, electrophysiological, and radiological features of patients fulfilling our ICCP criteria. RESULTS: Thirty patients (20 males) were included and followed during a median of 79.5 months (interquartile range [IQR] = 43-145). The median age at onset was 51.5 years (IQR = 39-58). Patients were assigned to one of four groups: (i) monophasic disease with concomitant CNS/PNS involvement including anti-GQ1b syndrome (acute polyradiculoneuropathy + rhombencephalitis, n = 2), checkpoint inhibitor-related toxicities (acute polyradiculoneuropathy + encephalitis, n = 3), and anti-glial fibrillary acidic protein astrocytopathy (subacute polyradiculoneuropathy and meningoencephalomyelitis with linear gadolinium enhancements, n = 2); (ii) chronic course with concomitant CNS/PNS involvement including paraneoplastic syndromes (ganglionopathy/peripheral hyperexcitability + limbic encephalitis, n = 4); (iii) chronic course with sequential CNS/PNS involvement including POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome (polyradiculoneuropathy + strokes, n = 2), histiocytosis (polyradiculoneuropathy + lepto-/pachymeningitis, n = 1), and systemic vasculitis (multineuropathy + CNS vasculitis/pachymeningitis, n = 2); and (iv) chronic course with concomitant or sequential CNS/PNS involvement including combined central and peripheral demyelination (polyradiculoneuropathy + CNS demyelinating lesions, n = 10) and connective tissue diseases (ganglionopathy/radiculopathy/multineuropathy + limbic encephalitis/transverse myelitis/stroke, n = 4). CONCLUSIONS: We diagnosed nine ICCPs. The timing of central and peripheral manifestations and the disease course help determine the underlying immune disease. When antibody against neuroglial antigen is identified, CNS and PNS involvement is systematically concomitant, suggesting a common CNS/PNS antigen and a simultaneous disruption of blood-nerve and blood-brain barriers.

Pulmonary hypertension reported with immune checkpoint inhibitors: a pharmacovigilance study.

Immune checkpoint inhibitors (ICI) restore immune response against cancer cells that can lead to immune-related adverse effects. While cardiovascular immune-related adverse effects are known to be associated with checkpoint inhibitors, recent case reports have raised concerns about the potential association with pulmonary hypertension (PH). By using the global pharmacovigilance database VigiBase, we investigated the onset of PH associated with ICI and propose a comprehensive description of the 42 cases of PH reported with ICI recorded in this database. Through this study and review of the cases published in the literature, we discuss the possible link between PH and ICI in the context of cancer in order to better understand this rare but potentially fatal event.

Mesenchymal stromal cells-derived extracellular vesicles alleviate systemic sclerosis via miR-29a-3p.

Systemic sclerosis (SSc) is a potentially lethal disease with no curative treatment. Mesenchymal stromal cells (MSCs) have proved efficacy in SSc but no data is available on MSC-derived extracellular vesicles (EVs) in this multi-organ fibrosis disease. Small size (ssEVs) and large size EVs (lsEVs) were isolated from murine MSCs or human adipose tissue-derived MSCs (ASCs). Control antagomiR (Ct) or antagomiR-29a-3p (A29a) were transfected in MSCs and ASCs before EV production. EVs were injected in the HOCl-induced SSc model at day 21 and euthanasized at day 42. We found that both ssEVs and lsEVs were effective to slow-down the course of the disease. All disease parameters improved in skin and lungs. Interestingly, down-regulating miR-29a-3p in MSCs totally abolished therapeutic efficacy. Besides, we demonstrated a similar efficacy of human ASC-EVs and importantly, EVs from A29a-transfected ASCs failed to improve skin fibrosis. We identified Dnmt3a, Pdgfrbb, Bcl2, Bcl-xl as target genes of miR-29a-3p whose regulation was associated with skin fibrosis improvement. Our study highlights the therapeutic role of miR-29a-3p in SSc and the importance of regulating methylation and apoptosis.

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.

Renal involvement in eosinophilic granulomatosis with polyangiitis (EGPA): a multicentric retrospective study of 63 biopsy-proven cases.

OBJECTIVE: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic small-vessel vasculitis characterized by asthma, hypereosinophilia and ANCA positivity in 40% of patients. Renal involvement is rare and poorly described, leading to this renal biopsy-proven based study in a large EGPA cohort. METHODS: We conducted a retrospective multicentre study including patients fulfilling the 1990 ACR criteria and/or the 2012 revised Chapel Hill Consensus Conference criteria for EGPA and/or the modified criteria of the MIRRA trial, with biopsy-proven nephropathy. RESULTS: Sixty-three patients [27 women, median age 60 years (18-83)] were included. Renal disease was present at vasculitis diagnosis in 54 patients (86%). ANCA were positive in 53 cases (84%) with anti-MPO specificity in 44 (83%). All patients had late-onset asthma. Peripheral neuropathy was present in 29 cases (46%), alveolar haemorrhage in 10 (16%). The most common renal presentation was acute renal failure (75%). Renal biopsy revealed pauci-immune necrotizing GN in 49 cases (78%). Membranous nephropathy (10%) and membranoproliferative GN (3%) were mostly observed in ANCA-negative patients. Pure acute interstitial nephritis was found in six cases (10%); important interstitial inflammation was observed in 28 (44%). All patients received steroids with adjunctive immunosuppression in 54 cases (86%). After a median follow-up of 51 months (1-296), 58 patients (92%) were alive, nine (14%) were on chronic dialysis and two (3%) had undergone kidney transplantation. CONCLUSION: Necrotizing pauci-immune GN is the most common renal presentation in ANCA-positive EGPA. ANCA-negative patients had frequent atypical renal presentation with other glomerulopathies such as membranous nephropathy. An important eosinophilic interstitial infiltration was observed in almost 50% of cases.

Extracellular Vesicles Are More Potent Than Adipose Mesenchymal Stromal Cells to Exert an Anti-Fibrotic Effect in an In Vitro Model of Systemic Sclerosis.

Systemic sclerosis (SSc) is a complex disorder resulting from dysregulated interactions between the three main pathophysiological axes: fibrosis, immune dysfunction, and vasculopathy, with no specific treatment available to date. Adipose tissue-derived mesenchymal stromal cells (ASCs) and their extracellular vesicles (EVs) have proved efficacy in pre-clinical murine models of SSc. However, their precise action mechanism is still not fully understood. Because of the lack of availability of fibroblasts isolated from SSc patients (SSc-Fb), our aim was to determine whether a TGFß1-induced model of human myofibroblasts (Tß-Fb) could reproduce the characteristics of SSc-Fb and be used to evaluate the anti-fibrotic function of ASCs and their EVs. We found out that Tß-Fb displayed the main morphological and molecular features of SSc-Fb, including the enlarged hypertrophic morphology and expression of several markers associated with the myofibroblastic phenotype. Using this model, we showed that ASCs were able to regulate the expression of most myofibroblastic markers on Tß-Fb and SSc-Fb, but only when pre-stimulated with TGFß1. Of interest, ASC-derived EVs were more effective than parental cells for improving the myofibroblastic phenotype. In conclusion, we provided evidence that Tß-Fb are a relevant model to mimic the main characteristics of SSc fibroblasts and investigate the mechanism of action of ASCs. We further reported that ASC-EVs are more effective than parental cells suggesting that the TGFß1-induced pro-fibrotic environment may alter the function of ASCs.

Compliance with Prescription Guidelines for Glucose-Lowering Therapies According to Renal Function: Real-Life Study in Inpatients of Internal Medicine, Endocrinology and Cardiology Units.

Background and objectives: Renal failure is a contraindication for some glucose-lowering drugs and requires dosage adjustment for others, particularly biguanides, sulfonylureas, and inhibitors of dipeptidyl peptidase 4. In this study, we assessed adherence to prescription recommendations for glucose-lowering drugs according to renal function in hospitalized diabetic subjects. Materials and Methods: This prospective cohort study was carried out over a 2-year period in a university hospital. Glomerular filtration rate (GFR) was determined by averaging all measurements performed during hospitalization. Glucose-lowering drug dosages were analyzed according to the recommendations of the relevant medical societies. Results: In total, 2071 diabetic patients (53% hospitalized in cardiology units) were examined. GFR was <30 mL/min/1.73 m2 in 13.4% of these patients, 30-44 in 15.1%, 45-60 in 18.3%, and >60 in 53.3%. Inappropriate oral glucose-lowering treatments were administered to 273 (13.2%) patients, including 53 (2.6%) with a contraindication. In cardiology units, 53.1% and 14.3% of patients had GFRs of <60 and <30 mL/min/1.73 m2, respectively, and 179 (15.4%) patients had a contraindication or were prescribed an excessive dose of glucose-lowering drugs. Conclusions: We showed that the burden of inappropriate prescriptions is high in diabetic patients. Given the high number of patients receiving these medications, particularly in cardiology units, a search for potential adverse effects related to these drugs should be performed.

Sicca/Sjögren's syndrome triggered by PD-1/PD-L1 checkpoint inhibitors. Data from the International ImmunoCancer Registry (ICIR).

OBJECTIVES: To analyse the worldwide occurrence of sicca/Sjögren's (SS) syndrome associated with the use of immune checkpoint inhibitors (ICI) in patients with cancer. METHODS: The ImmunoCancer International Registry (ICIR) is a Big Data-Sharing multidisciplinary network composed by 40 specialists in Rheumatology, Internal Medicine, Immunology and Oncology from 18 countries focused on the clinical and basic research of the immune-related adverse events (irAEs) related to cancer immunotherapies. For this study, patients who were investigated for a clinical suspicion of SS after being exposed to ICI were included. RESULTS: We identified 26 patients (11 women and 15 men, with a mean age at diagnosis of 63.57 years). Underlying cancer included lung (n=12), renal (n=7), melanoma (n=4), and other (n=3) neoplasia. Cancer immunotherapies consisted of monotherapy (77%) and combined regimens (23%). In those patients receiving monotherapy, all patients were treated with PD-1/PD-L1 inhibitors (nivolumab in 9, pembrolizumab in 7 and durvalumab in 4); no cases associated with CTLA-4 inhibitors were identified. The main SS-related features consisted of dry mouth in 25 (96%) patients, dry eye in 17 (65%), abnormal ocular tests in 10/16 (62%) and abnormal oral diagnostic tests in 12/14 (86%) patients. Minor salivary gland biopsy was carried out in 15 patients: histopathological findings consisted of mild chronic sialadenitis in 8 (53%) patients and focal lymphocytic sialadenitis in the remaining 7 (47%); a focus score was measured in 5 of the 6 patients (mean of 1.8, range 1-4). Immunological markers included positive ANA in 13/25 (52%), anti-Ro/ SS-A in 5/25 (20%), RF in 2/22 (9%), anti-La/SS-B in 2/25 (8%), low C3/C4 levels in 1/17 (6%) and positive cryoglobulins in 1/10 (10%). Classification criteria for SS were fulfilled by 10 (62%) out of 16 patients in whom the two key classificatory features were carried out. Among the 26 patients, there were only 3 (11%) who presented exclusively with sicca syndrome without organ-specific autoimmune manifestations. Therapeutic management included measures directed to treat sicca symptoms and therapies against autoimmune-mediated manifestations (glucocorticoids in 42%, second/third-line therapies in 31%); therapeutic response for systemic features was observed in 8/11 (73%). No patient died due to autoimmune involvement. CONCLUSIONS: Patients with Sjögren's syndrome triggered by ICI display a very specific profile different from that reported in idiopathic primary SS, including more frequent occurrence in men, a higher mean age, a predominant immunonegative serological profile, and a notable development of organ-specific autoimmune involvement in spite of the poor immunological profile. The close association found between sicca/Sjögren's syndrome and primarily PD-1 blockade requires further specific investigation.

Impact of MPO-ANCA-mediated oxidative imbalance on renal vasculitis.

Glomerulonephritis is a severe complication of microscopic polyangiitis (MPA), a small-vessel vasculitis associated with anti-myeloperoxidase antibodies (MPO-ANCA). We previously showed the pathogenic effects of MPO-ANCA that activate MPO to trigger an oxidative burst mainly through HOCl production, contributing to endothelial injury and lung fibrosis. The aim of this study was to investigate the relationship between MPO-induced oxidative stress, anti-oxidant defenses and renal histological lesions in MPA patients. We therefore analyzed histological data from a prospective cohort of ANCA-associated glomerulonephritis. Serum-mediated HOCl production, advanced oxidation protein products (AOPP), and thiol concentration in sera were determined. From 38 patients included, histological classification noted 50% focal glomerulonephritis, 15.8% crescentic-glomerulonephritis, and 34.2% mixed-glomerulonephritis. MPA patients' sera displayed higher HOCl production by MPO ( P < 0.001), higher AOPP ( P < 0.001) and thiol ( P < 0.01) levels, compared with healthy subjects. The presence of cellular crescents was associated with higher serum-mediated HOCl production ( P = 0.049) and lower thiol levels ( P = 0.022) at disease onset. Higher thiol concentrations were associated with focal glomerulonephritis ( P = 0.042), less interstitial fibrosis ( P = 0.039) and hyalinosis ( P = 0.066). In remission, HOCl production was decreased ( P < 0.01), and thiol concentration remained high ( P = 0.39). Our findings suggest that HOCl production by activated MPO could contribute to the very early stage of glomerulonephritis, whereas thiol may exert a protective effect against the development of renal vasculitis and glomerulosclerosis. This study highlights the importance of oxidative defenses to counteract the process of MPO-ANCA associated glomerulonephritis.

Imbalance of the Vanin-1 Pathway in Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and visceral organs and vascular alterations. SSc pathophysiology involves systemic inflammation and oxidative stress. Because the vanin-1 gene (vnn1) encodes an enzyme with pantetheinase activity that converts vasculoprotective pantethine into profibrotic pantothenic acid and pro-oxidant cystamine, we tested this pathway in the pathophysiology of SSc. Activation of the vanin-1/pantetheinase pathway was investigated in wild-type BALB/c mice with hypochlorous acid (HOCl)-induced SSc by ELISA and Western blotting. We then evaluated the effects of the inactivation of vnn1 on the development of fibrosis, endothelial alterations, and immunological activation in mice with HOCl- and bleomycin-induced SSc. We then explored the vanin-1/pantetheinase pathway in a cohort of patients with SSc and in controls. In wild-type mice with HOCl-induced SSc, the vanin-1/pantetheinase pathway was dysregulated, with elevation of vanin-1 activity in skin and high levels of serum pantothenic acid. Inactivation of the vnn1 gene in vnn1-/- mice with HOCl-induced SSc prevented the development of characteristic features of the disease, including fibrosis, immunologic abnormalities, and endothelial dysfunction. Remarkably, patients with diffuse SSc also had increased expression of vanin-1 in skin and blood and elevated levels of serum pantothenic acid that correlated with the severity of the disease. Our data demonstrate that vanin-1/pantetheinase controls fibrosis, vasculopathy, autoimmunity, and oxidative stress in SSc. The levels of vanin-1 expression and pantothenic acid determine SSc severity and can be used as markers of disease severity. More importantly, inhibition of vanin-1 can open new therapeutic approaches in SSc.

About the complexity of adult onset Still's disease and advances still required for its management.

Adult onset Still's disease (AOSD) is a rare inflammatory disorder that remains poorly understood. Its pathophysiology is yet to be completely elucidated, but is known to consist mainly on a cytokine cascade, responsible for the systemic manifestations. AOSD diagnosis is usually difficult and delayed, with physicians having to rule out several other conditions, including cancer or infectious diseases. Prognosis is heterogeneous and difficult to establish, ranging from benign outcome to chronic destructive polyarthritis and/or life-threatening events. In addition, treatment remains to be codified, especially considering the development of new drugs. In this commentary, we attempt to elucidate the complexity of AOSD and to highlight the need of working on prognostic tools for this disorder. We also discuss the numerous advances that would be useful for patients in the daily management of this disease.Please see related article: http://bmcmedicine.biomedcentral.com/articles/ 10.1186/s12916-016-0738-8 .