Mouth opening in systemic sclerosis: A longitudinal analysis from the French National Cohort Study.

BACKGROUND: Few studies have evaluated mouth opening (MO) in systemic sclerosis (SSc). None have studied MO trajectories. OBJECTIVE: To study MO trajectories in SSc. METHODS: This multicentre study included patients enrolled in the French national SSc cohort with at least one MO assessment, described patients based on MO baseline measure, modeled MO trajectories, and associated MO measures with SSc prognosis. RESULTS: We included 1101 patients. Baseline MO was associated with disease severity. On Kaplan-Meier analysis, MO < 30 mm was associated with worse 30-year-survival (p<0.01) and risk of pulmonary arterial hypertension (p<0.05). Individual MO trajectories were heterogenous among patients. The best model of MO trajectories according to latent-process mixed modeling showed that 88.8% patients had a stable MO trajectory and clustered patients into 3 groups that predicted SSc survival (p<0.05) and interstitial lung disease (ILD) occurrence (p<0.05). The model highlighted a cluster of 9.5% patients with diffuse cutaneous SSc (dcSSc) (p<0.05) and high but decreasing MO over 1 year (p<0.0001) who were at increased risk of poor survival and ILD. CONCLUSION: MO, which is a simple and reliable measure, could be used to predict disease severity and survival in SSc. Although MO remained stable in most SSc patients, dcSSc patients with high but decreasing MO were at risk of poor survival and ILD. This article is protected by copyright. All rights reserved.

Heart and systemic sclerosis-findings from a national cohort study.

OBJECTIVES: Heart involvement is one of the leading causes of death in systemic sclerosis (SSc). The prevalence of SSc-related cardiac involvement is poorly known. Our objective was to investigate the prevalence and prognosis burden of different heart diseases in a nationwide cohort of patients with SSc. METHODS: We used data from a multicentric prospective study using the French SSc national database. Focusing on SSc-related cardiac involvement, we aimed to determine its incidence and risk factors. RESULTS: Over the 3528 patients with SSc 312 (10.9%) had SSc-related cardiac involvement at baseline. They tended to have a diffuse SSc subtype more frequently, more severe clinical features, and presented more cardiovascular risk factors. From the 1646 patients available for follow-up analysis, SSc-related cardiac involvement was associated with an increased risk of death. There was no significant difference in overall survival between SSc-related cardiac involvement, ischaemic heart disease or pulmonary arterial hypertension. Regarding survival analysis, 98 patients developed SSc-related cardiac involvement at five years (5-year event rate: 11.15%). Regarding reduced LVEF < 50% and left ventricular diastolic dysfunction, the 5-year event rate was 2.49% and 5.84% respectively. Pericarditis cumulative incidence at five years was 3%. Diffuse SSc subtype was a risk factor for SSc-related cardiac involvement and pericarditis. Female sex was associated with less left ventricular diastolic dysfunction incidence. CONCLUSIONS: Our results describe the incidence and prognostic burden of SSc-related cardiac involvement at a large scale, with gender and diffuse SSc subtype as risk factors. Further analyses should assess the potential impact of treatment on these various cardiac outcomes.

6-Sulfo LacNAc monocytes are quantitatively and functionally disturbed in systemic sclerosis patients.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis, microangiopathy, and autoantibodies. We previously reported that circulating follicular helper T (cTfh) cells are increased in SSc and induce plasmablast differentiation. However, mechanisms leading to cTfh cell expansion and activation in SSc remain to be established. Tfh cells require IL-12 for their expansion and differentiation. 6-Sulfo LacNAc monocytes (slanMo), a subset of monocytes, have a higher capacity to produce IL-12 and to induce CD4+ T cell proliferation in comparison with dendritic cells (DC) or classical monocytes. The aim of this study was to perform a quantitative and functional analysis of monocytes and DC and to correlate them with cTfh cell expansion and clinical manifestations in SSc. Using flow cytometry, we analyzed different monocyte subsets including slanMo and DC from 36 SSc patients and 26 healthy controls (HC). In vitro culture experiments of sorted slanMo were performed for functional analysis and cytokine production. We observed that slanMo, intermediate and non-classical monocytes were increased in SSc in comparison with HC. Furthermore, the increase in slanMo cells was more potent in patients with diffuse SSc. We observed a significant positive correlation between slanMo and cTfh cell levels in SSc patients but not in HC. Other monocyte subsets did not correlate with cTfh cell expansion. In addition, we observed that in vitro, slanMo cells from SSc patients produced less IL-12 than slanMo from HC. SlanMo are increased in SSc and may participate in the activation of cTfh cells in SSc.

The Economic Burden of Disease in France From the National Health Insurance Perspective: The Healthcare Expenditures and Conditions Mapping Used to Prepare the French Social Security Funding Act and the Public Health Act.

BACKGROUND: Identifying the most frequently treated and the costliest health conditions is essential for prioritizing actions to improve the resilience of health systems. OBJECTIVES: Healthcare Expenditures and Conditions Mapping describes the annual economic burden of 58 health conditions to prepare the French Social Security Funding Act and the Public Health Act. DESIGN: Annual cross-sectional study (2015-2019) based on the French national health database. SUBJECTS: National health insurance beneficiaries (97% of the French residents). MEASURES: All individual health care expenditures reimbursed by the national health insurance were attributed to 58 health conditions (treated diseases, chronic treatments, and episodes of care) identified by using algorithms based on available medical information (diagnosis coded during hospital stays, long-term diseases, and specific drugs). RESULTS: In 2019, €167.0 billion were reimbursed to 66.3 million people (52% women, median age: 42 y). The most prevalent treated diseases were diabetes (6.0%), chronic respiratory diseases (5.5%), and coronary diseases (3.2%). Coronary diseases accounted for 4.6% of expenditures, neurotic and mood disorders 3.7%, psychotic disorders 2.8%, and breast cancer 2.1%. Between 2015 and 2019, the expenditures increased primarily for diabetes (+€906 million) and neurotic and mood disorders (+€861 million) due to the growing number of patients. "Active lung cancer" (+€797 million) represented the highest relative increase (+54%) due to expenditures for the expensive drugs and medical devices delivered at hospital. CONCLUSIONS: These results have provided policy-makers, evaluators, and public health specialists with key insights into identifying health priorities and a better understanding of trends in health care expenditures in France.

Rituximab plus belimumab in non-infectious refractory cryoglobulinemia vasculitis: A pilot study.

OBJECTIVE: To report the efficacy of rituximab plus belimumab in patients with refractory cryoglobulinemia vasculitis (CV). METHODS: Belimumab was administered intravenously at a dose of 10 mg/kg on days 0, 14, 28 and then every month in association with rituximab in 4 patients with refractory CV. Demographic, clinical and laboratory characteristics, treatment modalities and outcomes were recorded. RESULTS: All patients had type II IgM Kappa cryoglobulinemia, which was associated with primary Sjögren syndrome (n = 1), hepatitis C virus infection (n = 1), and essential (n = 2). Main manifestations of CV included purpura (n = 4), arthralgia and peripheral neuropathy (n = 3), and glomerulonephritis and skin ulcers (n = 1). In all cases, CV was refractory and/or relapse following rituximab. Intravenous belimumab infusion along with rituximab resulted in rapid clinical response in the four patients. Osteitis and recurrent urinary tract infections occurred in two patients. CONCLUSION: Belimumab along with rituximab showed promising results in refractory patients with CV.

Cutaneous Kikuchi disease-like inflammatory pattern without lymph node involvement is associated with systemic disease and severe features in lupus erythematous: A case-control study.

INTRODUCTION: Kikuchi-Fujimoto disease (KFD) is a self-limited histiocytic necrotizing lymphadenitis sometimes affecting the skin. "Kikuchi disease-like inflammatory pattern" (KLIP) has been described in cutaneous lesions as similar pathological features in patients without lymph node involvement and as a potential clue for the diagnosis of lupus. We aimed to describe KLIP-associated clinical and immunological features in lupus patients with a retrospective case-control study. METHODS: Thirteen cases of KLIP were included as well as thirty-nine age- and sex-matched control lupus patients without KLIP. At the time of KLIP diagnosis, 4/13 patients (31%) had isolated cutaneous lupus erythematosus (CLE) and 9/13 had (69%) systemic lupus erythematosus (SLE) including 6 (46%) with severe haematological, lung, cardiac or renal disease. KLIP features were observed in skin biopsies of different clinical presentations. RESULTS: Compared with our control group, KLIP patients more frequently had SLE 9/13 (69%) versus 8/39 (21%) (OR 12.9; IC95% [2.86-58.2]; p = 0.0004) and more frequently severe SLE. Two out of four CLE exhibiting KLIP lesions (50%) developed severe SLE with cardiac or renal involvement after 12 and 24 months, respectively.Treatment with thalidomide 100 mg/day allowed rapid and complete clearance of cutaneous lesions in 6/6 KLIP patients. The need to use thalidomide tended to be more frequent in KLIP patients than in controls. CONCLUSION: Our study suggests that KLIP features in lupus skin lesions are associated with SLE and severe systemic features. Despite a limited number of isolated CLE patients with KLIP features in the skin, this observation may warrant closer follow-up on patients with a higher risk of developing SLE.

Regulatory B cell imbalance correlates with Tfh expansion in systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease with fibrosis, microangiopathy and immune dysfunction. B cell abnormalities characterised by autoantibody production and polyclonal B cell activation play an important role in the pathogenesis of SSc. We previously identified an expansion of functional and activated circulating T follicular helper (cTfh) cells in SSc patients. The aim of this study was to analyse the frequency of regulatory B (Breg) cell subsets and the correlation with Tfh in SSc patients. METHODS: Circulating Breg cells CD24hiCD38hi and CD27+CD24hi levels and cTfh cells CD4+CXCR5+PD1+ were determined by cytometry in 50 SSc patients and 32 healthy subjects. RESULTS: The frequency of Breg cells CD24hiCD38hi and CD24hiCD27+ was significantly reduced in patients with SSc as compared to controls (p=0.02 and p<0.001, respectively). In contrast, when examining the CD21low B cell subset, the frequency was significantly increased in SSc patients compared to healthy controls, (p<0.001). There was no difference in Breg cell levels in patients with diffuse SSc and limited SSc. However, CD24hiCD27+ Breg cell frequency was significantly decreased in SSc patients with pulmonary arterial hypertension (p=0.014), but not in patients with interstitial lung disease (p=0.058). Furthermore, we observed a negative correlation between cTfh and CD24hiCD27+ Breg cell levels in SSc patients but not in healthy controls (p=0.02). CONCLUSIONS: These results suggest that Breg cell subsets may participate in the regulation of cTfh and disease severity. Decreased CD24hiCD27+ Breg cell frequency may contribute to the development of SSc.

Clonal haematopoiesis is increased in early onset in systemic sclerosis.

OBJECTIVES: SSc is an autoimmune disease characterized by fibrosis, microangiopathy and immune dysfunctions including dysregulation of proinflammatory cytokines. Clonal haematopoiesis of indeterminate potential (CHIP) is defined by the acquisition of somatic mutations in haematopoietic stem cells leading to detectable clones in the blood. Recent data have shown a higher risk of cardiovascular disease in patients with CHIP resulting from increased production of proinflammatory cytokines and accelerated atherosclerosis. Eventual links between CHIP and autoimmune diseases are undetermined. The aim of our study was to evaluate the prevalence of CHIP in SSc patients and its association with clinical phenotype. METHODS: Forty-one genes frequently mutated in myeloid malignancies were sequenced in peripheral blood mononuclear cells from 90 SSc patients and 44 healthy donors. RESULTS: A total of 15 somatic variants were detected in 13/90 SSc patients (14%) and four somatic variants in 4/44 (9%) healthy donors (HD) (P = 0.58). The prevalence of CHIP was significantly higher in younger SSc patients than in HD: 25% (6/24) vs 4% (1/26) (P = 0.045) under 50 years and 17% (7/42) vs 3% (1/38) (P = 0.065) under 60 years. The prevalence of CHIP in patients over 70 years was similar in SSc patients and healthy donors. The most common mutations occurred in DNMT3A (seven variants). No major clinical differences were observed between SSc patients with or without CHIP. CONCLUSION: Whether CHIP increases the risk to develop SSc or is a consequence of a SSc-derived modified bone marrow micro-environment remains to be explored.

Borderline personality disorder and prior suicide attempts define a severity gradient among hospitalized adolescent suicide attempters.

BACKGROUND: Borderline personality disorder (BPD) and history of prior suicide attempt (SA) have been shown to be high predictors for subsequent suicide. However, no previous study has examined how both factors interact to modify clinical and suicide severity among adolescents. METHODS: This study presents a comprehensive assessment of 302 adolescents (265 girls, mean age = 14.7 years) hospitalized after a SA. To test clinical interactions between BPD and history of prior SA, the sample was divided into single attempters without BPD (non-BPD-SA, N = 80), single attempters with BPD (BPD-SA, N = 127) and multiple attempters with BPD (BPD-MA, N = 95). RESULTS: Univariate analyses revealed a severity gradient among the 3 groups with an additive effect of BPD on the clinical and suicide severity already conferred by a history of SA. This gradient encompassed categorical (anxiety and conduct disorders and non-suicidal-self-injury [NSSI]) and dimensional comorbidities (substance use and depression severity) and suicide characteristics (age at first SA). According to regression analyses, the BPD-MA group that was associated with the most severe clinical presentation also showed specific features: the first SA at a younger age and a higher prevalence of non-suicidal self-injury (NSSI) and anxiety disorders. The BPD-MA group was not associated with higher impulsivity or frequency of negative life events. CONCLUSIONS: Based on these findings and to improve youth suicide prevention, future studies should systematically consider BPD and the efficacy of reinforcing early interventions for anxiety disorders and NSSI.

Repeating a suicide attempt during adolescence: risk and protective factors 12 months after hospitalization.

Suicide attempts (SAs) are a public health concern in adolescence. A brief hospitalization is recommended, but access to inpatient wards is often not available. In addition, numerous risk factors for SA recurrence have been identified, but few studies have explored protective factors. Here, we aimed to assess the role of both risk and protective factors on SA relapse in a context of free access to inpatient services. We performed a prospective follow-up study of 320 adolescents who were hospitalized for an SA between January 2011 and December 2014 in France. Assessments at baseline included socio-demographics, clinical characteristics, temperament, reasons for living, spirituality, and coping. Patients were re-evaluated at 6 months and 12 months for depression severity and SA relapse. A total of 135 and 91 patients (78 girls, 12 boys, aged 13-17) were followed up at 6 and 12 months, respectively. At the 12-month follow-up, 28 (30%) subjects had repeated an SA. Adolescents who either had a history of SA or were receiving psychotropic treatment at baseline were at higher risk of recurrence. Several variables had a protective effect: (1) productive coping skills, namely, working hard and achieving, physical recreation, and seeking relaxing diversions; (2) a particular temperament trait, namely, cooperativeness; and (3) having experienced more life events. We also found a significant interaction: the higher the depression score during follow-up, the lower the protective effect of productive coping. Our findings confirm that a history of SA and seeking psychiatric care with medication are risk factors for SA relapse. However, productive coping strategies and cooperativeness are protective factors, and the improvement of such strategies as well as treatment of persisting depression should be a goal of psychotherapy treatment offered to suicidal adolescents.

Circulating follicular helper T cells are increased in systemic sclerosis and promote plasmablast differentiation through the IL-21 pathway which can be inhibited by ruxolitinib.

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease characterised by widespread fibrosis, microangiopathy and autoantibodies. Follicular helper T (Tfh) cells CD4+CXCR5+PD-1+ cooperate with B lymphocytes to induce the differentiation of plasmocytes secreting immunoglobulins (Ig). Circulating Tfh (cTfh) cells are increased in several autoimmune diseases. However, there are no data about cTfh cells and their interaction with B cells in SSc. The aim of this study was to perform a quantitative and functional analysis of cTfh cells in SSc. METHODS: Using flow cytometry, we analysed cTfh cells from 50 patients with SSc and 32 healthy controls (HC). In vitro coculture experiments of sorted cTfh and B cells were performed for functional analysis. IgG and IgM production were measured by ELISA. RESULTS: We observed that cTfh cell numbers are increased in patients with SSc compared with HC. Furthermore, the increase in cTfh cells was more potent in patients with severe forms of SSc such as diffuse SSc and in the presence of arterial pulmonary hypertension. cTfh cells from patients with SSc present an activated Tfh phenotype, with high expression of BCL-6, increased capacity to produce IL-21 in comparison with healthy controls. In vitro, cTfh cells from patients with SSc had higher capacity to stimulate the differentiation of CD19+CD27+CD38hi B cells and their secretion of IgG and IgM through the IL-21 pathway than Tfh cells from healthy controls. Blocking IL-21R or using the JAK1/2 inhibitor ruxolitinib reduced the Tfh cells' capacity to stimulate the plasmablasts and decreased the Ig production. CONCLUSIONS: Circulating Tfh cells are increased in SSc and correlate with SSc severity. The IL-21 pathway or JAK1/2 blockade by ruxolitinib could be a promising strategy in the treatment of SSc.

Healthcare use by 30,000 patients with irritable bowel syndrome (IBS) in France: a 5-year retrospective and one-year prospective national observational study.

BACKGROUND: Irritable bowel syndrome (IBS) can be responsible for alteration in quality of life and economic burden. The aim of this study was to evaluate healthcare use related to this disorder in France. METHODS: The French health data system was used to select adults covered by the general health scheme (87% of population) through their first IBS hospitalization in 2015. We studied the healthcare refunded during the previous 5 years, 1 year before and after hospitalization. RESULTS: Among 43.7 million adults who used refunded healthcare in 2015, 29,509 patients were identified (0.07, 33% males, 67% females, mean age 52 years, 30% admitted through emergency room). During their hospitalization, 33% had upper endoscopy and 64% colonoscopy. Over the five previous years, 3% had at least one hospitalization with an IBS diagnosis, 58% had abdominal ultrasonography, 27% CT scan, 21% upper endoscopy, 13% colonoscopy and 83% a gastroenterologist visit. The year before, these rates were respectively: 0, 36, 16, 6, 4 and 78%. Some of those rates decreased the year after the hospitalization with respectively: 1, 27, 13, 5, 4 and 19%. The year before, 65% had at least one CRP dosage (13% three or more), 58% a TSH dosage (7%) and 8% a test for coeliac diseases (1%) and the year after: 44% (8%), 43% (5%) and 3% (0.3%). At least one refund of a drug used to treat IBS was found for 85% of patients 5 years before, 65% one year before and 51% one year after. CONCLUSION: This first study using French health data system for healthcare consumption assessment in IBS points out the repetition of outpatient visits, examinations and in particular radiological examinations, without a strong decrease after hospitalization for IBS and gastroenterologist visit.

Subclasses of Monoclonal (Type I) Immunoglobulin G Cryoglobulins: Report on Two Distinct Cases with Myeloma.

BACKGROUND: While different clinical manifestations of IgM and IgG monoclonal cryoglobulins have been demonstrated, little is known about the roles of IgG subclasses in the pathophysiology of these conditions. METHODS: In two cases of myeloma-associated monoclonal (type I) cryoglobulinemia with quite distinct clinical and biological features, serum samples were analyzed using an original IgG subclass-specific immunoblotting technique. RESULTS: The first case had painful arthritis of hands and feet, with skin purpura and a sharp decrease of complement C4 level, and the cryoglobulin was of IgG1 subclass. The second case displayed mostly thrombotic lesions of the limb extremities, C3 and C4 serum levels were normal, and the cryoglobulin belonged to the IgG2 subclass. CONCLUSIONS: Type I cryoglobulins of distinct IgG subclasses may result in different syndromes. In both cases, the treatment relies on eradication of the underlying plasma cell dyscrasia.

Evidence-based treatments for youths with severely dysregulated mood: a qualitative systematic review of trials for SMD and DMDD.

The aim of this literature review was to examine the evidence for psychotherapeutic and pharmacological treatments in subjects with severely dysregulated mood and to identify potential areas for improvements in research designs. A literature search was conducted using several databases for published (PubMed, PsycINFO) and ongoing (clinical trial registries) studies conducted in youths who met NIMH's criteria for Severe Mood Dysregulation (SMD) or the DSM-5 diagnosis of Disruptive Mood Dysregulation Disorder (DMDD). Eight completed studies were identified: three randomized trials, four open pilot studies and one case report. Seven ongoing studies were found in trial registries. The available evidence suggests potential efficacy of psychotherapies which have previously been developed for internalizing and externalizing disorders. The two main pharmacological strategies tested are, first, a monotherapy of psychostimulant or atypical antipsychotic such as risperidone, already used in the treatment of severe irritability in youths with developmental disorders; and second, the use of a serotonergic antidepressant as an add-on therapy in youths treated with psychostimulant. Ongoing studies will further clarify the effectiveness of psychotherapeutic interventions for DMDD individuals and whether they should be given alone or in conjunction with other treatments. The short duration of the trials for a chronic disorder, the low number of studies, the lack of placebo or active comparator arm, and restrictive inclusion criteria in most of the controlled trials dramatically limit the interpretation of the results. Finally, future research should be conducted across multiple sites, with standardized procedures to measure DMDD symptoms reduction, and include a run-in period to limit placebo effect.

Prognostic factors of early death in a cohort of 162 adult haemophagocytic syndrome: impact of triggering disease and early treatment with etoposide.

Reactive haemophagocytic syndrome is a life-threatening disease for which factors influencing the outcome remain unclear. We sought to identify determinants of early mortality in patients with reactive haemophagocytic syndrome by conducting a non-interventional retrospective multicentre study in three tertiary care teaching hospitals over a 6-year period. The medical files of 162 patients fulfilling our diagnostic criteria of haemophagocytic syndrome were reviewed. Patients were classified according to 30-d outcome following diagnosis. Thirty-three patients (20·4%) died within 30 d. Clinical features at diagnosis associated with 30-d death in univariate analysis were older age (P = 0·004), underlying lymphoma (P = 0·04), lower platelet count (P = 0·001) and elevated aspartate aminotransferase and lactate dehydrogenase (P = 0·04 both). The use of etoposide as a first-line treatment tended to be associated with a better outcome (P = 0·079). In multivariate analyses, increasing age, decreasing platelet count, underlying lymphoma and no etoposide in the management were associated with a poorer prognosis (P = 0·03, 0·01, 0·003 and 0·04, respectively). These prognostic factors could help to identify those patients more severely affected by reactive haemophagocytic syndrome, who should benefit from aggressive supportive care, combined with specific treatment of the precipitating factor.

Homeopathy in France in 2011-2012 according to reimbursements in the French national health insurance database (SNIIRAM).

BACKGROUND: The use of homeopathic medicine is poorly described and the frequency of combined allopathic and homeopathic prescriptions is unknown. OBJECTIVE: To analyse data on medicines, prescribers and patients for homeopathic prescriptions that are reimbursed by French national health insurance. METHODS: The French national health insurance databases (SNIIRAM) were used to analyse prescriptions of reimbursed homeopathic drugs or preparations in the overall French population, during the period July 2011-June 2012. RESULTS: A total of 6,705,420 patients received at least one reimbursement for a homeopathic preparation during the 12-month period, i.e. 10.2% of the overall population, with a predominance in females (68%) and a peak frequency observed in children aged 0-4 years (18%). About one third of patients had only one reimbursement, and one half of patients had three or more reimbursements. A total of 120,110 healthcare professionals (HCPs) prescribed at least one homeopathic drug or preparation. They represented 43.5% of the overall population of HCPs, nearly 95% of general practitioners, dermatologists and pediatricians, and 75% of midwives. Homeopathy accounted for 5% of the total number of drug units prescribed by HCPs. Allopathic medicines were coprescribed with 55% of homeopathic prescriptions. CONCLUSION: Many HCPs occasionally prescribe reimbursed homeopathic preparations, representing however a small percentage of reimbursements compared to allopathic medicines. About 10% of the French population, particularly young children and women, received at least one homeopathic preparation during the year. In more than one half of cases, reimbursed homeopathic preparations are prescribed in combination with allopathic medicines.

[Treating accident or chemical attack casualties in hospital]. / Préparer l'accueil de victimes d'accident ou d'attentat chimique à l'hôpital.

It is mandatory for all hospitals to be prepared for the occurrence of a chemical biological, radiological or nuclear (CBRN) event. This preparation requires specific investment on the part of the hospital management, as well as from the nursing teams on the frontline. Teams from Lariboisière hospital in Paris have been working on these risks for several years.

Exhaled NO predicts cyclophosphamide response in scleroderma-related lung disease.

Cyclophosphamide (CYC) is not always effective in patients with scleroderma-related interstitial lung disease (SSc-ILD), hence the need for biomarkers able to predict beneficial responses to CYC therapy. We therefore assessed whether baseline alveolar concentration of nitric oxide (CANO) could predict the favourable response to CYC therapy in patients with SSc-ILD. Nineteen non-smoker patients with SSc-ILD, were enrolled and treated with 6 courses of CYC (0.75 g/m2/monthly) for lung function decline the year before inclusion, and followed-up for 2 years period. We assessed the proportion of favourable response to CYC, defined as improvement of forced vital capacity (FVC) or total pulmonary capacity (TLC) more than 10% between the inclusion and each following visit, according to the validated cut-off of CANO at 8.5 ppb identifying progressive SSc-ILD subset. At inclusion, 7 patients out of 19 had CANO >8.5 ppb. Clinical parameters were comparable between patients with high (>8.5 ppb) and low level of CANO (≤8.5 ppb). After CYC therapy, and during the follow-up, 9 out of 19 patients had favourable response to CYC therapy, 10 did not meet responder's criteria, from whom 4 patients died from respiratory failure. Six out of 7 patients with CANO >8.5 ppb at inclusion had favourable response to CYC therapy, while only 3 out of 12 patients with CANO ≤8.5 ppb responded favourably to CYC therapy (p=0.001). High level of CANO >8.5 ppb reflecting alveolar inflammation identify SSc patients with a greater chance to benefit from CYC treatment with a significant lung function improvement.

Cell cycle and mitosis progression during ZIKA virus infection: The viral non-structural protein NS5 as a master regulator of the APC/cyclosome?

Alterations in cell cycle regulation contribute to Zika virus (ZIKV)-associated pathogenesis and may have implications for the development of therapeutic avenues. As a matter of fact, ZIKV alters cell cycle progression at multiple stages, including G1, S, G2, and M phases. During a cell cycle, the progression of mitosis is particularly controlled to avoid any abnormalities in cell division. In this regard, the critical metaphase-anaphase transition is triggered by the activation of anaphase-promoting complex/cyclosome (APC/C) by its E3 ubiquitin ligase subunit Cdc20. Cdc20 recognizes substrates by interacting with a destruction box motif (D-box). Recently, the ZIKV nonstructural protein 5 (NS5), one of the most highly conserved flavivirus proteins, has been shown to localize to the centrosome in each pole and to spindle fibers during mitosis. Inducible expression of NS5 reveals an interaction of this viral factor with centrosomal proteins leading to an increase in the time required to complete mitosis. By analyzing the NS5 sequence, we discovered the presence of a D-box. Taken together, these data support the idea that, in addition to its role in viral replication, NS5 plays a critical role in the control of the cell cycle of infected cells and, more specifically, in the regulation of the mitotic spindle. Here we propose that the NS5 protein may interfere with the metaphase-anaphase progression, and thus cause the observed delay in mitosis via the regulation of APC/C.