Survival and prognosis factors in systemic sclerosis: data of a French multicenter cohort, systematic review, and meta-analysis of the literature.

BACKGROUND: Data on survival and prognosis factors in incident cohorts are scarce in systemic sclerosis (SStc). To describe survival, standardized mortality ratio (SMR), and prognosis factors in systemic sclerosis (SSc), we analyzed a multicenter French cohort of incident patients and performed a systematic review of the literature and meta-analysis. METHODS: A multicenter, French cohort study was conducted between January 1, 2000, and December 31, 2013. Patients were followed-up until July 1, 2016. A systematic review of the literature was carried out in MEDLINE and EMBASE up to July 2017. Meta-analysis was performed using all available data on SMR and hazard ratios of prognosis factors. RESULTS: A total of 625 patients (493 females, 446 lcSSc) were included. During the study period, 104 deaths (16.6%) were recorded and 133 patients were lost to follow-up. Overall survival rates at 1, 3, 5, and 10 years from diagnosis were 98.0%, 92.5%, 85.9%, and 71.7% respectively in the French cohort. Overall SMR was 5.73 (95% CI 4.68-6.94). Age at diagnosis > 60 years, diffuse cutaneous SSc, scleroderma renal crisis, dyspnea, 6-min walking distance (6MWD), forced vital capacity < 70%, diffusing capacity of the lungs for carbon monoxide < 70%, pulmonary hypertension (PH), telangiectasia, valvular disease, malignancy, anemia, and CRP > 8 mg/l were associated with a poorer survival after adjustment. Eighteen studies (11,719 patients) were included in the SMR meta-analysis and 36 studies (26,187 patients) in the prognosis factor analysis. Pooled SMR was 3.45 (95%CI 3.03-3.94). Age at disease onset, male sex, African origin, diffuse cutaneous SSc, anti-Scl70 antibodies, cardiac and renal involvement, interstitial lung disease, PH, and malignancy were significantly associated with a worse prognosis. Anti-centromere antibodies were associated with a better survival. CONCLUSIONS: Overall, our study highlights a high mortality rate in SSc patients and confirms previously described prognosis factors related to skin extension and organ involvement while identifying additional prognosis factors such as autoantibody status, telangiectasia, 6MWD, and valvular disease.

[Diagnosis of an increased serum level of ferritin]. / Démarche diagnostique devant une hyperferritinémie.

The discovery of a hyperferritinemia is most of the time fortuitous. The diagnostic approach aims at looking for the responsible etiology and at verifying if an iron hepatic overload is present or not. Three diagnostic steps are proposed. The clinical elements and a few straightforward biological tests are sufficient at first to identify one of the four main causes: alcoholism, inflammatory syndrome, cytolysis, and metabolic syndrome. None of these causes is associated with a significant iron hepatic overload. If the transferring saturation coefficient is raised (>50%) a hereditary hemochromatosis should be discussed. Secondly, less common disorders will be discussed. Among these, only the chronic hematological disorders either acquired or congenital are at risk of iron hepatic overload. Thirdly, if a doubt persists in the etiologic research, and the serum ferritin level is very high or continues to rise, it is essential to verify that there is no iron hepatic overload. For that purpose, the MRI with study of the iron overload is the main test, which will guide the therapeutic attitude. Identification of more than a single etiology occurs in more than 40% of the cases.

Measurement of interatrial dyssynchrony using tissue Doppler imaging predicts functional capacity and cardiac involvement in systemic sclerosis.

OBJECTIVES: We aimed to assess the prevalence of interatrial electromechanical dyssynchrony in systemic sclerosis (SSc) patients, and to study the correlation between interatrial delay and standard follow-up parameters. METHODS: Forty consecutive patients with SSc were studied. Classical echocardiographic measurements were obtained, including indices of left ventricular (LV) systolic and diastolic function, right ventricular function, and pulmonary artery pressure (PAP). Left atrial (LA) function was studied using volume measurements. The interatrial mechanical (IAMD) delay was obtained by measuring the time delay between the peak atrial velocities at the lateral tricuspid and mitral annuli using tissue Doppler imaging. A cut-off value of 35 ms was chosen to define the presence of a significant interatrial delay. The IAMD was compared to NYHA class, six-minute walking test (6MWT), NT proBNP levels, and the carbon monoxide diffusion capacity over alveolar volume ratio (DLCO/VA), as well as to classical echocardiographic parameters. RESULTS: Forty percent of patients were found to have significant interatrial dyssynchrony with an IAMD of 35 ms or more. Patients with interatrial dyssynchrony were more symptomatic, had a shorter 6MWT, higher NT proBNP levels, and a lower DLCO/VA compared with those without dyssynchrony. Regarding conventional echocardiographic parameters, increased IAMD was associated with more pronounced LV diastolic dysfunction, LA enlargement and dysfunction, altered RV function, and higher PAP. CONCLUSIONS: IAMD correlated with all of the standard follow-up parameters in SSc, and is probably a sensitive marker of LA involvement. This easy to measure parameter should be added to the routine echocardiographic assessment of these patients.

Severe cardiomyopathy revealing antineutrophil cytoplasmic antibodies-negative eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare form of systemic vasculitis in which cardiac involvement is frequent and severe, and accounts for half of EGPA-related deaths. ANCA-positive EGPA differs from ANCA-negative EGPA in that the former is significantly associated with renal involvement, peripheral neuropathy and biopsy proven vasculitis, whereas the latter is associated with cardiac involvement. Herein, we report a case of EGPA with myocarditis in a woman, who was successfully treated with steroids and cyclophosphamide. This report highlights the importance of diagnosing cardiac involvement in EGPA early, especially in ANCA-negative patients.

Finite element modeling of the radiative properties of Morpho butterfly wing scales.

With the aim of furthering the explanation of iridescence in Morpho butterflies, we developed an optical model based on the finite-element (FE) method, taking more accurately into account the exact morphology of the wing, origin of iridescence. We modeled the photonic structure of a basal scale of the Morpho rhetenor wing as a three-dimensional object, infinite in one direction, with a shape copied from a TEM image, and made out of a slightly absorbing dielectric material. Periodic boundary conditions were used in the FE method to model the wing periodic structure and perfectly matched layers permitted the free-space scattering computation. Our results are twofold: first, we verified on a simpler structure, that our model yields the same result as the rigorous coupled wave analysis (RCWA), and second, we demonstrated that it is necessary to assume an absorption gradient in the true structure, to account for experimental reflectivity measured on a real wing.

Haemolytic-uraemic syndrome during severe lupus nephritis: efficacy of plasma exchange.

Systemic lupus erythematosus (SLE) has been described as a cause of thrombotic microangiopathy, especially thrombotic thrombocytopenic purpura (TTP). Haemolytic-uraemic syndrome (HUS) is less frequent in SLE. We report a case of such an association during an episode of severe lupus nephritis in a young woman, who was successfully treated with steroids, cyclophosphamide and especially plasma exchange with plasma replacement. This report highlights the importance of recognising atypical HUS in SLE patients by looking for schistocytes in case of haemolytic anemia with a negative antiglobulin test, in order to begin plasma exchange.

Scalp vein thrombosis mimicking giant cell arteritis relapse.

Scalp vein thrombosis is an unusual complication during giant cell arteritis. Revealed by headache, it can be misdiagnosed as a disease relapse. An ultrasound scan should rapidly be performed to make the diagnosis, avoiding inappropriate treatment escalation.

Structural origin of the green iridescence on the chelicerae of the red-backed jumping spider, Phidippus johnsoni (Salticidae: Araneae).

The structurally coloured chelicerae of jumping spiders (Salticidae) display some of the most striking of all colours in this family, in which they predominantly occur. Remarkably, however, the source of this iridescence has not been studied. For this reason, we chose to investigate the green iridescent chelicerae of the red-backed jumping spider, Phidippus johnsoni. The colour is restricted to the dorsal region of the basal chelicera segment--the paturon. This was confirmed by reflectance measurements taken at normal incidence and in backscatter, which gave a peak reflectance in the green (520 nm), arising from the first harmonic of a Bragg resonance in the near infrared. Transmission electron microscope analysis of the paturon cuticle revealed a stack of 86 layers of alternating low and high density materials, identified as air and chitin respectively. Simulations based on a periodic multilayer model of the ten outermost layers of this structure gave theoretical reflectance spectra, closely matching those observed, suggesting that the stack functions as a multilayer reflector for green. The colour is thought to function as a conspecific signal, since studies of vision in a closely related species, also displaying green chelicerae, have shown that the eyes have a peak spectral sensitivity, matching that of the chelicerae.

Expression of S100A8 in leukemic cells predicts poor survival in de novo AML patients.

Cytogenetic stratification remains insufficient for almost half of the acute myeloblastic leukemia (AML) cases, with AML patients requiring subsequent molecular investigation. In our study, we used mass spectrometry (MS)-based proteomic approaches to characterize de novo AML. Fifty-four samples (mononuclear cells from bone marrow or peripheral blood mononuclear cells collected and frozen before treatment) from two independent cohorts of newly diagnosed AML patients were analyzed. We showed that the protein signature of leukemic cells defined two clusters that displayed significant variation for overall and disease-free survival (P=0.001 and 0.0004, respectively). This proteomic classification refines the cytogenetic classes. AML patients with intermediate and unfavorable cytogenetic classifications could be subdivided according to their protein profiles into subgroups with significantly different survival rates. Among the proteins expressed by leukemic cells, we isolated a 10,800-Da marker that retained the highest discriminative value between living and deceased patients. The 10,800-Da marker was identified by MS peptide sequencing as S100A8 (also designated MRP8 or calgranulin A). Western blot analysis confirmed its expression mainly in AML patients with the worst prognosis, arguing for a selective deregulation associated with poor prognosis. These results suggest that the expression of S100A8 in leukemic cells is a predictor of low survival.

[Treatment of immune thrombocytopenia: a retrospective study of 40 patients]. / Traitement du purpura thrombopénique immunologique : étude rétrospective de 40 patients.

PURPOSE: Immune thrombocytopenia (ITP) is an auto-immune disease associating a peripheral platelet destruction without increased central production. METHODS: Forty patients with chronic ITP were retrospectively analyzed for clinical and biological presentation and response to treatment. RESULTS: Mean age at diagnosis was 54 years. ITP was revealed by hemorrhage in 65 % of the patients. Despite very low platelet count, no life threatening hemorrhage was observed. Platelet associated antibodies were found in 66 %, usually directed against GPIIb/IIIa. Corticosteroids were used as first line treatment, with response in 54 %, and relapse in 86 %. A response was observed in 42.1 % with dapsone, which was well tolerated, a relapse occurring in 37.5 % of the patients. Rituximab (RTX) allowed a response rate of 42.1 %, prolonged in 40 % of the patients. A response was achieved in 42.9 % cases after splenectomy, without any relapse. No factor was identified to predict the response to treatment. CONCLUSION: ITP is a rare disorder occurring most frequently in middle aged patients. Because of high relapse or no response rates, many treatments should be used. Dapsone offers a good efficacy without major side effects. RTX is well tolerated and allows a good response rate. The use of new agents like thrombopoietin receptor agonist or new therapeutics against B lymphocytes should be defined.

[Excessive sweating related to hydromorphone]. / Sueurs profuses invalidantes sous hydromorphone.

Diffuse and abundant sweating in a middle age patient evolving for several weeks should raise suspicion of malignant lymphoma and infectious or neuroendocrine disorders before considering a drug origin. We report a patient who presented with severe and invalidating excessive sweating related to hydromorphone therapy for vertebral pain. Amongst their many reported side-effects, excessive sweating disappearing with discontinuation of the drug have been reported with some opiates.

[Case-control study evaluating the incidence of hyperhomocysteinemia in cancer patients in an internal medicine department]. / Etude cas témoin évaluant l'incidence de l'hyperhomocystéinémie chez des patients porteurs de néoplasie dans un service de médecine interne.

PURPOSE: Cancer is a cause of venous thromboembolism. However, the physiopathology remains unknown. Hyperhomocysteinemia could be a promoting factor. METHOD: We built a case-control study of 65 patients followed for 2 years to compare levels of homocystéinémie in cancer bearing patients with that in matched cancer free control patients. RESULTS: Fifty per cent of cancer bearing patients had significantly increased blood serum levels of homocystéine (P=0.006). This increase did not correlate with any deficiency in blood serum levels of folate or vitamin B12. CONCLUSION: High levels of homocystéinémie could be linked to tumor proliferation.

[Acute nonalcoholic nonbiliary pancreatitis. Difficulties in diagnosis and possibility of nicotine toxicity]. / Pancréatite aiguë non alcoolique non biliaire. Difficultés du diagnostic etiologique et toxicité possible de la nicotine.

INTRODUCTION: The possibility of nicotine toxicity, although rare, should be considered in cases of acute edematous pancreatitis. CASE: A 30-year-old woman was hospitalized to identify the cause of an initial episode of acute edematous pancreatitis. The observation of native anti-DNA and antiphospholipid antibodies suggested lupus pancreatitis and/or an antiphospholipid syndrome, both subsequently ruled out. The final diagnosis was nicotine poisoning induced by the combination of a nicotine patch and tobacco smoking. CONCLUSION: Although a nicotine patch has never been reported in connection with an episode of acute pancreatitis before, this case suggests that such an event might be a rare complication of an overdose of nicotine.

[Elevation of serum lactate dehydrogenase. Diagnostic, prognostic and evolutive values]. / Elévation des lactates-déshydrogénases sériques. Valeur diagnostique, pronostique et évolutive.

OBJECTIVE: Determination of serum lactate dehydrogenase (LDH) levels is an usual practice. However, its place in the diagnosis process is not clear. We have collected serum LDH levels superior to 2-fold the normal rate and we tried to determine their diagnostics interest and, predictive and progressive values. METHODS: Retrospective study during 3 months in hospitalized adults. LDH levels were measured by spectrophotometry (Normal rate: 313-618 UI/L). RESULTS: 196 cases with LDH level elevations higher than 1236 UI/L were analyzed. The etiology of LDH level elevations were was benign in 60% of cases, malignant in 36% and, undetermined in 5%. There was no difference in between average values of LDH level average values of benign and malignant etiology (2708 vs 2842 UI/l). LDH rates and high LDH level elevations were not helpful for in the diagnosis process (a variety of 43 etiology was able to elevate increased LDH rates). In 45% cases, LDH level was 2 to 3-fold the normal rate; in 47.5% cases, 3 to 10-fold normal rate, and in 7.5% cases, superior to 10-fold normal rate. LDH elevations superior to 10-fold the normal rate were caused by benign etiology in 11 cases and malignant disease in 4 cases. A level superior to 10-fold the normal rate was not helpful in determining to determine the benign or malignant characteristics of the initial disease. However, LDH rate superior to 10 normal rate was a pejorative predictive criteria (hospitalization in intensive careunity in 73% of cases and mortality rate of 53%). During follow up of a neoplasia or malignant hemopathy follow up, several LDH measurements LDH level determinations were determined in for a small number of patients. LDH level normalizations is are attributable to efficientan effective treatment; LDH level elevations are associated with a therapeutic failure echappment. Evolution in LDH levels evolution was influenced by progression in neoplasia and malignant hemopathy evolution and also by various several treatments such as like blood transfusions, growth factors, radiotherapy and chemotherapy. CONCLUSION: LDH level elevation, however whatever its rate, don't seem to do not help in differentiating have interest to differentiate benign from malignant diseases. However, an elevation LDH elevation higher than 10-fold the normal rate is a pejorative predictive criteria, since because the mortality rate is superior toupper than 50%. During follow-up of in the neoplasia and malignant hemopathy follow up, so long as they are measured at distance from treatment, variations in LDH levels are a good marker of evolution, rate variations represent an evolutive marker conditionally the level determination would be realize remote several treatment.

Population pharmacokinetics of everolimus in de novo renal transplant patients: impact of ethnicity and comedications.

BACKGROUND: Everolimus is a macrolide immunosuppressant intended for acute rejection prophylaxis after kidney transplantation. METHODS: A total of 5260 blood samples were collected in the context of two randomized, double-blind, multicenter efficacy trials in 673 patients over a 6-month period after kidney transplantation. The data were evaluated in a nonlinear mixed-effects model. The influence of demographic characteristics (age, weight, sex, and ethnicity) and of comedications on everolimus exposure was explored. RESULTS: For a reference 44-year-old, 71-kg Caucasian kidney allograft recipient receiving everolimus as part of a cyclosporine (INN, ciclosporin)-prednisone immunosuppressive regimen, the absorption rate constant was 6.07 h(-1) (standard error [SE], 0.70 h(-1)), the apparent clearance was 8.8 L/h (SE, 0.2 L/h), and the apparent central distribution volume was 110 L (SE, 5 L). There were no clinically relevant influences of age, weight, or sex on clearance. No significant difference in clearance was detected for Asian patients, whereas black patients had an average clearance that was 20% higher than that of nonblack patients. Patients concomitantly receiving erythromycin or azithromycin had an average 19% lower clearance. One patient receiving itraconazole had a 74% reduction in clearance. After we accounted for covariates, the remaining interindividual variability in clearance was 27% and the variability for distribution volume was 36%. The combined intraindividual and assay/measurement residual error in everolimus blood concentrations was 31%. CONCLUSIONS: Dose adjustment of everolimus on the basis of weight does not appear necessary. Black patients may need a higher dose to achieve exposure that is similar to that of nonblack patients. Concomitant administration of potent inhibitors of the cytochrome P450 isozyme CYP3A may reduce everolimus clearance and increase its blood concentrations.

[Myelodysplasias and systemic diseases. A non-fortuitous association]. / Myélodysplasies et maladies systémiques. Une association non fortuite.

PURPOSE: Myelodysplastic syndromes are clonal hematologic disorders, expanded from myeloid stem cells. A primitive immunologic disorder is discussed. This hypothesis could explain a non-casual association with systemic diseases. The aim of our study is to test this hypothesis. METHODS: We retrospectively investigated the data of 60 patients with myelodysplastic syndromes (group I) hospitalized in our unit from 1990 to 1999. The frequency of systemic disorders was screened and compared to controls (group II). Group II consisted of 120 patients matched for age and sex and hospitalized in the same hospital during the same period. RESULTS: Sixty patients were included (mean age: 83 years old). Myelodysplastic syndrome subtypes were refractory anemia with excessive blasts (52%), refractory anemia (43%) and sideroblastic anemia (5%). Fourteen cases of systemic manifestations were reported in group I (23%) and five in the controls (4%) (P < 0.0001). Systemic manifestations in group I included vasculitis in six cases (42%), polyarthritis in three cases (21%), systemic amyloidosis AA in two cases (14%), relapsing polychondritis in one case, pyoderma gangrenosum in one case and celiac disease associated with a systemic granulomatosis in one case. In the controls, vasculitis was present in four cases and polyarthritis in one. Median age at onset of myelodysplastic syndrome was not influenced by the association with systemic disorders which, in return, have not influenced the myelodysplastic syndromes' subtypes. Myelodysplastic syndromes succeeded to systemic manifestations in 71.4% of cases and could not be attributed to immunosuppressive therapy. CONCLUSIONS: The association of myelodysplastic syndromes with systemic manifestations seems not to be casual. It raises the hypothesis of a primitive immunological disorder in both diseases. Moreover, the description of two cases of systemic amyloidosis and one case of pyoderma gangrenosum might suggest an additional disorder of macrophages or granular cells.

TIMP-1/MMP-9 imbalance in an EBV-immortalized B lymphocyte cellular model: evidence for TIMP-1 multifunctional properties.

Tissue inhibitors of metalloproteinases (TIMPs) were initially described as agents controlling metalloproteinase activity. The purpose of this study was to investigate the expression and the roles of TIMP-1 secreted by Epstein-Barr-virus (EBV)-immortalized B lymphocytes. TIMP-1 was isolated from conditioned medium of interleukin (IL)-1beta stimulated EBV-B lymphocytes; purified TIMP-1 was identified by mass spectrometry and immunochemistry. TIMP-1-free MMP-9 was quantified after purification by zymography and enzyme-linked immunosorbent assay. EBV-B lymphocyte-secreted TIMP-1 inhibited MMP-9 gelatinolytic activity resulting in decreased B-cell transmigration as measured in vitro. The release of huge amounts of TIMP-1 in proportion to MMP-9 from B lymphocytes after EBV transformation was shown to be correlated with secretion of IL-10 and dependent on culture time. In contrast, there was little TIMP-1 and almost no IL-10 released from native B cells, suggesting a possible IL-10 mediated autocrine regulation mechanism of TIMP-1 synthesis. The MMP-9/TIMP-1 imbalance observed in the culture medium of EBV-B lymphocytes (TIMP-1>MMP-9) and of native B cells (MMP-9>TIMP-1) is suggestive of a new function for TIMP-1. We propose that TIMP-1 acts as a survival factor controlling B-cell growth and apoptosis through an autocrine regulation process involving IL-10 secreted by EBV-B lymphocytes.