Publications (16)76.11 Total impact
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Article: High alveolar concentration of nitric oxide is associated with alveolitis in scleroderma.
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ABSTRACT: Alveolar concentration of nitric oxide (C(A)NO) is a non invasive prognostic marker of systemic sclerosis (SSc) lung disease. There is, however, as yet no direct evidence showing concomitant increase of C(A)NO and the presence of inflammatory cells in alveoli. We have therefore measured C(A)NO and performed broncho-alveolar lavage (BAL) in SSc patients. Exhaled NO was measured, by the means of two different models, the two-compartment model (2CM) and the trumpet model with axial diffusion (TMAD), in 22 SSc patients and compared with 15 healthy controls. BAL was performed in all SSc patients. Alveolitis was defined as lymphocytes> 14%, polymorphonuclears> 4%, or eosinophils> 3% on cell count in BAL fluid. Comparisons of C(A)NO levels were made between SSc patients with, and without, alveolitis. Levels of C(A)NO were significantly higher in SSc patients as compared with controls (p<0.001). Median C(A)NO was significantly higher in SSc patients with alveolitis as compared with SSc patients without alveolitis (8.4 ppb; 1(st) and 3(rd) interquartile range: 6.0-10.5 vs 3.3 ppb; 2.2-3.5; p=0.004 for 2CM and 5.4 ppb; 3.2-9.2 vs 3.2 ppb; 1.4-3.3, p=0.02 for TMAD), while bronchial airway output of NO (J'aw NO, p= 0.19), and fractional exhaled NO (F(E)NO, p=0,12) were comparable. C(A)NO was consistently high in SSc patients with alveolitis irrespective of the methods chosen (TMAD or 2CM). Our findings showed that increased C(A)NO was associated with alveolitis in patients with SSc. We submit that C(A)NO could be used as a reliable non-invasive surrogate biomarker of alveolitis in scleroderma lung disease.Nitric Oxide 10/2012; · 3.55 Impact Factor -
Article: Aldolase predicts subsequent myopathy occurrence in systemic sclerosis.
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ABSTRACT: Myopathy related to systemic sclerosis (Myo-SSc) is a disabling and unpredictable complication of SSc. We assessed the predictive value of serum aldolase, creatine kinase (CK), alanine transaminase (ALT), aspartate transaminase (AST) and C-reactive protein (CRP) to estimate the risk of developing Myo-SSc. We enrolled 137 SSc patients without proximal muscle weakness in a prospective monocentric study to follow them longitudinally over a four-year period. The risk of occurrence of Myo-SSc was ascertained according to the European NeuroMuscular Centre criteria and was analyzed according to levels of plasma aldolase, CK, transaminase enzymes and CRP at inclusion. Performance of each parameter to predict Myo-SSc occurrence was assessed and compared with the others. The area under the receiver operating characteristic curves (ROC) of plasma aldolase for Myo-SSc occurrence prediction was 0.80 (95% CI: 0.67 to 0.94, P < 0.001), which was higher than that of plasma CK (0.75, P = 0.01), and that of ALT (0.63, P = 0.04). AST and CRP had no predictive value for Myo-SSc occurrence. The best cut-off of aldolase for prediction of Myo-SSc occurrence within three years after inclusion was 9 U/L and higher than the upper normality limit (7 U/L), unlike that of CK and ALT. Myo-SSc occurred more frequently in patients whose plasma aldolase was higher than 9 U/L. Adjusted Hazard Ratio for patients with aldolase > 9 U/L was 10.3 (95% CI: 2.3 to 45.5), P < 0.001. Increased plasma aldolase level accurately identified SSc patients with high risk to develop subsequent Myo-SSc. This could help initiate appropriate treatment when the disabling muscle damage is still in a reversible stage.Arthritis research & therapy 06/2012; 14(3):R152. · 4.27 Impact Factor -
Article: Brief report: candidate gene study in systemic sclerosis identifies a rare and functional variant of the TNFAIP3 locus as a risk factor for polyautoimmunity.
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ABSTRACT: Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) share some pathophysiologic bases as evidenced by individual and familial polyautoimmunity and common susceptibility genetic factors. With regard to the latter, there has been a recent shift from the "common variant" to the "rare variant" paradigm, since rare variants of TNFAIP3 and TREX1 with large effect sizes have recently been discovered in SLE. The present study was undertaken to investigate whether rare variants of TNFAIP3 and TREX1 are also associated with SSc. TREX1 single-nucleotide polymorphisms (SNPs) rs3135946, rs7626978, rs3135943, and rs11797 and TNFAIP3 SNPs rs9494883, rs72063345, rs5029939, rs2230926, rs117480515, and rs7749323 were genotyped in a discovery set (985 SSc patients and 1,011 controls), and replication analysis of the most relevant results was performed in a second set (622 SSc patients and 493 controls). No association between TREX1 variants and SSc was observed. For TNFAIP3, we first demonstrated that a low-frequency variant, rs117480515, tagged the recently identified TT>A SLE dinucleotide. In the discovery sample, we observed that all tested TNFAIP3 variants were in linkage disequilibrium and were associated with SSc and various SSc subsets, including the polyautoimmune phenotype. We subsequently genotyped rs117480515 in the replication sample and found it to be associated solely with the SSc polyautoimmune subset (odds ratio 3.51 [95% confidence interval 2.28-5.41], P = 8.58 × 10(-9) ) in the combined populations. Genotype-messenger RNA (mRNA) expression correlation analysis revealed that the TNFAIP3 rs117480515 risk allele was associated with decreased mRNA expression. The present findings establish the TNFAIP3 locus as a susceptibility factor for the subset of SSc with a polyautoimmune phenotype. Our results support the implication of rare/low-frequency functional variants and the critical role of A20 in autoimmunity.Arthritis & Rheumatism 04/2012; 64(8):2746-52. · 7.87 Impact Factor -
Article: Alveolar concentration of nitric oxide predicts pulmonary function deterioration in scleroderma.
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ABSTRACT: Respiratory failure is a life-threatening and unpredictable complication of systemic sclerosis (SSc). A study was undertaken to assess the value of alveolar nitric oxide (NO) in predicting the risk of lung function deterioration leading to respiratory failure or death in patients with SSc. 105 patients with SSc were enrolled in this prospective cohort and were followed longitudinally over a 3-year period during which the risk of occurrence of deleterious events was analysed according to alveolar concentration (C(A)NO), conducting airway output (J'(aw)NO) and fractional concentration (F(E)NO(0.05)) of exhaled NO measured at inclusion. Comparison was made between each NO parameter to predict the occurrence of deleterious events, defined as a 10% decrease in total lung capacity or forced vital capacity from baseline, or death. The area under the receiver operating characteristic curve of C(A)NO to predict the occurrence of the combined events was 0.84 (95% CI 0.76 to 0.92; p<0.001), which was significantly higher than those of J'(aw)NO and F(E)NO(0.05) (p<0.001). A cut-off of C(A)NO of 5.3 ppb had a sensitivity of 88% and a specificity of 62% for the prediction of the occurrence of combined events during follow-up, and was validated in an independent cohort of patients with SSc. Combined events occurred more frequently in patients whose C(A)NO was >5.3 ppb. The adjusted HR for patients with C(A)NO >5.3 ppb was 6.06 (95% CI 2.36 to 15.53; p<0.001). C(A)NO accurately predicted the occurrence of combined events irrespective of forced vital capacity values or the presence of interstitial lung disease at baseline. Increased C(A)NO accurately identifies patients with SSc with a high risk of developing lung function deterioration and may help to initiate early appropriate treatment.Thorax 02/2012; 67(2):157-63. · 6.84 Impact Factor -
Article: Comparing HLA shared epitopes in French Caucasian patients with scleroderma.
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ABSTRACT: Although many studies have analyzed HLA allele frequencies in several ethnic groups in patients with scleroderma (SSc), none has been done in French Caucasian patients and none has evaluated which one of the common amino acid sequences, (67)FLEDR(71), shared by HLA-DRB susceptibility alleles, or (71)TRAELDT(77), shared by HLA-DQB1 susceptibility alleles in SSc, was the most important to develop the disease. HLA-DRB and DQB typing was performed for a total of 468 healthy controls and 282 patients with SSc allowing FLEDR and TRAELDT analyses. Results were stratified according to patient's clinical subtypes and autoantibody status. Moreover, standardized HLA-DRß1 and DRß5 reverse transcriptase Taqman PCR assays were developed to quantify ß1 and ß5 mRNA in 20 subjects with HLA-DRB1*15 and/or DRB1*11 haplotypes. FLEDR motif is highly associated with diffuse SSc (χ(2) = 28.4, p<10-6) and with anti-topoisomerase antibody (ATA) production (χ(2) = 43.9, p<10-9) whereas TRAELDT association is weaker in both subgroups (χ(2) = 7.2, p = 0.027 and χ(2) = 14.6, p = 0.0007 respectively). Moreover, FLEDR motif- association among patients with diffuse SSc remains significant only in ATA subgroup. The risk to develop ATA positive SSc is higher with double dose FLEDR than single dose with respectively, adjusted standardised residuals of 5.1 and 2.6. The increase in FLEDR motif is mostly due to the higher frequency of HLA-DRB1*11 and DRB1*15 haplotypes. Furthermore, FLEDR is always carried by the most abundantly expressed ß chain: ß1 in HLA DRB1*11 haplotypes and ß5 in HLA-DRB1*15 haplotypes.In French Caucasian patients with SSc, FLEDR is the main presenting motif influencing ATA production in dcSSc. These results open a new field of potential therapeutic applications to interact with the FLEDR peptide binding groove and prevent ATA production, a hallmark of severity in SSc.PLoS ONE 01/2012; 7(5):e36870. · 4.09 Impact Factor -
Article: Digestive tract involvement in systemic sclerosis.
Autoimmunity reviews 11/2011; 11(1):68-73. · 6.37 Impact Factor -
Article: Increased alveolar concentration of nitric oxide is related to serum-induced lung fibroblast proliferation in patients with systemic sclerosis.
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ABSTRACT: Lung inflammation is present in patients with systemic sclerosis (SSc) and interstitial lung disease (ILD), but the mechanisms linking inflammatory and fibrotic processes in ILD are unknown. Our aim was to investigate whether alveolar inflammation, reflected by increased alveolar concentration of exhaled nitric oxide (C(A)NO), is related to the ability of serum from patients with SSc to induce pulmonary fibroblast proliferation (PFP) and myofibroblast conversion. C(A)NO was measured in all subjects (37 patients with SSc and 10 healthy controls) whose sera were used to stimulate PFP (assessed by BrdU labeling index) and myofibroblast conversion (detected by alpha-smooth muscle actin expression). The PFP index in patients with SSc was compared to control values, and between patients with SSc who had elevated (> 4.3 ppb) and normal (<or= 4.3 ppb) C(A)NO values. Both C(A)NO and the PFP index were significantly greater in patients with SSc compared to controls. In patients with SSc, the PFP index was directly related to C(A)NO levels (r = 0.48; p = 0.002). The median PFP index was significantly higher in patients with SSc who had elevated C(A)NO (> 4.3 ppb; n = 25, median 1.1, range 0.98-1.23) than in patients with SSc who had normal C(A)NO (<or= 4.3 ppb; n = 12, median 0.93, range 0.82-1.08; p = 0.01). Similarly, myofibroblast conversion induced by SSc serum was significantly greater in patients with C(A)NO > 4.3 ppb than in patients whose C(A)NO was <or= 4.3 ppb (p < 0.001) and controls (p < 0.001). Alveolar inflammation reflected by increased nitric oxide production was related to serum-induced PFP and myofibroblast conversion, linking the active alveolitis process to cell proliferation and lung fibrosis in patients with SSc.The Journal of Rheumatology 08/2010; 37(8):1680-7. · 3.69 Impact Factor -
Article: Clinical features of scleroderma patients with or without prior or current ischemic digital ulcers: post-hoc analysis of a nationwide multicenter cohort (ItinérAIR-Sclérodermie).
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ABSTRACT: Digital ulcers are the most frequent vascular manifestations of systemic sclerosis (SSc). Clinical features of patients with prior or current digital ulcers have not been extensively described. This cross-sectional analysis of a large multicenter cohort compared the characteristics of SSc patients with prior or current digital ulcers with those never affected. Patients with prior/current digital ulcers or never affected were identified in the cohort of SSc patients enrolled in the French ItinérAIR-Sclérodermie registry. Rodnan skin scores, pulmonary function test results, and clinical and immunological data were analyzed to identify digital ulcerassociated clinical features. Of 599 SSc patients, 317 had prior or current digital ulcers. These patients were more frequently male, with impaired diffusing capacity for carbon monoxide (DLCO), and higher Rodnan skin scores than patients never affected by digital ulcers. In a multivariate analysis, male gender, early onset of SSc, increased duration of SSc, high Rodnan skin score, and presence of anti-topoisomerase I antibodies (anti-topo I) were associated with prior or current digital ulcers. Comparison of patients with current digital ulcers versus patients never affected indicated that affected patients had increased duration of SSc, impaired DLCO, increased Rodnan score, and younger age at onset of SSc. Male patients with early onset SSc, more severe skin fibrosis, impaired DLCO, and anti-topo I were most likely to exhibit prior or current digital ulcers. Confirmation of these results in a prospective longitudinal study may enable identification of patients at greatest risk of developing digital ulcers, facilitating management of this disabling complication.The Journal of Rheumatology 07/2009; 36(7):1470-6. · 3.69 Impact Factor -
Article: The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France.
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ABSTRACT: An algorithm for the detection of pulmonary arterial hypertension (PAH), based on the presence of dyspnea and the findings of Doppler echocardiographic evaluation of the velocity of tricuspid regurgitation (VTR) and right-sided heart catheterization (RHC), which was applied in a large multicenter systemic sclerosis (SSc) population, estimated the prevalence of PAH to be 7.85%. The aim of this observational study was to investigate the incidence of PAH and pulmonary hypertension (PH) during a 3-year followup of patients from the same cohort (the ItinérAIR-Sclérodermie Study). Patients with SSc and without evidence of PAH underwent evaluation for dyspnea and VTR at study entry and during subsequent visits. Patients in whom PAH was suspected because of a VTR of 2.8-3.0 meters/second and unexplained dyspnea or a VTR of >3.0 meters/second underwent RHC to confirm the diagnosis. A total of 384 patients were followed up for a mean+/-SD of 41.03+/-5.66 months (median 40.92 months). At baseline, 86.7% of the patients were women, and the mean+/-SD age of the patients was 53.1+/-12.0 years. The mean+/-SD duration of SSc at study entry was 8.7+/-7.6 years. After RHC, PAH was diagnosed in 8 patients, postcapillary PH in 8 patients, and PH associated with severe pulmonary fibrosis in 2 patients. The incidence of PAH was estimated to be 0.61 cases per 100 patient-years. Two patients who exhibited a mean pulmonary artery pressure of 20-25 mm Hg at baseline subsequently developed PAH. The estimated incidence of PAH among patients with SSc was 0.61 cases per 100 patient-years. The high incidence of postcapillary PH highlights the value of RHC in investigating suspected PAH.Arthritis & Rheumatism 06/2009; 60(6):1831-9. · 7.87 Impact Factor -
Article: Exhaled nitric oxide, but not serum nitrite and nitrate, is a marker of interstitial lung disease in systemic sclerosis.
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ABSTRACT: Nitric oxide metabolites (NOx) in serum, and alveolar concentration of NO (CA(NO)), are markers of inflammation and alveolitis, respectively, in systemic sclerosis (SSc). We prospectively evaluated the usefulness of both NOx and CA(NO) to assess lung involvement and skin fibrosis in SSc. Serum NOx, and CA(NO) measured by two different methods, namely the two-compartment (2CM) and the "trumpet" models (TM), were concomitantly assessed in 65 patients with SSc and 17 healthy controls. Whilst serum NOx remained comparable between groups, CA(NO) were significantly higher in SSc patients (n=65, 6.7ppb; 4.8-9.7 and 5.9ppb; 3.9-8.9) as compared with controls (n=17, 3.0ppb; 2.0-3.8 and 1.8ppb; 1.1-2.9, p<0.001, p<0.001) using the 2CM and the TM, respectively). CA(NO) from SSc patients with interstitial lung disease (ILD) (n=26, 8.6ppb; 6.5-10.9 and 8.5ppb; 5.9-10.7) or pulmonary arterial hypertension (n=12, 7.3ppb; 6.5-10.4 and 6.9ppb; 5.4-9.9) were significantly higher as compared with patients without ILD (n=27, 4.9ppb; 3.8-6.5 and 4.7ppb; 2.8-5.7; p<0.001 and p<0.001) using the 2CM and the TM, respectively). CA(NO) assessed either by the 2CM or the trumpet model were directly related to the extent of ILD and inversely related to DLCO. There was no correlation between NOx and ILD, or DLCO. Neither CA(NO) nor NOx was correlated with skin fibrosis and no relationship was found between CA(NO) and NOx. Alveolar concentration of NO, but not serum NOx, closely correlates with the extent of ILD in patients with systemic sclerosis. Neither parameter, however, is related to skin fibrosis.Nitric Oxide 12/2008; 20(3):200-6. · 3.55 Impact Factor -
Article: Digital photography as an operational tool for assessing corticosteroid-induced lipodystrophy.
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ABSTRACT: Corticosteroid-induced lipodystrophy (CIL) is exclusively diagnosed in a subjective manner. To evaluate the reliability of digital photographs in the diagnosis of CIL. All consecutive patients starting long-term, high dosage corticosteroid therapy were photographed at baseline and after 3 months of therapy. At the end of the study, 3 physicians with expertise in corticosteroids classified patients as lipodystrophic yes/no/unclassifiable. Photographs analyses performed by 9 medical readers and evaluation of CIL using visual analog scale (VAS) performed during the M3 visit were compared to this classification. Eighty-eight patients were monitored. Fifty of them were classified by the 3 experts as lipodystrophic and 30 as not lipodystrophic (8 were unclassifiable). Their intra- and inter-observer agreements were moderate or fair (kappa coefficient<or=0.57) when month 3 photographs were analysed alone and substantial or near perfect (kappa coefficient>or=0.75) when M3 photographs were analysed beside baseline ones. By comparison with expert consensus, only 3 out of 4 patients were correctly classified using VAS. The AUROC curve and inter-observer agreement significantly improved with experience for the 9 non-experts. The use of digital photographs do better than VAS to evaluate CIL. The accuracy of diagnosis improves with experience. Morphological changes are more important than morphological phenotype.European Journal of Internal Medicine 07/2008; 19(5):340-4. · 2.00 Impact Factor -
Article: Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study.
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ABSTRACT: Screening allows for early management of pulmonary arterial hypertension (PAH), a severe complication of systemic sclerosis (SSc). Since no consensus has been reached on the method and criteria for optimal screening, we sought to develop an algorithm based on symptoms, Doppler echocardiography, and right heart catheterization (RHC) for application to a nationwide multicenter SSc population in France. This prospective study was conducted from September 2002 to July 2003 by experts at 21 SSc centers. At each center, SSc patients without severe pulmonary function abnormalities underwent Doppler echocardiography by an experienced cardiologist. Patients with a peak velocity of tricuspid regurgitation (VTR) of >3 meters/second or 2.5-3 meters/second with unexplained dyspnea were asked to undergo RHC to confirm PAH according to international guidelines. Of the 599 patients analyzed, 29 had known PAH and 33 had suspected PAH, based on Doppler echocardiography, and underwent RHC. Of these 33, 18 were found to have PAH, 3 had left ventricular dysfunction, and 12 had no PAH. Newly diagnosed cases of PAH were of mild severity (mean +/- SD pulmonary artery pressure [mPAP] 30 +/- 9 mm Hg, mean +/- SD total pulmonary resistance [TPR] 524 +/- 382 dynes x second/cm(5)). Hemodynamic findings in patients with known PAH were mPAP 49 +/- 17 mm Hg and TPR 1,007 +/- 615 dynes x second/cm(5). The estimate of PAH prevalence was 7.85% (95% confidence interval 5.70-10.00). This screening algorithm, based on dyspnea, Doppler echocardiographic evaluation of VTR, and RHC, enabled early detection of PAH at a mild stage. Whether mild PAH will evolve to severe PAH in reported cases and whether this early diagnosis translates into improved prognosis for patients with mild PAH will be evaluated in the ongoing 3-year followup of this cohort.Arthritis & Rheumatism 01/2006; 52(12):3792-800. · 7.87 Impact Factor -
Article: Variability of the RNase L isoform ratio (37 kiloDaltons/83 kiloDaltons) in diagnosis of chronic fatigue syndrome.
Clinical and Diagnostic Laboratory Immunology 03/2005; 12(2):366. · 2.51 Impact Factor -
Article: RNase L levels in peripheral blood mononuclear cells: 37-kilodalton/83-kilodalton isoform ratio is a potential test for chronic fatigue syndrome.
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ABSTRACT: Chronic fatigue syndrome (CFS) is a disorder characterized by debilitating fatigue associated with immunological abnormalities. The etiology remains unclear. A low-molecular-mass (37 kDa) isoform of RNase L has been described in peripheral blood mononuclear cell (PBMC) extracts, and the ratio of two isoforms of RNase L (37 kDa/83 kDa) has been proposed as a potential biochemical marker of CFS. In a prospective case-control study, we tested whether the RNase L 37-kDa/83-kDa ratio could discriminate a SFC population. We compared the ratio of RNase L isoforms in PBMCs from 11 patients with CFS (6 women and 5 men; mean age +/- standard deviation, 43.2 +/- 13.8 years) and PBMCs from 14 healthy well-matched volunteers (10 women and 4 men; age, 39.1 +/- 11.6 years). A ratio of RNase L of 0.4 used as a threshold allowed diagnosis of CFS with high sensitivity (91%; 95% confidence interval [CI], 57 to 99%) and specificity (71%; 95% CI, 41 to 90%). The positive and negative prognostic values were 71% (95% CI, 41 to 90%) and 91% (95% CI, 57 to 99%), respectively. In the absence of acute infection or chronic inflammation, a high RNase L ratio could distinguish CFS patients from healthy volunteers. Additional large studies and follow-up studies are required to confirm the stability of this high ratio of RNase L isoforms in a CFS group.Clinical and Diagnostic Laboratory Immunology 04/2003; 10(2):315-6. · 2.51 Impact Factor -
Article: Pantoprazole-induced recurrent anaphylactic shock.
The American Journal of Gastroenterology 12/2002; 97(11):2933. · 7.28 Impact Factor -
Article: Association study of 3 rheumatoid arthritis risk loci in systemic sclerosis in European Caucasian population.
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ABSTRACT: Accumulating evidences show that shared autoimmunity is critical for the pathogenesis of many inflammatory rheumatic conditions. Specific phenotype could arise from specific genes, and/or combination of genetic factors and environment. Systemic sclerosis (SSc) belongs to connective tissue disorders and recent data have highlighted strong associations with some autoimmunity genes shared with other autoimmune diseases. To determine whether novel risk loci associated with rheumatoid arthritis (RA) may confer susceptibility to SSc. Single nucleotide polymorphism from CCL21, CD244 and CDK6 were tested for association. SNPs harbouring association with RA, CCL21-rs2812378, CDK6-rs42041 and CD244-rs6682654 were genotyped in a cohort of 1031 SSc patients and 1014 controls. All individuals were of European Caucasian origin. The three polymorphisms were in Hardy-Weinberg equilibrium in the control population and allelic frequencies were similar to those expected in European populations. Allelic and genotypic frequencies for these three polymorphisms were found to be similar in SSc patients and controls. Moreover, sub-phenotype analyses in particular for subgroups having diffuse subcutaneous subtype, specific auto-antibodies or fibrosing alveolitis did not detect any difference between SSc patients and controls. These results obtained through a large cohort of European Caucasian SSc patients do not support the implication of CCL21, CD244 and CDK6 genes in the pathogenesis of SSc although these genes were recently identified as RA susceptibility genes.Clinical and experimental rheumatology 29(2 Suppl 65):S6-9. · 2.15 Impact Factor
Top co-authors
Top Journals
Institutions
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2012
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Assistance Publique – Hôpitaux de Paris
Paris, Ile-de-France, France
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2008–2012
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Université Pierre et Marie Curie Paris 6
Paris, Ile-de-France, France
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2010
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Université René Descartes - Paris 5
- Faculté de Médecine
Paris, Ile-de-France, France
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