Efficacy of Nanoencapsulated Daptomycin in an Experimental Methicillin-Resistant Staphylococcus aureus Bone and Joint Infection Model.

Staphylococcus aureus bone infections remain a therapeutic challenge, leading to long and expensive hospitalizations. Systemic antibiotic treatments are inconsistently effective, due to insufficient penetration into the infectious site. In an osteomyelitis model, the single local administration of nanoparticle-encapsulated daptomycin allows sterilization of the infectious sites after 4 and 14 days of treatment, while daily systemic daptomycin treatment for 4 days was not effective. These results demonstrate the great potential of this local antibiotic treatment.

Autoantibodies to human citrullinated fibrinogen and their subfamilies to the α36-50Cit and ß60-74Cit fibrin peptides similarly predict radiographic damages: a prospective study in the French ESPOIR cohort of very early arthritides.

OBJECTIVE: To investigate whether subfamilies of the RA-specific autoantibodies to human citrullinated fibrinogen (AhFibA) differentially associate with the RA risk factors, HLA-DRB1 shared epitope containing alleles (SE alleles) and cigarette smoking, and thus help to predict the disease outcome. METHODS: AhFibA and their anti-α36-50Cit and anti-ß60-74Cit subfamilies were assayed by ELISA, at baseline, in the French ESPOIR (Etude et Suivi des Polyarthrites Indifférenciées Récentes) cohort composed of undifferentiated arthritides and RA patients of < 6 months' duration. Cigarette smoking, SE alleles' presence, DAS28, HAQ and modified Sharp-van der Heijde Score data were obtained at baseline, and after follow-up. RESULTS: After 3 years, 701 patients were classified as having RA according to the ACR/EULAR 2010 criteria. Among them, 349 (50%), 203 (29%) and 257 (37%) were AhFibA-, anti-α36-50Cit- and anti-ß60-74Cit-positive, respectively. The presence and titres of AhFibA and their subfamilies similarly associated with SE alleles, irrespective of their fine specificity, without significant effect of smoking. Neither their presence nor their titre was associated with DAS28 or HAQ. The presence of at least one subfamily was associated with a faster Sharp/van der Heijde score progression, albeit without correlation with the titre. CONCLUSION: AhFibA and their main subfamilies are similarly associated with SE alleles without additional effect of smoking. Whatever their fine specificity was, their presence (but not their titre) similarly constituted a marker of faster joint destruction.

Non-TNF-Targeted Biologic vs a Second Anti-TNF Drug to Treat Rheumatoid Arthritis in Patients With Insufficient Response to a First Anti-TNF Drug: A Randomized Clinical Trial.

IMPORTANCE: One-third of patients with rheumatoid arthritis show inadequate response to tumor necrosis factor α (TNF-α) inhibitors; little guidance on choosing the next treatment exists. OBJECTIVE: To compare the efficacy of a non-TNF-targeted biologic (non-TNF) vs a second anti-TNF drug for patients with insufficient response to a TNF inhibitor. DESIGN, SETTING, AND PARTICIPANTS: A total of 300 patients (conducted between 2009-2012) with rheumatoid arthritis, with persistent disease activity (disease activity score in 28 joints-erythrocyte sedimentation rate [DAS28-ESR] ≥ 3.2 [range, 0-9.3]) and an insufficient response to anti-TNF therapy were included in a 52-week multicenter, pragmatic, open-label randomized clinical trial. The final follow-up date was in August 2013. INTERVENTIONS: Patients were randomly assigned (1:1) to receive a non-TNF-targeted biologic agent or an anti-TNF that differed from their previous treatment. The choice of the biologic prescribed within each randomized group was left to the treating clinician. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients with good or moderate response according to the European League Against Rheumatism (EULAR) scale at week 24. Secondary outcomes included the EULAR response at weeks 12 and 52; at weeks 12, 24, and 52; DAS28ESR, low disease activity (DAS28 ≤3.2), remission (DAS28 ≤2.6); serious adverse events; and serious infections. RESULTS: Of the 300 randomized patients (243 [83.2%] women; mean [SD] age, 57.1 [12.2] years; baseline DAS28-ESR, 5.1 [1.1]), 269 (89.7%) completed the study. At week 24, 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response (OR, 2.06; 95% CI, 1.27-3.37; P = .004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group than in the second anti-TNF group (mean difference adjusted for baseline differences, -0.43; 95% CI, -0.72 to -0.14; P = .004). At weeks 24 and 52, more patients in the non-TNF group vs the second anti-TNF group showed low disease activity (45% vs 28% at week 24; OR, 2.09; 95% CI, 1.27 to 3.43; P = .004 and 41% vs 23% at week 52; OR, 2.26; 95% CI, 1.33 to 3.86; P = .003). CONCLUSIONS AND RELEVANCE: Among patients with rheumatoid arthritis previously treated with anti-TNF drugs but with inadequate primary response, a non-TNF biologic agent was more effective in achieving a good or moderate disease activity response at 24 weeks than was the second anti-TNF medication. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01000441.

Body mass index and response to infliximab in rheumatoid arthritis.

OBJECTIVES: Excess adipose tissue in obese individuals may have immunomodulating properties and pharmacokinetics consequences. Previous studies have suggested that obesity could negatively affect the response to anti-TNF-α agents, notably infliximab (IFX). We aimed to determine whether body mass index (BMI) is involved in the response to IFX in rheumatoid arthritis (RA). METHODS: We retrospectively examined data for 76 RA patients receiving IFX. BMI was calculated before treatment, and change from baseline in DAS28, pain on a visual analog scale, erythrocyte sedimentation rate, C-reactive protein level, tender and swollen joint count was analysed at 6 months after treatment. The primary outcome was decrease in DAS28 ≥1.2. Secondary outcomes were good response and remission according to EULAR. RESULTS: At baseline, the median [interquartile range] BMI was 26.6 [22.6-30.6] kg/m2. The number of patients with normal weight, overweight and obesity was 25, 29 and 22. In multivariable analyses, IFX treated patients with lower BMI showed a more frequent DAS28 decrease ≥1.2 (25.5 [22.3-28.3] vs. 28.0 [23.2-32.5], p=0.02, odds ratio [OR] 0.88 [95% confidence interval 0.79-0.98]), EULAR good response (25.3 [21.9-27.5] vs. 27.5 [24.3-31.2], p=0.03, OR 0.87 [0.76-0.99]) and EULAR remission, although not significant (25.3 [21.9-26.4] vs. 27.5 [23.2-30.9], p=0.14, OR 0.88 [0.75-1.04]). CONCLUSIONS: Obesity may negatively influence the response to IFX in RA. These data could help physicians to choose biologic agents for obese RA patients.

Quantification of the atmospheric scintillation for laser illumination in active imaging.

Most of the analytical scintillation models used by experts to simulate the illumination performances of active imaging systems are based on the use of monochromatic, punctual, and coherent sources. These analytical models seem pessimistic regarding lightpipe-based illumination techniques. Outdoor trials have been made with 1.57 µm laser illuminators with and without lightpipe to record illumination maps and associated refractive index structure parameter C(n)2 with a propagation distance of 1 km. Analysis shows a reduction of the scintillation by a factor of 2.5 comparing analytical models and laser illumination with lightpipe.

Association study of CRP gene in systemic sclerosis in European Caucasian population.

Opsonization and apoptotic cell elements are critical in systemic lupus erythematosus (SLE) and could act through the activation of the innate immunity. C-reactive protein (CRP) belongs to opsonins, and polymorphisms of CRP gene have been shown to be associated with SLE susceptibility. Accumulating evidences show that SLE and systemic sclerosis (SSc) share some genetic susceptibility factors. To determine whether polymorphisms of CRP confer susceptibility to SSc, four SNPs (rs1130864, rs1205, rs1800947 and rs1341665), chosen using Hapmap linkage disequilibrium data and published data, were genotyped in a cohort of 651 SSc patients (569 with antinuclear antibodies, 258 with anti-centromere and 153 with anti-topoisomerase I) and 442 controls. All individuals were of French Caucasian origin. The four polymorphisms were in Hardy-Weinberg equilibrium in the control population. Allelic and genotypic frequencies for these four polymorphisms were found to be similar in SSc patients and controls. Moreover, subphenotype analyses in particular for subgroups having antinuclear antibodies 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 CRP gene in the pathogenesis of SSc.

Autoantibodies to citrullinated fibrinogen compared with anti-MCV and anti-CCP2 antibodies in diagnosing rheumatoid arthritis at an early stage: data from the French ESPOIR cohort.

OBJECTIVES: To compare the performance of anticitrullinated peptides/protein antibodies (ACPA) detected by three immunoassays in the French ESPOIR cohort of patients with early rheumatoid arthritis (RA) and undifferentiated arthritis (UA) and to study the relationship between ACPA and disease activity. METHODS: A diagnosis of RA (1987 American College of Rheumatology (ACR) criteria) was established at baseline in 497 patients and after a 2-year follow-up in 592 patients. At baseline, antibodies to citrullinated fibrinogen (AhFibA), antimutated citrullinated vimentin (anti-MCV) and anticyclic citrullinated peptide (anti-CCP2) were assayed and the individual and combined diagnostic sensitivities and predictive values of the tests were determined. Relationships between ACPA positivity and the 28-joint disease activity score and Health Assessment Questionnaire scores were analysed. RESULTS: At a diagnostic specificity of at least 98%, the three tests exhibited similar diagnostic sensitivities (47-48.5%). When considering as positive patients with at least one positive test, the sensitivity increased to 53.5% with a probable loss of specificity. Among the patients classified as having UA at baseline, 30% were positive for one ACPA, the positive predictive values for RA of the three tests ranging from 73% to 80% but increasing when two tests were associated. Whatever the test used, the addition of ACPA positivity to the 1987 criteria enhanced their sensitivity by 6%, close to that of the 2010 ACR/European League Against Rheumatism (EULAR) criteria. CONCLUSIONS: In early arthritis, AhFibA, anti-MCV and anti-CCP2 showed similar diagnostic sensitivity with a high diagnostic specificity and a similar high positive predictive value for RA. Adding ACPA to the 1987 ACR criteria significantly increased the number of patients classified as having RA, confirming the validity of the recent inclusion of the serological criterion in the ACR/EULAR criteria.

Efficacy of rituximab in systemic manifestations of primary Sjogren's syndrome: results in 78 patients of the AutoImmune and Rituximab registry.

OBJECTIVES: To evaluate the efficacy and safety of rituximab in patients with primary Sjögren's syndrome (pSS). METHODS: The AutoImmune and Rituximab registry has included 86 patients with pSS treated with rituximab, prospectivey followed up every 6 months for 5 years. RESULTS: Seventy-eight patients with pSS (11 men, 67 women), who already had at least one follow-up visit, were analysed. Median age was 59.8 years (29-83), median duration of disease was 11.9 years (3-32). Indications for treatment were systemic involvement for 74 patients and only severe glandular involvement in four patients. The median European Sjögren's Syndrome disease activity index (ESSDAI) was 11 (2-31). 17 patients were concomitantly treated with another immunosuppressant agent. Median follow-up was 34.9 months (6-81.4) (226 patient-years). Overall efficacy according to the treating physician was observed in 47 patients (60%) after the first cycle of rituximab. Median ESSDAI decreased from 11 (2-31) to 7.5 (0-26) (p<0.0001). Median dosage of corticosteroid decreased from 17.6 mg/day (3-60) to 10.8 mg/day (p=0.1). Forty-one patients were retreated with rituximab. Four infusion reactions and one delayed serum sickness-like disease resulted in rituximab discontinuation. Three serious infections (1.3/100 patient-years) and two cancer-related deaths occurred. CONCLUSIONS: In common practice, the use of rituximab in pSS is mostly restricted to patients with systemic involvement. This prospective study shows good efficacy and tolerance of rituximab in patients with pSS and systemic involvement.

Brief report: candidate gene study in systemic sclerosis identifies a rare and functional variant of the TNFAIP3 locus as a risk factor for polyautoimmunity.

OBJECTIVE: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Pattern recognition analysis of digital ECGs: decreased QT measurement error and improved precision compared to semi-automated methods.

BACKGROUND AND PURPOSE: Machine-read QT measurements employing T-wave detection algorithms (ALG) are not accepted by regulatory agencies for the primary analysis of thorough QT (TQT) studies. Newly developed pattern recognition software (PRO) which matches ECG waveforms to user-defined templates may improve this situation. METHODS: We compared RR, QT, QTc, QT variability, T-end measurement errors, and individual QT rate correction factors and their associated coefficients of determination (R(2)) following ALG and PRO analysis. Machine-read QTc values were compared with core laboratory semi-automated (SA) values for verification. RESULTS: Compared to ALG, PRO reduced the frequency of T-end measurement errors (5.6% vs. 0.1%), reduced the intra-individual QT variability (12.6±5.9 vs. 4.9±1.1ms) and allowed the recovery of 3/58 subjects that exhibited an unacceptable (<0.9) R(2). CONCLUSIONS: PRO adjusted for ALG-based T-end measurement errors and provided an accurate and precise automated method for continuous QT analysis, thus offering an alternative to resource-intensive semi-automated analyses currently performed by ECG core laboratories.

Comparative TQT analysis with three fully-automated platforms: comparison to core laboratory semi-automated results.

BACKGROUND AND PURPOSE: Technological advances in machine-read QT measurement now enable detailed and precise cardiac repolarization assessments. This study assessed the applicability of three state-of-art ECG measurement applications to provide reliable continuous analyses from data obtained in a positive thorough QT study previously characterized with sparse semi-automated measurements performed by an ECG core laboratory. METHODS: Continuous RR, QT, QTc measurements, and individual QT/RR relationships and their associated intra- and inter-subject variability were derived in parallel with BioQT, Ponemah PRO, and WinAtrec analysis software. RESULTS: Despite slight vendor-specific differences in measurement variability and QTc, all machine-read methods demonstrated requisite assay sensitivity and yielded similar conclusions in accordance with SA analysis. CONCLUSIONS: Three commercially available ECG analytical software applications reliably detected the drug-induced QT prolonging effects and replicated the SA core-laboratory conclusions, with greatly improved temporal resolution and reduced analytical costs. With broader experience, these data suggest that current SA methodologies could be effectively replaced by fully automated ECG analysis.

A tool to identify recent or present rheumatoid arthritis flare from both patient and physician perspectives: the 'FLARE' instrument.

INTRODUCTION: There is a lack of consensus about the definition of flare of rheumatoid arthritis (RA) and a measurement tool. OBJECTIVES: To develop a self-administered tool integrating the perspectives of the patient and the rheumatologist, enabling the detection of present or recent-past RA flare. METHODS: The patient perspective was explored by semistructured individual interviews of patients with RA. Two health psychologists conducted a content analysis to extract items best describing flare from the interviews. The physician's perspective was explored through a Delphi exercise conducted among a panel of 13 rheumatologists. A comprehensive list of items produced in the first round was reduced in a four-round Delphi process to select items cited by at least 75% of the respondents. The identified elements were assembled in domains-each converted into a statement-to constitute the final self-administered Flare Assessment in Rheumatoid Arthritis (FLARE) questionnaire. RESULTS: The content of 99 patient interviews was analysed, and 10 domains were identified: joint swelling or pain, night pain, fatigue and different emotional consequences, as well as analgesic intake. The Delphi process for physicians identified eight domains related to objective RA symptoms and drug intake, of which only four were common to domains for patients. Finally, 13 domains were retained in the FLARE questionnaire, formulated as 13 statements with a Likert-scale response modality of six answers ranging from 'absolutely true' to 'completely untrue'. CONCLUSION: Two different methods, for patient and physician perspectives, were used to develop the FLARE self-administered questionnaire, which can identify past or present RA flare.

C8orf13-BLK is a genetic risk locus for systemic sclerosis and has additive effects with BANK1: results from a large french cohort and meta-analysis.

OBJECTIVE: Accumulating evidence suggests that B cells are involved in systemic sclerosis (SSc). BANK1 has been reproducibly reported to be associated with diffuse cutaneous SSc (dcSSc). BLK encodes another B cell signal transducer, and a functional variant at the C8orf13-BLK locus has been found to be associated with SSc in Caucasians. However, no independent replication has been reported, and there are discrepancies in the genotype-phenotype correlation between these studies in Caucasians and another study performed in the Japanese population. Therefore, in a large cohort of French Caucasians and using a meta-analysis of the available data, this study was undertaken to determine whether the C8orf13-BLK locus is associated with SSc, and to assess the possibility of interaction between BLK and BANK1 in SSc. METHODS: The C8orf13-BLK rs13277113 genotype was determined in 1,031 patients with SSc and 1,014 control subjects for whom BANK1 genotypes were available. Meta-analysis of the 3 available data sets (6,078 individuals) was also performed. RESULTS: Minor allele frequencies for rs13277113 revealed an association restricted to the dcSSc subtype (P = 0.012, odds ratio [OR] 1.29) in the French sample. Meta-analysis of the combined Caucasian populations showed an association of this genotype with both SSc (P = 0.0013, OR 1.16, 95% confidence interval [95% CI] 1.06-1.26) and dcSSc (P = 0.0012, OR 1.23, 95% CI 1.08-1.39). Inclusion of the Japanese population confirmed the overall association with the disease, with the strongest association observed with dcSSc (P = 3.27 × 10⁻5, OR 1.27). Secondary analysis in the French sample revealed additive effects between C8orf13-BLK and BANK1, mainly in the dcSSc subset. CONCLUSION: These results confirm C8orf13-BLK as an SSc risk locus. The strongest effects, and particularly additive effects, were observed in the interaction between C8orf13-BLK and BANK1 in the dcSSc subset.

The interferon regulatory factor 5 gene confers susceptibility to rheumatoid arthritis and influences its erosive phenotype.

BACKGROUND: Increased expression of type I IFN genes, also referred to as an IFN signature, has been detected in various autoimmune diseases including rheumatoid arthritis (RA). Interferon regulatory factors, such as IRF5, coordinate type I IFN expression. Multiple IRF5 variants were suggested as autoimmunity susceptibility factors. OBJECTIVE: As the linkage proof remains important to establish fully any genetic RA susceptibility factor, the authors took advantage of the largest reported European trio family resource dedicated to RA to test for linkage IRF5 and performed a genotype-phenotype analysis. METHODS: 1140 European Caucasian individuals from 380 RA trio families were genotyped for IRF5 rs3757385, rs2004640 and rs10954213 single nucleotide polymorphisms (SNP). RESULTS: Single marker analysis provided linkage evidence for each IRF5 SNP investigated. IRF5 linked to RA with two haplotypes: the CTA risk haplotype 'R' (transmission (T)=60.6%, p=23.1×10(-5)) and the AGG protective haplotype 'P' (T=39.6%, p=0.0015). Linkage was significantly stronger in non-erosive disease for both IRF5 R and P haplotypes (T=73.9%, p=4.20×10(-5) and T=19.6%, p=3.66×10(-5), respectively). Multivariate logistic regression analysis found IRF5 linked to RA independently of the rheumatoid factor status. IRF5 RR and PP haplotypic genotypes were associated with RA, restricted to the non-erosive phenotype: p=1.68×10(-4), OR 4.80, 95% CI 2.06 to 11.19; p=0.003, OR 0.17, 95% CI 0.05 to 0.57, respectively. CONCLUSION: This study provides the 'association and linkage proof' establishing IRF5 as a RA susceptibility gene and the identification of a genetic factor that seems to contribute to the modulation of the erosive phenotype. Further studies are warranted to clarify the role of IRF5 in RA and its subphenotypes.

PTPN22 R620W genotype-phenotype correlation analysis and gene-environment interaction study in early rheumatoid arthritis: results from the ESPOIR cohort.

OBJECTIVES: To investigate genotype-phenotype correlation and gene-environment interaction between PTPN22 R620W environmental factors such as tobacco/hormonal treatments in an inception cohort of RA patients. METHODS: An intra-cohort study including 532 Caucasian RA patients genotyped for the PTPN22 rs2476601 polymorphism was performed. Anti-CCP and RF status at baseline, presence of bone erosions at 1 year, HLADR1 and/or DR4 status, demography, comorbidities, exposure to tobacco with the cumulative dose in pack-years, hormonal treatments and treatments received for RA were collected. Logistic regression was performed to estimate the ORs and multiplicative interaction with adjustment for confounding factors. Gene-environment interaction was estimated by the relative excess risk due to interaction (RERI), attributable proportion (AP) and synergy index (SI). RESULTS: PTPN22 620W risk allele was associated with ACPA production [odds ratio (OR) = 2.21, 95% CI 1.4, 3.4, P < 0.0001]. Hormonal treatment exposition and smoking were found to act with a protective effect against ACPA production (OR = 0.44, 95% CI 0.3, 0.7, P = 0.001) and early bone erosion (OR = 0.56, 95% CI 0.4-0.8, P = 0.003), respectively, and independently of HLADR and PTPN22 status. No evidence for a gene-environment interaction was detected. CONCLUSION: These data provide new insights into the pathogenesis of RA, underlying the pivotal key role of environmental factors in the typical heterogeneity of RA.

Association study of B-cell marker gene polymorphisms in European Caucasian patients with systemic sclerosis.

BACKGROUND: BANK1 and BLK B-cell genetic markers have been reproducibly and convincingly found to contribute to susceptibility to systemic sclerosis (SSc). OBJECTIVES: To determine whether other B-cell genetic markers including CD19, CD20, CD22 and CD24 polymorphisms affect susceptibility to SSc in the European Caucasian population. METHODS: A case-control study was performed in 900 patients with SSc and 1034 healthy controls. Among the whole SSc population, 304 (34%) had the diffuse cutaneous subtype, 551 (61%) had the limited cutaneous subtype, 732 (81%) were positive for antinuclear antibodies , 331 (37%) were positive for anticentromere antibodies and 228 (25%) for the topo-isomerase I. Genotyping has been performed for CD19 rs35979293, CD19 rs2904880, CD20 rs7126354, CD20 rs3802954, CD20 rs105146, CD20 rs4939364, CD22 rs10406069, CD22 rs10413500, CD22 rs10419538, CD22 rs34826052 and CD24 ins-del polymorphisms. RESULTS: Genotype frequencies were at the Hardy-Weinberg equilibrium in the control population for all the SNPs investigated and observed frequencies were very similar to those expected in the European population. Allelic and genotypic frequencies for all these tested SNPs were found to be similar in SSc patients and controls. Moreover, subphenotype analyses in particular for subgroups having the diffuse cutaneous subset or topo-isomerase I positive antibodies, which are the most associated with BANK1 variants, did not detect any difference between SSc patients and controls. CONCLUSIONS: These results obtained through a large cohort of European caucasian patients with SSc do not support the contribution of CD19, CD20, CD22, CD24 variants to the genetic susceptibility of SSc.

Association study of 3 rheumatoid arthritis risk loci in systemic sclerosis in European Caucasian population.

INTRODUCTION: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry.

OBJECTIVE: A number of open-label studies have suggested the potential benefit of rituximab (RTX) in systemic lupus erythematosus (SLE). However, in 2 recent randomized controlled trials (RCTs) of RTX, the primary end points were not met. We undertook this study to evaluate the safety and efficacy of RTX in off-trial patients with SLE seen in regular clinical practice. METHODS: We analyzed prospective data from the French AutoImmunity and Rituximab (AIR) registry, which includes data on patients with autoimmune disorders treated with RTX. RESULTS: One hundred thirty-six patients received treatment for SLE. The mean +/- SD score on the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) was 11.3 +/- 8.9 at baseline. Severe infections were noted in 12 patients (9%), corresponding to a rate of 6.6/100 patient-years. Most severe infections occurred within the first 3 months after the last RTX infusion. Five patients died, due to severe infection (n = 3) or refractory autoimmune disease (n = 2). Overall response was observed in 80 of 113 patients (71%) by the SELENA-SLEDAI assessment. Efficacy did not differ significantly between patients receiving RTX monotherapy and those receiving concomitant immunosuppressive agents (who had higher baseline disease activity). Articular, cutaneous, renal, and hematologic improvements were noted in 72%, 70%, 74%, and 88% of patients, respectively. Among responders, 41% experienced a relapse of disease, with a response in 91% after retreatment with RTX. CONCLUSION: Data from the AIR registry show a satisfactory tolerance profile and clinical efficacy of RTX in patients with SLE. The contrasting results with those from recent RCTs leave open the question of the therapeutic use of RTX in SLE. Additional controlled studies with new designs are needed to define the place of RTX in the therapeutic arsenal for SLE.

Evaluation of two strategies (initial methotrexate monotherapy vs its combination with adalimumab) in management of early active rheumatoid arthritis: data from the GUEPARD trial.

OBJECTIVES: In early and active RA despite MTX, continuous treatment with TNF blockers in combination with MTX is recommended. To compare this strategy with an initial combination of MTX and adalimumab (ADA) given for 3 months and then adjusted based on the disease activity status. METHODS: Prospective unblinded randomized multicentre controlled 1-year trial in which 65 patients with early (<6 months) and active [disease activity score (DAS28(ESR)) >5.1] RA were assigned to Group 1 (32 patients): MTX (0.3 mg/kg/week, maximum of 20 mg/week, without escalating dose regimen) or to Group 2 (33 patients): initial combination therapy with MTX (as in Group 1) and ADA (40 mg eow). In both groups, treatment was adjusted every 3 months. The aim was to achieve a low DAS (DAS28(ESR) <3.2). RESULTS: From Week 12 until Week 52, seven patients in Group 1 and 11 patients in Group 2 remained in low disease activity state while receiving MTX monotherapy (P = 0.28). The 1-year area under the curve (AUC) of DAS28 was lower in Group 2 owing to an initial better response. The total intake of anti-TNF-alpha and the mean increase in total modified Sharp score was similar in the two groups. CONCLUSIONS: Initial combination of MTX and ADA and then an adjusted based on the disease activity status achieved a faster control of disease activity but did not increase the number of patients for whom anti-TNF-alpha treatment was not needed after 12 weeks nor a better subsequent clinical or radiological outcome than a 3-month delayed initiation of anti-TNF in patients with still active disease despite MTX.

Drug delivery to tumours using a novel 5-FU derivative encapsulated into lipid nanocapsules.

In this work, a novel lipophilic 5-fluorouracil (5-FU) derivative was synthesised and encapsulated into lipid nanocapsules (LNC). 5-FU was modified with lauric acid to give a lipophilic mono-lauroyl-derivative (5-FU-C12, MW of about 342 g/mol, yield of reaction 70%). 5-FU-C12 obtained was efficiently encapsulated into LNC (encapsulation efficiency above 90%) without altering the physico-chemical characteristics of LNC. The encapsulation of 5-FU-C12 led to an increased stability of the drug when in contact with plasma being the drug detectable until 3 h following incubation. Cytotoxicity assay carried out using MTS on 2D cell culture showed that 5-FU-C12-loaded LNC had an enhanced cytotoxic effect on glioma (9L) and human colorectal (HTC-116) cancer cell line in comparison with 5-FU or 5-FU-C12. Then, HCT-116 tumour spheroids were cultivated and the reduction of spheroid volume was measured following treatment with drug-loaded LNC and drugs alone. Similar reduction on spheroids volume was observed following the treatment with drug-loaded LNC, 5-FU-C12 and 5-FU alone, while blank LNC displayed a reduction in cell viability only at high concentration. Globally, our data suggest that the encapsulation increased the activity of the 5-FU-C12. However, in-depth evaluations of LNC permeability into spheroids are needed to disclose the potential of these nanosystems for cancer treatment.