Suboptimal management of rheumatoid arthritis in France: a real-world study based on data from the French National Health Data System.

OBJECTIVES: The emergence of targeted therapy is changing rheumatoid arthritis (RA) management, but real-world data remain limited. This study aimed to describe real-world RA treatment patterns using data from a French national claims database. METHODS: This longitudinal study used the French Permanent Representative Sample (Echantillon Généraliste des Bénéficiaires) claims database. Patients with RA were identified between 2013 and 2017, with treatment patterns, persistence and adherence described. RESULTS: The study population included 2553 patients with RA. Disease-modifying antirheumatic drugs (DMARDs) were prescribed for 1512 (59.2%) patients, of whom 721 (47.6%) did not require discontinuation or treatment switch. There were 377 (24.9%) treatment discontinuations and 114 patients (7.5%) switched to a targeted DMARD (biological and synthetic (Janus kinase inhibitor) DMARDs). Among the 2315 patients with RA in 2017, almost half (n=1102, 47.6%) were not treated with a DMARD. Most (85.7%) received symptomatic treatment (analgesics (81.0%), steroids (49.2%), non-steroidal anti-inflammatory drugs (39.5%)). Of the 1142 treatment initiations identified, 713 (62.4%) were conventional synthetic DMARDs (csDMARDs), with methotrexate being the most frequent (n=553, 48.45%). One-year persistence rates varied between 55.9% (49.2-62.0%) for tumour necrosis factor inhibitors, and 63.4% (59.6-67.0%) for csDMARDs. Treatment adherence, assessed through medication possession ratio, varied between 71.9% and 90.8%, with ≥80% being the adherence cut-off. Almost half of DMARD initiations were associated with long-term (>6 months), high-dose oral steroid use (~7 mg/day prednisone equivalent). CONCLUSION: Despite a diverse therapeutic arsenal, there remains a medical need that is not covered by current RA management, which is frequently compensated for by overprescription of steroids.

How can a joint European health technology assessment provide an 'additional benefit' over the current standard of national assessments? : Insights generated from a multi-stakeholder survey in hematology/oncology.

OBJECTIVES: We conducted a multi-stakeholder survey to determine key areas where a joint European health technology assessment (HTA) could provide 'additional benefit' compared to the status quo of many parallel independent national and subnational assessments. METHODS: Leveraging three iterative Delphi cycles, a semiquantitative questionnaire was developed covering evidence challenges and heterogeneity of value drivers within HTAs across Europe with a focus on hematology/oncology. The questionnaire consisted of five sections: i) background information; ii) value drivers in HTA assessments today; iii) evolving evidence challenges; iv) heterogeneity of value drivers across Europe; v) impact of Europe's Beating Cancer Plan (EBCP). The questionnaire was circulated across n = 189 stakeholder institutions comprising HTA and regulatory bodies, clinical oncology associations, patient representatives, and industry associations. RESULTS: N = 30 responses were received (HTA bodies: 9; regulators: 10; patients' and physicians' associations: 3 each; industry: 5). Overall, 17 countries and EU level institutions were represented in the responses. Consistency across countries and stakeholder groups was high. Most relevant value drivers in HTAs today (scale 1, low to 5, high) were clinical trial design (mean 4.45), right endpoints (mean 4.40), and size of comparative effect (mean 4.33). Small patient numbers (mean 4.28) and innovative study designs (mean 4.1) were considered the most relevant evolving evidence challenges. Heterogeneity between regulatory and HTA evidence requirements and heterogeneity of the various national treatment standards and national HTA evidence requirements was high. All clinical and patient participants stated to have been with EBCP initiatives. CONCLUSIONS: For a European HTA to provide an 'additional benefit' over the multitude of existing national assessments key methodological and process challenges need to be addressed. These include approaches to address uncertainty in clinical development; comparator choice; consistency in approaching patient-relevant endpoints; and a transparent and consistent management of both HTA and regulatory procedures as well as their interface, including all involved stakeholder groups.

Pneumococcal vaccination coverage in France by general practitioners in adults with a high risk of pneumococcal disease.

Streptococcus pneumoniae, the main cause of community-acquired pneumonia (CAP), also leads to exacerbations, hospitalizations, and mortality in chronic obstructive pulmonary disease (COPD) and congestive heart failure (CHF). The risk of CAP is increased in patients with diabetes mellitus (DM), and the risk of invasive pneumococcal disease is increased in HIV-infected patients. Pneumococcal vaccination is recommended for these patients in France. The objective was a large survey of pneumococcal vaccination coverage (PVC) by general practitioners (GPs) in these patients in France. Diagnosis and treatment forms were extracted from the database of 2000 GPs. The GPs and population panels were representative of the metropolitan populations. The primary endpoint was the comparison of PVC in the adult patients diagnosed with COPD, CHF, DM, or HIV infection during the study (April 2013-April 2017) and the control (March 2012-March 2013) periods. Of the 17,865 and 4,690 patients identified, 756 (4%) and 267 (6%) were vaccinated, respectively. During the study period, the PVC was significantly higher (35/282, 12%) in HIV-infected patients and lower in patients with DM (95/5994, 2%) than in other patients. Even though French pneumococcal vaccine recommendations in adults were updated in 2013, the PVC did not increase according to the years of the study period and slightly increased according to time after diagnosis. S. pneumoniae is responsible only for some CAP and meningitis, and incomplete protection by vaccine, hesitancy from practitioners and patients, and the moving schedule of vaccination could explain the results. New tools and/or strategies must be implemented to increase PVC in France. Abbreviations: CAP: community-acquired pneumonia; COPD: chronic obstructive pulmonary diseases; CHF: congestive heart failure; DM: diabetes mellitus; IPD: invasive pneumococcal disease; HIV: human immunodeficiency virus; PVC: pneumococcal vaccination coverage; PCV7: 7-valent pneumococcal conjugate vaccine; PCV13: 13-valent pneumococcal conjugate vaccine; PPSV23: 23-valent pneumococcal polysaccharide vaccine; GPs: general practitioners; CLM: Cegedim Logiciels Médicaux; MLM: monLogicielMedical; ICD-10: International Classification of Diseases; CNIL: Commission nationale de l'informatique et des libertés; HPV: human papillomavirus; HBV: hepatitis B virus.

Early access to health products in France: Major advances of the French "Conseil stratégique des industries de santé" (CSIS) to be implemented (modalities, regulations, funding).

In a context of perpetual evolution of treatments, access to therapeutic innovation is a major challenge for patients and the various players involved in the procedures of access to medicines. The revolutions in genomic and personalized medicine, artificial intelligence and biotechnology will transform the medicine of tomorrow and the organization of our health system. It is therefore fundamental that France prepares for these changes and supports the development of its companies in these new areas. The recent "Conseil stratégique des industries de santé" launched by Matignon makes it possible to propose a regulatory arsenal conducive to the implementation and diffusion of therapeutic innovations. In this workshop, we present a number of proposals, our approach having remained pragmatic with a permanent concern to be effective in the short term for the patients and to simplify the procedures as much as possible. This was achieved thanks to the participation in this workshop of most of the players involved (industrial companies, "Agence nationale de sécurité du médicament et des produits de santé", "Haute Autorité de santé", "Institut national du cancer", "Les entreprises du médicament", hospitals, "Observatoire du médicament, des dispositifs médicaux et de l'innovation thérapeutique"…). The main proposals tend to favor the implementation of clinical trials on our territory, especially the early phases, a wider access to innovations by favoring early access programs and setting up a process called "autorisation temporaire d'utilisation d'extension" (ATUext) that make it possible to prescribe a medicinal product even if the latter has a marketing authorisation in another indication. In addition, we propose a conditional reimbursement that will be available based on preliminary data but will require re-evaluation based on consolidated data from clinical trials and/or real-life data. Finally, in order to better carry out these assessments, with a view to access or care, we propose the establishment of partnership agreements with health agencies/hospitals in order to encourage the emergence of field experts, in order to prioritize an ascending expertise closer to patients' needs and to real life.

Characteristics, outcome and treatments with cranial pachymeningitis: A multicenter French retrospective study of 60 patients.

The aim of this study was to determine the characteristics, treatment, and outcome according to each etiology of pachymeningitis.We conducted a retrospective multicenter French nationwide study between 2000 and 2016 to describe the characteristics, outcome, and treatment of pachymeningitis.We included 60 patients (median age 55.5 years; interquartile range [IQR] 30-80, female/male ratio 0.43). Neurologic signs were present in 59 patients (98%) and consisted of headache in 43 (72%), cranial nerve palsy in 33 (55%), confusion in 10 (17%), seizures in 7 (12%), and focal neurologic signs in 9 (15%). Fever and weight loss were present in 8 (13%) and 13 cases (22%), respectively. Cerebral venous thrombosis was present in 8 cases (13%). Analysis of cerebrospinal fluid showed moderate hyperproteinorachia (median 0.68 g/L; IQR 0.46-3.2) with or without pleiocytosis. Diagnosis included idiopathic pachymeningitis (n = 18; 30%); granulomatosis with polyangiitis (n = 13; 17%); Erdheim-Chester disease (n = 10; 17%); IgG4-related disease and tuberculosis (n = 3; 5% each); Rosai-Dofman disease, microscopic polyangiitis, and sarcoidosis (n = 2, 3% each); cryptococcal meningitis, Lyme disease, ear-nose-throat infection, postlumbar puncture, low spinal-fluid pressure syndrome, and lymphoma (n = 1 each). We found no difference in demographics and neurologic presentation among idiopathic pachymeningitis, Erdheim-Chester disease, and granulomatosis with polyangiitis. In contrast, frequencies were lower with idiopathic pachymeningitis than Erdheim-Chester disease for general signs (6% and 40%, respectively, P = .041) and complete neurologic response (0% vs 39%, P = .045).The detection of extraneurologic signs and routine screening are needed to classify the pachymeningitis origin. Prospective studies are warranted to determine the best treatment in each case.

Acceptability and feasibility of HIV testing in general medicine by ELISA or rapid test from finger-stick whole blood.

OBJECTIVES: Guidelines recommend routine universal HIV testing in adults to reduce the pool of infected patients unaware of their status, without specific recommendations concerning the method. We compared acceptability and feasibility of HIV testing by ELISA tests or rapid tests from finger-stick whole blood. METHODS: Prospective randomized multi-center study comparing acceptability and feasibility of routine universal HIV testing by ELISA tests, with a charge, subsequently reimbursed by Social Security for affiliated patients, or rapid tests from finger-stick whole blood, without any charge from the patients or the general practitioner for the study. A single investigator performed all interventions. After consent, all adults (18-70 years old) consulting their general practitioner in Paris, France, unaware of their status, were enrolled. Testing was performed immediately for the patients in the rapid test arm; a prescription was given for testing in a lab for the patients in the ELISA arm. The primary endpoint was acceptability of each method. The secondary endpoint was feasibility of each method, assessed one month after the consultation. RESULTS: Two hundred and seventy patients were enrolled: 133 patients in the ELISA arm, 137 in the rapid test arm. Acceptability of the rapid test (92%) was higher than that of the ELISA (63.9%), P<0.0001. Feasibility of the rapid test (100%) was higher than that of the ELISA (50.5%), P<0.0001. A center effect was shown concerning feasibility of ELISA but not concerning feasibility of rapid tests. CONCLUSION: Rapid testing from finger-stick whole blood is more acceptable and feasible than ELISA for routine universal HIV testing. A larger use of rapid tests, ideally free of charge, by general practitioners could reduce the pool of infected patients unaware of their status.

Long-term mortality in older patients discharged after acute decompensated heart failure: a prospective cohort study.

BACKGROUND: Data are available on short- and intermediate-term mortality rates after discharge for acutely decompensated heart failure (ADHF). However, few studies specifically addressed ADHF outcomes in patients aged 75 years or over, who contribute more than half of all ADHF admissions. Our objectives here were to estimate the long-term mortality of patients aged 75 years or over who were discharged after admission for ADHF and to identify factors, especially geriatric findings, independently associated with 2-year mortality. METHODS: This prospective cohort study in five French hospitals included consecutive patients aged 75 years or older and discharged after emergency-department admission for ADHF meeting Framingham criteria (N = 478; median age, 85 years; 68% female). Kaplan-Meier 1-year and 2-year survival curves were plotted. Admission characteristics independently associated with overall 2-year mortality were identified using multivariable Cox proportional-hazards regression. RESULTS: Mortality was 41.7% (95% confidence interval [95% CI], 37.2%-53.5%) after 1 year and 56.0% (95% CI, 51.5%-60.7%) after 2 years. By multivariable analysis, independent predictors of 2-year mortality were male sex (hazard ratio [HR], 1.36; 95% CI, 1.00-1.82), age >85 years (HR, 1.57; 95% CI, 1.19-2.07), higher number of impaired activities of daily living (HR, 1.11 per impaired item; 95% CI, 1.05-1.17), recent weight loss (HR, 1.61; 95% CI, 1.14-2.28), and lower systolic blood pressure (HR, 0.86 per standard deviation increase; 95% CI, 0.74-0.99). Creatinine clearance ≤30 mL/min showed a trend toward an association with 2-year mortality (HR, 1.36; 95% CI, 0.97-2.00). CONCLUSION: Functional impairment before admission is associated with higher long-term mortality in patients ≥75 years admitted for ADHF. This study focused on geriatric markers not traditionally collected in heart-failure patients but did not analyse all cardiologic parameters associated with outcomes in other studies. Nevertheless, our findings may contribute to identify those patients admitted for ADHF who have the worst prognosis.

The effect of morbid obesity on morphine glucuronidation.

The purpose of the present work was to study the change in morphine metabolic ratio in obese subjects before and after Roux-en-Y Gastric Bypass (RYGB) and to identify clinical and/or biological factors associated with this change. The pharmacokinetics (PK) of oral morphine (30mg), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was performed in patients before (n=25; mean BMI=43.2 (35.4-61.9)kg/m2), 7-15days (n=16) and 6 months after RYGB (n=19; mean BMI=32.3 (25.4-46.0)kg/m2). Morphine Cmax and AUC0-inf were significantly increased and morphine Tmax significantly shortened at 6 months after RYGB compared with preoperative data, indicating an important increase in the rate and extent of morphine absorption. The morphine metabolic ratio 0-inf M3G+M6G/Morphine, decreased significantly from the preoperative to 6 months postoperative period with an average of -26% (range -74%; +21%; p=0.004), but not in the immediate post-operative period. The change in morphine metabolic ratio was associated with a change in BMI, fat mass in kg, and triglyceride levels (rho=0.5, p≤0.04). The degree of change in several markers of low-grade inflammation, or the level of liver steatosis and fibrosis before surgery, was not associated with the change in morphine metabolic ratios. Our findings indicate that RYGB-induced weight loss significantly decreases morphine metabolic ratio, arguing for an effect of morbid obesity on glucuronidation. With glucuronide exposure at 6 months similar to preoperative values, a higher morphine AUC0-inf should encourage reducing morphine dosage in patients undergoing RYGB and chronically receiving immediate-release oral morphine.

Predictive Factors of Chronic Post-Surgical Pain at 6 Months Following Knee Replacement: Influence of Postoperative Pain Trajectory and Genetics.

BACKGROUND: The frequency of chronic postsurgical pain (CPSP) after knee replacement remains high, but might be decreased by improvements to prevention. OBJECTIVES: To identify pre- and postsurgical factors predictive of CPSP 6 months after knee replacement. STUDY DESIGN: Single-center prospective observational study. SETTING: An orthopedic unit in a French hospital. METHODS: Consecutive patients referred for total or unicompartmental knee arthroplasty from March to July 2013 were prospectively invited to participate in this study. For each patient, we recorded preoperative pain intensity, anxiety and depression levels, and sensitivity and pain thresholds in response to an electrical stimulus. We analyzed OPRM1 and COMT single-nucleotide polymorphisms. Acute postoperative pain (APOP) in the first 5 days after surgery was modeled by a pain trajectory. Changes in the characteristics and consequences of the pain were monitored 3 and 6 months after surgery. Bivariate analysis and multivariate logistic regression were conducted to identify predictors of CPSP. RESULTS: We prospectively evaluated 104 patients in this study, 74 (28.8%) of whom reported CPSP at 6 months. Three preoperative factors were found to be associated with the presence of CPSP in multivariate logistic regression analysis: high school diploma level (OR = 3.83 [1.20 - 12.20]), consequences of pain in terms of walking ability, as assessed with the Brief Pain Inventory short form "walk" item (OR = 4.06 [1.18 - 13.94]), and a lack of physical activity in adulthood (OR = 4.01 [1.33 - 12.10]). One postoperative factor was associated with the presence of CPSP: a high-intensity APOP trajectory. An association of borderline statistical significance was found with the A allele of the COMT gene (OR = 3.4 [0.93 - 12.51]). Two groups of patients were identified on the basis of their APOP trajectory: high (n = 28, 26%) or low (n = 80, 74%) intensity. Patients with high-intensity APOP trajectory had higher anxiety levels and were less able to walk before surgery (P < 0.05). LIMITATIONS: This was a single-center study and the sample may have been too small for the detection of some factors predictive of CPSP or to highlight the role of genetic factors. CONCLUSION: Our findings suggest that several preoperative and postoperative characteristics could be used to facilitate the identification of patients at high risk of CPSP after knee surgery. All therapeutic strategies decreasing APOP, such as anxiety management or performing knee replacement before the pain has a serious effect on ability to walk, may help to decrease the risk of CPSP. Further prospective studies testing specific management practices, including a training program before surgery, are required.

Quantitative Atlas of Cytochrome P450, UDP-Glucuronosyltransferase, and Transporter Proteins in Jejunum of Morbidly Obese Subjects.

Protein expression levels of drug-metabolizing enzymes and transporters in human jejunal tissues excised from morbidly obese subjects during gastric bypass surgery were evaluated using quantitative targeted absolute proteomics. Protein expression levels of 15 cytochrome P450 (CYP) enzymes, 10 UDP-glucuronosyltransferase (UGT) enzymes, and NADPH-P450 reductase (P450R) in microsomal fractions from 28 subjects and 49 transporters in plasma membrane fractions from 24 of the same subjects were determined using liquid chromatography-tandem mass spectrometry. Based on average values, UGT1A1, UGT2B15, UGT2B17, SGLT1, and GLUT2 exhibited high expression levels (over 10 fmol/µg protein), though UGT2B15 expression was detected at a high level in only one subject. CYP2C9, CYP2D6, CYP3A5, UGT1A6, P450R, ABCG2, GLUT5, PEPT1, MCT1, 4F2 cell-surface antigen heavy chain (4F2hc), LAT2, OSTα, and OSTß showed intermediate levels (1-10 fmol/µg protein), and CYP1A1, CYP1A2, CYP1B1, CYP2C18, CYP2C19, CYP2J2, CYP3A7, CYP4A11, CYP51A1, UGT1A3, UGT1A4, UGT1A8, UGT2B4, ABCC1, ABCC4, ABCC5, ABCC6, ABCG8, TAUT, OATP2A1, OATP2B1, OATP3A1, OATP4A1, OCTN1, CNT2, PCFT, MCT4, GLUT4, and SLC22A18 showed low levels (less than 1 fmol/µg protein). The greatest interindividual difference (364-fold) was detected for UGT2B17. However, differences in expression levels of other quantified UGTs (except UGT2B15 and UGT2B17), CYPs (except CYP1A1 and CYP3A5), and P450R, and all quantified transporters, were within 10-fold. Expression levels of CYP1A2 and GLUT4 were significantly correlated with body-mass index. The levels of 4F2hc showed significant gender differences. Smokers showed increased levels of UGT1A1 and UGT1A3. These findings provide a basis for understanding the changes in molecular mechanisms of jejunal metabolism and transport, as well as their interindividual variability, in morbidly obese patients.

Oral Morphine Pharmacokinetic in Obesity: The Role of P-Glycoprotein, MRP2, MRP3, UGT2B7, and CYP3A4 Jejunal Contents and Obesity-Associated Biomarkers.

The objective of our work was to study the association between the jejunal expression levels of P-gp, MRP2, MRP3, UGT2B7, CYP3A4, the ABCB1 c.3435C > T polymorphism, and several obesity-associated biomarkers, as well as oral morphine and glucuronides pharmacokinetics in a population of morbidly obese subjects. The pharmacokinetics of oral morphine (30 mg) and its glucuronides was performed in obese patients candidate to bariatric surgery. A fragment of jejunal mucosa was preserved during surgery. Subjects were genotyped for the ABCB1 single nucleotide polymorphism (SNP) c.3435C > T. The subjects were 6 males and 23 females, with a mean body mass index of 44.8 (35.4-61.9) kg/m(2). The metabolic ratios AUC0-inf M3G/morphine and AUC0-inf M6G/morphine were highly correlated (rs = 0.8, p < 0.0001) and were 73.2 ± 24.6 (34.7-137.7) and 10.9 ± 4.1 (3.8-20.6). The pharmacokinetic parameters of morphine and its glucuronides were not associated with the jejunal contents of P-gp, CYP3A4, MRP2, and MRP3. The jejunal content of UGT2B7 was positively associated with morphine AUC0-inf (rs = 0.4, p = 0.03). Adiponectin was inversely correlated with morphine Cmax (rs = -0.44, p = 0.03). None of the factors studied was associated with morphine metabolic ratios. The interindividual variability in the jejunal content of drug transporters and metabolizing enzymes, the ABCB1 gene polymorphism, and the low-grade inflammation did not explain the variability in morphine and glucuronide exposure. High morphine metabolic ratio argued for an increased morphine glucuronidation in morbidly obese patients.

Biosimilars: from technical to pharmacoeconomic considerations. 30th Rencontres Nationales de Pharmacologie et Recherche clinique pour l'Innovation et l'Evaluation des Technologies de Santé. Tables rondes.

A biosimilar is a biological medicinal product claimed to be similar to a reference biological medicinal product. Its development plan includes studies comparing it with the reference product in order to confirm its similarity in terms of quality, preclinical safety, clinical efficacy, and clinical safety, including immunogenicity. Biosimilars differ from generics both in their molecular complexity and in the specific requirements that apply to them. Since patents on many biological medicinal products will expire within the next 5 years in major therapeutic areas such as oncology, rheumatology and gastroenterology and as those products are so costly to the French national health insurance system, the availability of biosimilars would have a considerable economic impact. The round table has issued a number of recommendations intended to ensure that the upcoming arrival of biosimilars on the market is a success, in which prescribing physicians would have a central role in informing and reassuring patients, an efficient monitoring of the patients treated with biologicals would be set up and time to market for biosimilars would be speeded up.

Methadone dose in heroin-dependent patients: role of clinical factors, comedications, genetic polymorphisms and enzyme activity.

AIMS: Methadone is characterized by wide intersubject variability regarding the dose needed to obtain full therapeutic response. We assessed the influence of sociodemographic, ethnic, clinical, metabolic and genotypic variables on methadone maintenance dose requirement in opioid-dependent responder patients. METHODS: Eighty-one stable patients (60 men and 21 women, 43.7 ± 8.1 years old, 63.1 ± 50.9 mg day(-1) methadone), divided into quartiles with respect to the median daily dose, were enrolled and underwent clinical examination, treatment history and determination of liver/intestinal cytochrome P450 (CYP) 3A4 activity measured by the midazolam test, R,S-methadone trough concentration and clinically significant polymorphisms of the OPRM1, DRD2, COMT, ABCB1, CYP2B6, CYP3A5, CYP2C19 and CYP2D6 genes. RESULTS: Methadone maintenance dose was correlated to the highest dose ever used (r(2) = 0.57, P < 0.0001). Fractioned methadone intake (odds ratio 4.87, 95% confidence interval 1.27-18.6, P = 0.02), bodyweight (odds ratio 1.57, 95% confidence interval 1.01-2.44, P = 0.04), history of cocaine dependence (80 vs. 44 mg day(-1) in never-addict patients, P = 0.005) and ethnicity (Asian > Caucasian > African, P = 0.04) were independently associated with high-dose methadone in multiple regression analysis. A modest correlation was observed between liver/intestinal CYP3A4 activity and methadone dose at steady state (Spearman rank correlation coefficient [rs ] = 0.21, P = 0.06) but not with highest dose ever used (rs = 0.15, P = 0.18) or dose-normalized R,S-methadone trough concentrations (rs = -0.05, P = 0.64). Concomitant CYP3A4 inhibitors only affected the relationship between methadone dose and R,S-methadone trough concentration. None of the genetic polymorphisms explored was predictive of the methadone maintenance dose. CONCLUSIONS: Methadone maintenance dose was predicted by sociodemographic and clinical variables rather than genetic polymorphisms or liver/intestinal CYP3A4 activity in stable patients.

Biosimilars: from Technical to Pharmacoeconomic Considerations.

A biosimilar is a biological medicinal product claimed to be similar to a reference biological medicinal product. Its development plan includes studies comparing it with the reference product in order to confirm its similarity in terms of quality, preclinical safety, clinical efficacy, and clinical safety, including immunogenicity. Biosimilars differ from generics both in their molecular complexity and in the specific requirements that apply to them. Since patents on many biological medicinal products will expire within the next 5 years in major therapeutic areas such as oncology, rheumatology and gastroenterology and as those products are so costly to the French national health insurance system, the availability of biosimilars would have a considerable economic impact. The round table has issued a number of recommendations intended to ensure that the upcoming arrival of biosimilars on the market is a success, in which prescribing physicians would have a central role in informing and reassuring patients, an efficient monitoring of the patients treated with biologicals would be set up and time to market for biosimilars would be speeded up.

Effect of a Roux-en-Y gastric bypass on the pharmacokinetics of oral morphine using a population approach.

BACKGROUND AND OBJECTIVES: Obesity and opioid use for chronic pain in obese individuals are both important public health concerns. The pharmacokinetics of oral morphine after Roux-en-Y gastric bypass (RYGB) are unknown. Therefore, we aimed to study the pharmacokinetics of oral morphine in morbidly obese patients before and after RYGB surgery, to identify the effects of RYGB and the subsequent reversal of morbid obesity on the pharmacokinetic parameters of morphine. METHODS: The pharmacokinetics of oral morphine (30 mg) were studied in 30 obese patients before (Visit 1) and then 7-15 days (Visit 2) and 6 months (Visit 3) after RYGB. A population pharmacokinetic model was used to describe the time course of the plasma morphine concentration, to study the effect of RYGB on morphine pharmacokinetics and to estimate inter-patient variability. RESULTS: The oral morphine time to maximum plasma concentration (t max) was twofold lower and maximum plasma concentration (C max) was 1.7 times higher at Visit 2, and t max was 7.5 times lower and C max 3.3 times higher at Visit 3 than at Visit 1. The mean oral morphine area under the plasma concentration-time curve (AUC) increased significantly (1.55-fold) between Visits 1 and 3. Changes in body mass index (BMI) after RYGB were clearly associated with decreased apparent oral morphine clearance and apparent central and peripheral morphine volumes of distribution. None of the other anthropometric parameters explained the inter-subject variability in morphine exposure better than BMI. CONCLUSION: RYGB and the BMI reduction that followed it dramatically increased the rate of morphine absorption and slightly increased morphine exposure. The dose of immediate-release forms of morphine may be divided in obese patients after RYGB to prevent adverse events due to early and high morphine plasma peaks.

Pain management and pain characteristics in obese and normal weight patients before joint replacement.

RATIONALE, AIMS AND OBJECTIVES: The objective was to compare the extent of pain interference and pain medication among persons who were classified as obese [body mass index (BMI)≥ 30 kg m(-2) ] and normal weighted (BMI ≤ 25 kg m(-2) ), before a hip or knee replacement surgery. METHODS: Patients candidate for an orthopaedic surgery were successively enrolled, over a 6-month period, and classified in either the normal weight (BMI ≤ 25 kg m(-2) ) or the obese (BMI ≥ 30 kg m(-2) ) categories. Data were collected using self-administered questionnaires with items concerning pain characteristics, pain medication and pain interference. Two standardized questionnaires were associated: the Brief Pain Inventory (BPI) and the Hospital Anxiety and Depression scale (HAD). RESULTS: Fifty-two obese patients (candidates for 24 hip replacements and 28 knee replacements) and 51 non-obese (23 hip replacements and 28 knee replacements) were enrolled. Obese patients suffered from a higher rate of acute pain episodes than non-obese patients (65 versus 44%, P<0.05). Pain interference on walking distance, sleep and relations with others was higher in obese patients. HAD score showed no significant difference between groups. The use of strong opioids and of non-steroidal anti-inflammatory drugs (NSAIDs) was significantly more important in obese patients (13 versus 0% and 31 versus 14%). CONCLUSIONS: Obese patients suffer more significantly of unrelieved chronic pain, which lowers considerably their quality of life. Pain relief is more difficult to obtain, as it requires stronger pain medication and NSAIDs.

Optimizing the use of intravenous therapy in internal medicine.

BACKGROUND: We aimed to evaluate the impact of physicians' educational programs in the reduction of inappropriate intravenous lines in internal medicine. METHODS: Fifty-six French internal medicine units were enrolled in a nationwide, prospective, blinded, randomized controlled trial. Forms describing the patients with an intravenous line and internal medicine department characteristics were filled out on 2 separate days in January and April 2007. Following the first visit, all units were randomly assigned to either a specific education program on the appropriate indications of an intravenous line, during February and March 2007, or no training (control group). The Investigators' Committee then blindly evaluated the clinical relevance of the intravenous line according to pre-established criteria. The primary outcome was the percentage of inappropriate intravenous lines. RESULTS: During January 2007, intravenous lines were used in 475 (24.9%) of the 1910 hospitalized patients. Of these, 80 (16.8%) were considered inappropriate. In April 2007, 416 (22.8%) of the 1823 hospitalized patients received an intravenous line, which was considered in 10.2% (21/205) of patients managed by trained physicians, versus 16.6% (35/211) of patients in the control group (relative difference 39%; 95% confidence interval, -0.6-13.3; P = .05). Reduced intravenous administration of fluids, antibiotics, and analgesics accounted for the observed decrease. CONCLUSION: The use of a simple education program reduced the rate of inappropriate intravenous lines by almost 40% in an internal medicine setting (NCT01633307).

Sensory impairment in obese patients? Sensitivity and pain detection thresholds for electrical stimulation after surgery-induced weight loss, and comparison with a nonobese population.

INTRODUCTION: Obese patients have a high prevalence of painful musculoskeletal disorders that may decrease after massive weight loss. Pain thresholds may be different in obese participants. OBJECTIVES: To assess the sensitivity and pain detection thresholds, through the application of an electrical sensitivity, before and after massive weight loss, and to compare the thresholds obtained with those in a control population. METHODS: The sensitivity and pain detection thresholds obtained in participants subjected to electrical stimulation were determined in 31 obese individuals (age: 40.3 ± 10.5 y) before (body mass index: 45.7 ± 6.8 kg/m) and 6 months after a mean weight loss of 32 kg induced by gastric bypass. The results obtained were compared with those for 49 nonobese control participants (38.5 ± 11.2 y; body mass index: 22.6 ± 2.6 kg/m). Body composition and metabolic biomarkers, such as leptin, adiponectin, insulin, and interleukin 6, were assessed and single-nucleotide polymorphisms of the mu opioid receptor [OPRM1 (c.118A > G) and COMT (p.Val158Met)] were genotyped in obese patients. RESULTS: Sensitivity and pain detection thresholds (3.9 ± 1.1; 11.6 ± 6.0) were significantly higher in obese than in nonobese participants (3.1 ± 1.1; 6.0 ± 3.0), respectively (P < 0.0001), and were not affected by drastic weight loss (mean change: 32 kg). Pain thresholds in obese participants were not correlated with any of the clinical and biological variables studied. The obese participants in the highest quartile for both sensitivity and pain detection thresholds were significantly older than those in the lowest quartile. CONCLUSIONS: Further studies are required to explore sensory dysfunction in obese individuals and to investigate the implications of this dysfunction for pain management.

[Proposal of HIV, HBV and HCV targeted screening: short period feasibility study in a free-access outpatient medical structure]. / Faisabilité du dépistage ciblé VIH, VHB, VHC dans une structure de soins ambulatoires avec un système de permanence d'accès aux soins de santé intégré

OBJECTIVES: In France, patients coming from sub-Saharan Africa, French Indies and French Guiana are frequently missed HIV, HBV and HCV diagnosis, despite high prevalence of these infections. METHODS: Targeted proposal of HIV, HBV and HCV screening, using sensitive enzyme immunoassays, to any adult patient originating of the above mentioned areas, with/without medical insurance, consulting for a medical issue in outpatients' department. Monocentric prospective study in a hospital in Paris during 28 consecutive days in 2010. RESULTS: Among the 272 eligible patients, 166 were tested (patients' acceptance: 61%). 180/272 (66%) alleged being tested previously for HIV, women (66/87, 76%) more frequently than men (114/185, 62%), P=0.02. Patients' acceptance seemed higher in patients mentioning no previous test than in patients reporting previous test. Among the patients who refused being tested, reporting a previous negative HIV test, more than a quarter has been tested more than 1 year ago. Among the 166 tested patients, 120 (72%) came back to get their results, men (89/113, 79%) more frequently than women (31/53, 58.5%), P=0.009; recently metropolitan patients more frequently than longer metropolitan patients, P=0.01; patients without any job more frequently than patients with a job, P=0.01. Three (1.8%) HIV tests returned positive; HBsAg was positive in 13 (7.8%) patients; 54 patients (32.7%) had a negative hepatitis B screening (anti-HBcAb+HBsAg+anti-HBsAb), attesting to sensitivity to this infection, only 18 patients (10.9%) showed isolated anti-HBsAb at protective levels. Eighty-one patients (49.1%) exhibited anti-HBcAb, confirming the high prevalence of HBV infection in the areas the patients came from. Six patients (3.6%) had anti-HCVAb. There was no co-infection. CONCLUSION: Targeted HIV, HBV and HCV screening to patients coming from high prevalence areas in outpatients' department appears a very cost-effective strategy.