Controlled human infection trials: Legitimacy and conditions of implementation in France.

This round table is the result of an observation. The observation being that controlled human infection clinical trials (also called "infectious challenge" trials or "Controlled Human Infection Models", "CHIM") recommended or even encouraged in the context of vaccine developments in particular, are not carried out in France. However, there are no formal prohibitions within regulations or ethical principles, which point to the prior assessment of risks and benefits for individuals and for society. The participants in this Round Table thus wished to examine, through the prism of their respective disciplines, the scientific and medical relevance of conducting such trials in France and, if possible, to imagine the conditions under which they would be carried out, thus resulting in recommendations on (1) the advisability of their conduct in France (2), the conditions under which they would be implemented in terms of logistics and regulations, and (3) their social acceptability. The recommendations on which the participants of the Round Table came to an agreement are presented as the analysis progresses.

Paediatric drug development and evaluation: Existing challenges and recommendations.

Despite various international regulatory initiatives over the last 20 years, many challenges remain in the field of paediatric drug development and evaluation. Indeed, drug research and development is still focused essentially on adult indications, thereby excluding many paediatric patients, limiting the feasibility of trials and favouring competing developments. Off-label prescribing persists and the development of age-appropriate dosage forms for children remains limited. Against this background, the members of this panel (TR) recommend the launch of multi-partner exchange forums on specific topics in order to focus new drug research and development on the real, unmet medical needs of children and adolescents, and in keeping with the underlying mechanisms of action. Scientific information sharing and cooperation between stakeholders are also essential for defining reference evaluation methods in each medical field. These forums can be organised through existing paediatric facilities and research networks at the French and European level. The latter are specifically dedicated to paediatric research and can facilitate clinical trial implementation and patient enrolment. Moreover, specific grants and public/private partnerships are still needed to support studies on the repositioning of drugs in paediatric indications, and pharmacokinetic studies aimed at defining appropriate dosages. The development of new pharmaceutical forms, better suited for paediatric use, and the promotion of resulting innovations will stimulate future investments. Initiatives to gather observational safety and efficacy data following off-label and/or derogatory early access should also be encouraged to compensate for the lack of information available in these situations. Finally, the creation of Ethics Committees (EC) with a specific "mother-child" advisory expertise should be promoted to ensure that the current regulation (Jardé law in France) is implemented whilst also taking into account the paediatric specificities in medical trials.

Autoantibodies versus Skin Fibrosis Extent in Systemic Sclerosis: A Case-Control Study of Inverted Phenotypes.

Objective: to describe the prevalences, characteristics, and survivals of patients with anti-topoisomerase 1 antibodies (ATA) and limited cutaneous systemic sclerosis (lSSc) and anti-centromere antibodies (ACA) and diffuse cutaneous systemic sclerosis (dSSc). Methods: patients with ATA lSSc or with ACA dSSc were included in a case-control retrospective study. Results: In our cohort of scleroderma, the prevalence of ACA dSSc and ATA lSSc was 1.1% (12/1040) and 8.9% (93/1040), respectively. ACA dSSc patients had less interstitial lung disease (ILD) (5 (41.7) vs. 74 (79.6); p < 0.01), more cardiac involvement, and more muscle involvement (3 (25) vs. 4 (4.3); p = 0.03 and 4 (33.3) vs. 4 (7.5); p = 0.02,) than ATA dSSc patients. ATA lSSc patients had a higher modified Rodnan skin score than ACA lSSc patients (4 [2−7.5] vs. 2 [0−5]; p < 0.01) and less cardiac or muscle involvement than ATA dSSc patients (6 (6.5) vs. 19 (20.4%); p < 0.01 and 15 (16.1) vs. 54 (58.1); p < 0.0001, respectively). The cumulative 5-year survival rate was 71% in ACA dSSc patients, 95% in ATA lSSc patients, 84% in ACA lSSc patients, and 66% in ATA dSSc patients (p < 0.0001). Conclusion: ATA lSSc and ACA dSSc have specific characteristics when compared to ATA dSSc or ACA lSSc. ATA lSSc patients have more ILD than ACA lSSc patients, and ATA dSSc patients have the worst prognosis. Overall, inverted phenotypes show the value of a patient assessment combining antibody and skin subset and should be considered as a separate group.

How has the future investment program stimulated research and innovation in health?

Ten years after the launch of the Future Investment Program (Programme d'Investissement d'Avenir, PIA) and the implementation of these tools, one of Giens' roundtable workshop wanted to further explore the impact of PIA on health research and innovation with the aim of preparing action reports (bibliometrics, valuation, reputation) based on 2019 findings and the history of PIA deployment in relation to the healthcare sector; to analyze the development of the industrial sector vis-a-vis the PIA actions and to examine how the specific actions and the healthcare sector in general were able to duly articulate themselves, or, take form, given existing structures or organizations and contribute to site policies through Idex/Isite. Five success keys have been identified, which should serve as a strategic compass for future action plans to develop health innovation: Full trust governance between the project manager and the institution, driven by project objectives; An increased role of universities in the steering of PIA objects, joining together in a federation, in a site policy with the Hospital University Centres and Public Scientific and Technological Establishments; A simplification of public/private partnership schemes, in the nature of the Assessment and Action Plans, and in the responsiveness of the institutions; help with the development of local ecosystems, the fostering and support of young researchers; early cross-fertilization between the academic and industrial worlds.

Management of severe renal disease in anti-neutrophil-cytoplasmic-antibody-associated vasculitis: the place of rituximab and plasma exchange?

OBJECTIVE: The optimal induction therapy for severe glomerulonephritis of ANCA-associated vasculitis (AAV) is debated. We compared the efficacy of glucocorticoid and rituximab (RTX) or CYC induction therapy for severe AAV-related glomerulonephritis and evaluated the potential benefit of plasma exchange (PE) as adjunct therapy to CYC. METHODS: This retrospective, multicentre study included AAV patients with severe renal active disease (serum creatinine level ≥350 µmol/l and/or estimated glomerular filtration ratio ≤15 ml/min/1.73 m2). Propensity-score analysis was used to adjust for potential confounders. RESULTS: Between 2005 and 2017, 153 patients with AAV-related glomerulonephritis were studied (96 [60%] men; mean [s.d.] age 63 [13.1] years): 19 (12%) were treated with RTX and 134 (88%) with CYC. Remission rates did not differ between RTX- and CYC-treated groups. Although more patients with RTX than CYC were dialysis-free at month (M) 12 (79% vs 68%), the difference was not significant after adjustment. Among 134 patients with CYC-treated glomerulonephritis, 76 (57%) also had PE. M3 and M6 remission rates were comparable for weighted CYC groups with or without PE. For weighted groups, the dialysis-free survival rate with CYC was higher with than without PE at M6 (72% vs 64%; odds ratio 2.58) and M12 (74% vs 60%; odds ratio 2.78) reaching statistical significance at M12. CONCLUSION: We could not find any difference between RTX and CYC as induction therapy for patients with severe AAV-related glomerulonephritis. In patients receiving CYC induction regimen, the addition of PE conferred short-term benefits with higher dialysis-free rate at M12.

[Analysis of off-label prescriptions of medicines in hospital in adult patients and feasibility study of their detection using CIM-10 coding]. / Analyse des prescriptions hospitalières hors AMM des médicaments chez l'adulte et étude de la faisabilité de leur détection par le codage CIM-10 du PMSI.

Analysis of off-label prescriptions of medicines in hospital in adult patients and study of feasibility of their detection by use of international disease classification, 10th version (IDC-10 codes). CONTEXT: In order to improve the appropriate use of medicines, a method of detection of off label prescriptions, especially in hospitalised patients, should be available. STUDY OBJECTIVES: Evaluate the performance of the detection of off-label prescriptions in hospitalised patients by use of IDC-10 codes. METHODS: Data prescriptions (excluding those directly taken in charge by the national health care system), clinical history and biological results were extracted from Assistance publique des Hôpitaux de Paris (AP-HP) data-warehouse for 108 in-hospital adults patients' journeys. An adjudication committee established the classification reference for the appropriate or off label drug prescriptions status after analysis of medical information for each patient. IDC-10 codification that is performed after every hospitalisation was crossed with those IDC-10 codes that were to be expected corresponding to the marketing authorisation labelling (section 4.1 of specifications of product characteristics [SPC]). Results of IDC-10 coding were compared to the reference for off label use identification. RESULTS: Out of the 1131 analysed prescriptions, 44 (3.9%) were classified as off label by the adjudication committee. Sensitivity of detection by IDC-10 coding was 87 (95% CI [0.73-0.96]) to 92% (95% CI [0.79-0.98]) and specificity 25 (95% CI [0.22-0.27]) to 41% (95% CI [0.38-0.44]) according to the number of characters of ICD-10 that could be used. CONCLUSIONS: Incidence of in-hospital off label use of drugs (restricted to within drug related groups prescriptions) appeared relatively low (3.9%). Its semi-automatic detection by IDC-10 coding appears feasible with a good sensitivity but a low specificity. Such method could be further assessed as a first step detection focusing on one pharmacological class or on one pathologic condition.

Osteitis in Systemic Sclerosis: A Nationwide Case-Control Retrospective Study.

OBJECTIVE: Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by skin fibrosis, vasculopathy, and dysimmunity. Data regarding osteitis in SSc are scarce. METHODS: We performed a nationwide multicenter, retrospective, case-control study including patients with SSc, according to the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification, with a diagnosis of osteitis. The objectives of the study were to describe, to characterize, and to identify associated factors for osteitis in patients with SSc. RESULTS: Forty-eight patients were included. Twenty-six patients (54.1%) had osteitis beneath digital tip ulcers. Physical symptoms included pain (36 of 48, 75%), erythema (35 of 48, 73%), and local warmth (35 of 48, 73%). Thirty-one (65%) patients had median (interquartile range) C-reactive protein levels >2 mg/liter of 8 (2.7-44.3) mg/liter. On radiography, computed tomography, or magnetic resonance imaging, osteitis was characterized by swelling or abscess of soft tissues, with acro-osteolysis or lysis in 28 patients (58%). Microbiological sampling was performed in 45 (94%) patients. Most pathogens were Staphylococcus aureus (43.8%), anaerobes and Enterobacteriaceae (29.1%), and Pseudomonas aeruginosa (10.4%). Management comprised antibiotics in 37 (77.1%) patients and/or surgery in 26 (54.2%). Fluoroquinolones were used in 22 (45.8%) patients, and amoxicillin plus ß-lactamase inhibitor in 7 (14.6%). Six (12.6%) patients relapsed, 6 (12.6%) patients had osteitis recurrence, 15 (32%) sequelae, and 2 patients had septic shock and died. CONCLUSION: This study confirmed digital tip ulcers as an associated factor for osteitis and revealed a high rate of functional sequelae. Antimicrobial therapy with oral fluoroquinolone or intravenous amoxicillin and ß-lactamase inhibitor are used as first-line antibiotic therapy in SSc patients with osteitis.

The Clinical Spectrum and Outcome of Uveomeningitis: A Comprehensive Analysis of 110 Cases.

PURPOSE: Uveitis can be associated with meningitis (uveomeningitis) and the inflammation shared with the central nervous system. We aimed to describe the characteristics and outcome of uveomeningitis. METHODS: We retrospectively analyzed 110 consecutive adult patients with uveomeningitis. RESULTS: The main causes of uveomeningitis were Vogt-Koyanagi-Harada (31%), syphilis (16%), sarcoidosis (12%), Behçet's disease (7%), and multiple sclerosis (5%). Sixteen percent of uveomeningitis remained of undetermined origin. Compared to etiology-matched uveitis without meningitis, patients with uveomeningitis were younger, had more frequent neurological manifestations, and had more frequent abnormal cerebral magnetic resonance imaging findings. In contrast, no ocular feature upon examination was significantly associated with the presence of meningitis. Patients with uveomeningitis were more frequently treated with immunosuppressants but uveitis relapse and systemic complications did not differ between groups. CONCLUSION: Uveomeningitis is associated with a limited spectrum of diseases. Meningitis does not seem to impact ocular and extraocular outcomes. Therefore, lumbar puncture should be performed on an individual basis during the diagnostic workup of uveitis.

Ophthalmic involvement of chronic lymphocytic leukemia: A systematic review of 123 cases.

To identify clinical presentations, main causes, and prognosis of ophthalmic involvement in chronic lymphocytic leukemia (CLL), we performed a systematic review of articles describing CLL ophthalmic involvement in January 2019, using the PubMed database. We found 86 articles describing 123 cases of patients with ophthalmic involvement associated with CLL. Ophthalmic symptoms were CLL's first manifestation in 25.6% of patients and revealed Richter transformation in 11.0%. There were three main causes of ophthalmic features: CLL-infiltration (52.0%), lymphoma (26.0%), and infection (15.4%), with specific clinical and radiological characteristics. CLL-infiltration was mostly bilateral, whereas lymphoma was usually unilateral (P = 0.02). Optic neuropathy was always secondary to CLL-infiltration, and in those cases, cerebrospinal fluid immunophenotyping was a potential alternative to invasive biopsy as it confirmed the diagnosis in 4 patients (36.4%). On the contrary, lymphoma usually presented as adnexal involvement (P = 0.04), particularly as an orbital mass (P = 0.004). Infections concerned mostly patients previously treated for CLL (P < 0.0001), and main presentations included posterior uveitis (P = 0.0002) and retinal infiltrates (P < 0.0001). Overall, the prognosis was poor, as 29.3% of the patients died within 36 months of follow-up, and 26.1% had a partial or total visual loss. Eye infections were associated with the poorest prognosis as 47% of patients died, with a 6-month-median survival.

Lymphocyte Immunophenotyping and CD4/CD8 Ratio in Cerebrospinal Fluid for the Diagnosis of Sarcoidosis-related Uveitis.

Background: This study aimed to assess the diagnostic relevance of CD4/CD8 ratio in cerebrospinal fluid (CSF) for the etiological diagnosis work-up of uveitis.Methods: We consecutively included patients who were referred to our department for the diagnostic workup of intermediate and/or posterior uveitis. Etiological diagnoses were established in a blind manner regarding CD4/CD8 ratio.Results: Fifty-two patients were included. A diagnosis of ocular sarcoidosis was made in 15 (29%) patients, 21% had another determined diagnosis while 50% remained of undetermined origin. Median CD4/CD8 ratio in CSF was 4.57 (IQR 3.39-5.47) in ocular sarcoidosis, 1.74 (1.60-3.18) in uveitis due to other determined cause (P = .008), and 2.83 (2.34-3.54) in those with uveitis of undetermined origin (P = .007). CD4/CD8 ratio >3.23 was associated with a diagnosis of ocular sarcoidosis.Conclusion: Determination of CD4/CD8 ratio in CSF can be useful for diagnosis work-up since a CD4/CD8 ratio >3.23 in CSF is associated with ocular sarcoidosis.

Mycophenolic acid drug monitoring in patients with systemic sclerosis associated with diffuse skin and/or pulmonary involvement: A monocentric and retrospective French study.

Objective: To explore pharmacokinetic/pharmacodynamic relationship between mycophenolic acid area under the curve and clinical response at 1 year on skin involvement or interstitial lung disease in patients with systemic sclerosis. Method: Retrospective, monocentric study based on French Scleroderma Database in patients receiving mycophenolate mofetil who experienced a limited sampling strategy to estimate individual mycophenolic acid area under the curve plus two pulmonary function tests and skin evaluation after 1 month and 1 year. Efficacy criterions were variations of modified Rodnan skin score, forced vital capacity, and diffusing lung capacity for carbon monoxide at 1 year. Results: We included 52 patients; mean age was 49 years (range 17-79), and 36 (69%) were females. Fifty patients (96%) had skin sclerosis, 39 (75%) had diffuse skin involvement with a median modified Rodnan skin score of 14 (0-38). Thirty-eight (76%) had interstitial lung disease, with median forced vital capacity and diffusing lung capacity for carbon monoxide of 81% (37-127) and 56% (28-103) from predicted values, respectively. Twenty-five (51%) patients had pulmonary fibrosis. Mycophenolate mofetil was given for 10 months (0-173) at a median dose of 2000 mg/day (500-3000). In the entire population, no relationship was found between area under the curve and modified Rodnan skin score (p = 0.085), forced vital capacity (p = 0.80), or diffusing lung capacity for carbon monoxide (p = 0.72) variations at 1 year. Conclusion: In this retrospective study, we failed to document any relationship between mycophenolic acid area under the curve and skin involvement or interstitial lung disease evolution. Routine monitoring of mycophenolic acid in systemic sclerosis patients treated with mycophenolate mofetil cannot be recommended based on our results.

Skewed peripheral B- and T-cell compartments in patients with ANCA-associated vasculitis.

OBJECTIVES: To characterize lymphocytes dysregulation in patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). METHODS: Using flow cytometry, we analysed B- and T-cell subsets in peripheral blood from 37 untreated patients with active disease (29 GPA and 8 MPA) and 22 healthy controls (HCs). RESULTS: GPA patients had increased Th2 (1.8 vs 1.0%, P = 0.02), Th9 (1.1 vs 0.2%, P = 0.0007) and Th17 (1.4 vs 0.9%, P = 0.03) cells compared with HC. Patients with MPO-ANCAs had significantly more CD21- B cells than HC or PR3-ANCA patients (6.9 vs 3.3% and 4.4%, P = 0.01). CD69 expressing B cells were significantly higher in GPA and MPA (3.0 and 5.9 vs 1.4%, P = 0.02 and P = 0.03, respectively) compared with HC, whereas B-cell activating factor-receptor expression was decreased in GPA and MPA (median fluorescence intensity ratio 11.8 and 13.7 vs 45.1 in HC, P < 0.0001 and P = 0.003, respectively). Finally, IL-6-producing B cells were increased in GPA vs HC (25.8 vs 14.9%, P < 0.0001) and decreased in MPA vs HC (4.6 vs 14.9%, P = 0.005), whereas TNF-α-producing B cells were lower in both GPA and MPA patients compared with controls (15 and 8.4 vs 30%, P = 0.01 and P = 0.006, respectively). CONCLUSION: Skewed T-cell polarization towards Th2, Th9 and Th17 responses characterizes GPA, whereas B-cell populations are dysregulated in both GPA and MPA with an activated phenotype and a decreased B-cell activating factor-receptor expression. Finally, inflammatory B cells producing IL-6 are dramatically increased in GPA, providing an additional mechanism by which rituximab could be effective.

Balint groups and narrative medicine compared to a control condition in promoting students' empathy.

BACKGROUND: The perceived importance of clinical empathy may decline among students during medical training. Several interventions have been shown to be effective in promoting or preserving medical students' empathic abilities, such as empathy skills training or Balint groups. Although narrative medicine training shares some features with these interventions, no randomized study to date examined the efficacy of narrative medicine training. This study aimed to assess the effects of Balint groups and narrative medicine training on clinical empathy measured by the self-rated Jefferson's School Empathy Scale - Medical Student (JSPE-MS©) among fourth-year medical students. METHODS: Students who gave their consent to participate were randomly allocated in equal proportion to Balint groups, narrative medicine training or to the control group. Participants in the intervention groups received either seven sessions of 1.5-h Balint groups or a 2-h lecture and five sessions of 1.5-h narrative medicine training from October 2015 to December 2015. The main outcome was the change in JSPE-MS© score from baseline to one week after the last session. RESULTS: Data from 362 out of 392 participants were analyzed: 117 in the control group, 125 in the Balint group and 120 in the narrative medicine group. The change in JSPE-MS© score from baseline to follow-up was significantly higher in the Balint group than in the control group [mean (SD): 0.27 (8.00) vs. -2,36 (11.41), t = 2.086, P = 0.038]. The change in JSPE-MS© score in the narrative medicine group [mean (SD): - 0.57 (8.76)] did not significantly differ from the changes in the control group (t = 1.355, P = 0.18) or the Balint group (t = 0.784, P = 0.43). Adjusting for participants' characteristics at baseline, Balint groups remained associated with better outcomes compared to the control group (ß = 2.673, P = 0.030). CONCLUSIONS: Balint groups may promote clinical empathy to some extent among medical students, at least in the short run.

Handgrip strength is a comorbidity marker in systemic necrotizing vasculitides and predicts the risk of fracture and serious adverse events.

OBJECTIVE: Sarcopenia has been associated with poor outcomes in various medical and surgical conditions. However, its impact in systemic necrotizing vasculitides (SNV) had never been characterized. We aimed to assess the prevalence, associated factors and prognostic impact of sarcopenia in SNV. METHODS: Patients with SNV were successively included in a prospective longitudinal study assessing comorbidities. At inclusion, we evaluated sarcopenia by assessing skeletal muscle mass index using DXA and muscle strength using handgrip strength. Vasculitis and treatments-related events were recorded and analysed using Cox models. RESULTS: One hundred and twenty patients were included. At inclusion, low handgrip strength (<30 kg for men and 20 kg for women) was identified in 28 (23%) patients, while no patient exhibited low skeletal muscle mass index (<7.23 kg/m2 for men and 5.67 kg/m2 for women). Low handgrip strength was associated with age (P <0.0001), type of vasculitis (P =0.01), vasculitis damage index (P =0.01), history of falls (P =0.0002), osteoporosis (P =0.04), low serum albumin (P =0.003) and prealbumin (P =0.0007), high CRP (P =0.001), high FRAX® tool (P =0.002) and low bone mineral density at femoral neck (P =0.0002). After median follow-up of 42 months, low handgrip strength was associated with higher risk of bone fracture [HR 4.25 (1.37-13.2), P =0.01] and serious adverse events [HR 2.80 (1.35-5.81), P =0.006]. CONCLUSION: Handgrip strength is associated in SNV with nutritional status and comorbidities such as bone disease, and seems to predict, as in other medical conditions, the risk of fracture and serious adverse events during follow-up. In contrast, assessment of skeletal muscle mass index in this population remains uncertain.