Acute kidney injury in patients treated with anti-programmed death receptor-1 for advanced melanoma: a real-life study in a single-centre cohort.

BACKGROUND: Immune checkpoints inhibitors have transformed the prognosis of advanced melanoma but are associated with immune-related adverse events (irAEs). We evaluated the incidence, risk factors and causes of acute kidney injury (AKI) in a monocentric real-life cohort of patients treated with anti-programmed death receptor-1 (anti-PD1) antibodies for advanced melanoma. METHODS: Retrospective collection of medical charts and comprehensive analysis of lab results from patients treated with nivolumab or pembrolizumab for advanced melanoma between 2014 and 2018 was carried out. AKI was defined by Kidney Disease Improving Global Outcomes criteria, and causes were determined by chart review. Overall survival, survival without AKI and impact of AKI on survival were analysed. Risk factors for death and for AKI were identified. RESULTS: Two hundred and thirty-nine patients were included. Forty-one (17%) had at least one episode of AKI. Independent risk factors for AKI were treatment with renin-angiotensin-aldosterone system inhibitors (RAASi), pre-existing chronic kidney disease (CKD) and cumulated doses of anti-PD1. The main cause of AKI was prerenal, and only eight patients (3.3%) developed acute interstitial nephritis; 8% of patients developed CKD. The median overall survival was 13.4 months and was not affected by AKI. In multivariate analysis, the overall mortality was lower in overweight and obese patients and higher in patients treated with proton-pump inhibitors (PPI) or corticosteroids. CONCLUSIONS: AKI is common in patients treated with anti-PD1 for advanced melanoma but is mostly prerenal and favoured by the use of RAASi; renal irAE is rare. PPI and corticosteroids were associated with poor survival in this population, while overweight/obesity was protective.

The creation and implementation of advanced practice nursing in France: Experiences from the field.

AIM: This paper describes the characteristics of the new advanced practice nursing roles in France, as well as their challenges and perspectives, and compares the French model with the recommendations of the International Council of Nurses. BACKGROUND: Advanced practice nursing is particularly well established in English-speaking countries. Since 2018, France has become the second French-speaking region to legalize and regulate advanced practice nurses. SOURCE OF EVIDENCE: The International Council of Nurses and French government websites, and scientific databases (PubMed, CINALH, Cochrane Library) were explored. Feedback from French nursing academics was also requested. DISCUSSION: The advanced practice nursing model in France is described according to the scope and conditions of professional practice. The educational program leads to a State diploma with master's degree, which it is mandatory to be a registered nurse. Remuneration depends on the sector of practice in the public hospital, primary care or private sector. Although there is no national strategy for the implementation of advanced practice nursing roles, research projects are being initiated to guide and evaluate the practice. Based on concordance analysis with the recommendations of the International Council of Nurses, the French advanced practice nursing model appears to be similar to the nurse practitioner model. CONCLUSION: Adjustments in the scope of practice and education can be expected as the implementation of these roles is evaluated. IMPLICATIONS FOR NURSING PRACTICE: This is a historical evolution of the nursing profession in France, for which communication with patients and healthcare professionals is essential. IMPLICATIONS FOR NURSING POLICY: The implementation of advanced practice nursing roles in clinical settings requires the development of national strategies to support initiatives and ensure the sustainability of these roles.

Human Infection with Orf Virus and Description of Its Whole Genome, France, 2017.

Zoonotic transmission of parapoxvirus from animals to humans has been reported; clinical manifestations are skin lesions on the fingers and hands after contact with infected animals. We report a human infection clinically suspected as being ecthyma contagiosum. The patient, a 65-year-old woman, had 3 nodules on her hands. She reported contact with a sheep during the Aïd-el-Fitr festival in France during 2017. We isolated the parapoxvirus orf virus from these nodules by using a nonconventional cell and sequenced the orf genome. We identified a novel orf virus genome and compared it with genomes of other orf viruses. More research is needed on the genus Parapoxvirus to understand worldwide distribution of and infection by orf virus, especially transmission between goats and sheep.

Dipeptidyl peptidase IV inhibitors, a risk factor for bullous pemphigoid: Retrospective multicenter case-control study from France and Switzerland.

BACKGROUND: Case reports have suggested an association between dipeptidyl peptidase-4 inhibitors (DPP4is) and development of bullous pemphigoid (BP). OBJECTIVE: To evaluate the association between DPP4i treatment and development of BP. METHODS: We conducted a retrospective 1:2 case-control study, comparing case patients with diabetes and BP with age- and sex-matched control patients with diabetes issued from Swiss (Bern) and French (Marseille) dermatologic departments from January 1, 2014, to July 31, 2016. RESULTS: We collected 61 case patients with diabetes and BP and 122 controls. DPP4is were associated with an increased risk for development of BP (adjusted odds ratio, 2.64; 95% confidence interval, 1.19-5.85; P = .02), with vildagliptin showing the highest adjusted odds ratio (3.57 [95% confidence interval, 1.07-11.84; P = .04]). Stratified analysis showed a stronger association in males and patients age 80 years or older. DPP4i withdrawal and the initiation of first-line treatments led to clinical remission in 95% of cases. LIMITATIONS: This was a retrospective study in tertiary referral hospitals. We focused the analysis on DPP4i intake, without analyzing the potential isolated effect of metformin. CONCLUSIONS: DPP4is, especially vildagliptin, are associated with an increased risk for development of BP. Their use needs to be carefully evaluated, particularly in high-risk patients, such as males and those age 80 years or older.

Paradoxical pustular psoriasis induced by ustekinumab in a patient with Crohn's disease-associated spondyloarthropathy.

Palmoplantar pustular psoriasis (PPP) is a clinical form of psoriasis, for which tumor necrosis factor alpha inhibitors (TNFi) or interleukins 12/23 inhibitor (ustekinumab) can be a therapeutic option. Paradoxical psoriatic reactions induced by TNFi are now well known. We present the exceptional case of a paradoxical PPP appeared under ustekinumab in a patient with Crohn's disease-associated spondyloarthropathy. A 58-year-old woman presented with recent peripheral inflammatory arthralgias appeared in the context of a Crohn's disease diagnosed in 2008. Three weeks after the first injection of ustekinumab 390 mg for a refractory Crohn's disease, a slight pruritic erythematous and pustular dermatosis appeared on the right hand palm. The clinical aspect was strongly in favor of a PPP. Ustekinumab was discontinued and replaced by golimumab, leading to a complete healing of PPP after 15 days of discontinuation. Causality assessment calculated using the French method was plausible for ustekinumab in the induction of PPP. It was based on a compatible chronology according to time to onset associated with complete recovery 2 weeks after cessation of treatment, and on the negative assessment of an alternative etiology (nor bacterial or viral infection, nor other treatment taken by the patient, nor previous history of psoriasis). The worsening of underlying psoriasis under ustekinumab through the appearance of generalized or palmoplantar pustules has already been reported in five cases. We describe to our knowledge the first case of paradoxical PPP under ustekinumab in a patient with no known underlying psoriasis.

TWEAK-binding autoantibodies are generated during psoriatic arthritis and are not influenced by anti-TNF therapy.

BACKGROUND: TNF weakly inducer of apoptosis (TWEAK) is member of the TNF ligand superfamily. Various data support that TWEAK produced by synovial macrophages may contribute to synovitis observed in psoriatic arthritis (PsoA). In PsoA, anti-TNF therapy has been successful in agreement with the key role of TNF in the pathogenesis and the generation by PsoA patients of anti-TNF autoantibodies referred as "beneficial autoimmunity to pro-inflammatory mediators". However, the role of TNF-alpha in the regulation of TWEAK modulation of inflammation during PsoA remains unknown. METHODS: We have studied level course during anti-TNF therapy of serum soluble TWEAK. In the same cohort, we have investigated the generation of TWEAK-binding autoantibodies by PsoA patients before and after anti-TNF therapy. RESULTS: Patients with PsoA had significantly higher serum levels of TWEAK compared with controls [respective means (±SEM) were 645 pg/ml (64) and 467 pg/ml (23); (p = 0.006)] but serum soluble TWEAK levels were not correlated with BASDAI (Spearman's coefficients <0.003, p > 0.05). Our study showed that soluble TWEAK levels were not modulated by etanercept therapy [respective Means (±SEM) were 605 (95) (week 12) and 744 (97) (week 24) pg/ml; (p > 0.23)]. Anti-TWEAK autoantibodies were detected in 9/13 (69.2 %) PsoA patients at inclusion and only in 3/57 (5.3 %) healthy blood donors (p < 0.0001). These circulating antibodies were persistent in PsoA patients and detected at similar levels during etanercept therapy. Moreover we showed that they had a down regulating effect on CCL-2 secretion by endothelial cells stimulated by rh TWEAK in vitro. CONCLUSION: Our study revealed that during psoriatic arthritis (1) serum TWEAK was up regulated and (2) TWEAK-binding autoantibodies are generated. Both parameters were not influenced by anti-TNF therapy and persisted at high levels during anti-TNF therapy. For the first time we described here TWEAK-binding IgG autoantibodies with a down regulating effect on CCL-2 secretion by endothelial cells stimulated by rh TWEAK in vitro. Finally, our results suggest that TWEAK may be involved in PsoA pathogeny. Trial registration This clinical trial was approved by the local Ethics Committee "Comité de Protection des Personnes Sud-Méditerranée V" with the registration number: 2011-002954-29, and French health minister registration number AFSSAPS A110784-42 obtained the 08/22/2011. This clinical trial is registered in Clinical trial.gov under the number: NCT02164214.

ICOS is widely expressed in cutaneous T-cell lymphoma, and its targeting promotes potent killing of malignant cells.

The treatment of advanced-stage cutaneous T-cell lymphoma (CTCL) remains an unmet medical need. Mogamulizumab, anti-KIR3DL2, and brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate (ADC) coupled with monomethyl-auristatin-E (MMAE), provided encouraging results, but new targeted therapies are needed. Inducible T-cell costimulator (ICOS), a T-cell costimulatory receptor, is a promising therapeutic target, not only because it is expressed by malignant T cells in CTCL but also because of its connection with the suppressive activity of regulatory T (Treg) cells. Immunohistochemical analysis revealed that ICOS was widely expressed by malignant cells in skin biopsy specimens from 52 patients with mycosis fungoides and Sézary syndrome (SS), as well as in involved node biopsy specimens from patients with SS. Furthermore, flow cytometry demonstrated its strong expression by circulating tumor cells in all our patients with SS. Percentages of ICOS+ Treg cells were significantly higher in patients with SS than in healthy donors. We then investigated the preclinical efficacy of anti-ICOS ADCs generated by coupling murine anti-ICOS monoclonal antibodies with MMAE and pyrrolobenzodiazepine. In 3 CTCL cell lines (Myla, MJ, and HUT78), we observed a significant dose-dependent decrease in cell viability in the presence of anti-ICOS ADCs. In addition, anti-ICOS-MMAE ADCs had an in vitro and in vivo efficacy superior to BV in a mouse xenograft model (MyLa). Finally, we assessed the efficacy of anti-ICOS ADCs in ICOS+ patient-derived xenografts from patients with SS and angioimmunoblastic T-cell lymphoma. Collectively, our findings provide the preliminary basis for a therapeutic trial.

Efficacy and safety of oral alitretinoin as treatment for chronic hand eczema in France: a real-life open-label study.

BACKGROUND: Chronic hand eczema is an inflammatory dermatosis that results in a significant psychological and socio-economic burden. Alitretinoin (AL) is indicated in adults with severe chronic hand eczema (sCHE) unresponsive to potent topical corticosteroids. OBJECTIVES: To assess AL effectiveness and safety in patients with sCHE under real-life conditions based on a prospective observational study in France (2010-2014). MATERIALS & METHODS: Clinical severity was assessed using Physician Global Assessment (PGA) and Modified Total Lesion Symptom Score (mTLSS) and quality of life by Skindex and visual analogue scales. Patients were treated with AL for 12-24 weeks and followed for 24 months. Responders were patients with clear/almost clear skin based on PGA at the end of treatment and the primary outcome was remission (clear, almost clear, or mild skin) at one and two years after treatment. RESULTS: A total of 394 patients with severe or moderate PGA were included in the study by 109 dermatologists. AL treatment duration was 5.4 ± 4.1 months (mean ± SD) and 112/274 patients evaluated at the end of treatment were responders. Of the 112 responders, 41/51 evaluable patients were in remission after one year and 36/46 after two years. At the end of treatment, Skindex improved from 48.8 ± 18.1% to 27.1 ± 23.2%. Among the 112 responders, 68/84 did not relapse (mTLSS increased >75% from baseline). The most common adverse events were headache (24%) and dyslipidaemia (4%). CONCLUSIONS: This study supports a positive benefit/risk profile for AL for sCHE patients unresponsive to topical corticosteroids.

Cutaneous leishmaniasis treated with azithromycin in a child.

This report describes the case of a 10-year-old boy with cutaneous leishmaniasis presumed to be caused by Leishmania major and successfully treated with oral azithromycin. Clinical studies using azithromycin for the treatment of cutaneous leishmaniasis are reviewed.

Increased serum levels of fractalkine and mobilisation of CD34+CD45- endothelial progenitor cells in systemic sclerosis.

BACKGROUND: The disruption of endothelial homeostasis is a major determinant in the pathogenesis of systemic sclerosis (SSc) and is reflected by soluble and cellular markers of activation, injury and repair. We aimed to provide a combined assessment of endothelial markers to delineate specific profiles associated with SSc disease and its severity. METHODS: We conducted an observational, single-centre study comprising 45 patients with SSc and 41 healthy control subjects. Flow cytometry was used to quantify circulating endothelial microparticles (EMPs) and CD34+ progenitor cell subsets. Colony-forming unit-endothelial cells (CFU-ECs) were counted by culture assay. Circulating endothelial cells were enumerated using anti-CD146-based immunomagnetic separation. Blood levels of endothelin-1, vascular endothelial growth factor (VEGF) and soluble fractalkine (s-Fractalkine) were evaluated by enzyme-linked immunosorbent assay. Disease-associated markers were identified using univariate, correlation and multivariate analyses. RESULTS: Enhanced numbers of EMPs, CFU-ECs and non-haematopoietic CD34+CD45- endothelial progenitor cells (EPCs) were observed in patients with SSc. Patients with SSc also displayed higher serum levels of VEGF, endothelin-1 and s-Fractalkine. s-Fractalkine levels positively correlated with CD34+CD45- EPC numbers. EMPs, s-Fractalkine and endothelin-1 were independent factors associated with SSc. Patients with high CD34+CD45- EPC numbers had lower forced vital capacity values. Elevated s-Fractalkine levels were associated with disease severity, a higher frequency of pulmonary fibrosis and altered carbon monoxide diffusion. CONCLUSIONS: This study identifies the mobilisation of CD34+CD45- EPCs and high levels of s-Fractalkine as specific features of SSc-associated vascular activation and disease severity. This signature may provide novel insights linking endothelial inflammation and defective repair processes in the pathogenesis of SSc.

Ectoparasitism and vector-borne diseases in 930 homeless people from Marseilles.

Homeless people are particularly exposed to ectoparasites, but their exposure to arthropod-borne diseases has not been evaluated systematically. A medical team of 27 persons (7 nurses, 6 infectious disease residents or fellows, 2 dermatologists, and 12 infectious disease specialists) visited the 2 shelters in Marseilles, France, for 4 consecutive years. Homeless volunteers were interviewed, examined, and received care; and blood was sampled for cell counts and detection of bacteremia, antibodies to louse-borne (Rickettsia prowazekii, Bartonella quintana, and Borrelia recurrentis), flea-borne (R. typhi, R. felis), mite-borne (R. akari), and tick-borne (R. conorii) bacterial agents. We selected sex- and age-adjusted controls among healthy blood donors. Over 4 years, 930 homeless people were enrolled. Lice were found in 22% and were associated with hypereosinophilia (odds ratio, 5.7; 95% confidence intervals, 1.46-22.15). Twenty-seven patients (3%) with scabies were treated with ivermectin. Bartonella quintana was isolated from blood culture in 50 patients (5.3%), 36 of whom were treated effectively. The number of bacteremic patient increased from 3.4% to 8.4% (p = 0.02) over the 4 years of the study. We detected a higher seroprevalence to Borrelia recurrentis, R. conorii, and R. prowazekii antibodies in the homeless. Our study shows a high prevalence of louse-borne infections in the homeless and a high degree of exposure to tick-borne diseases and scabies. Despite effective treatment for Bartonella quintana bacteremia and the efforts made to delouse this population, Bartonella quintana remains endemic, and we found hallmarks of epidemic typhus and relapsing fever. The uncontrolled louse infestation of this population should alert the community to the possibility of severe re-emerging louse-borne infections.

Pepper mild mottle virus, a plant virus associated with specific immune responses, Fever, abdominal pains, and pruritus in humans.

BACKGROUND: Recently, metagenomic studies have identified viable Pepper mild mottle virus (PMMoV), a plant virus, in the stool of healthy subjects. However, its source and role as pathogen have not been determined. METHODS AND FINDINGS: 21 commercialized food products containing peppers, 357 stool samples from 304 adults and 208 stool samples from 137 children were tested for PMMoV using real-time PCR, sequencing, and electron microscopy. Anti-PMMoV IgM antibody testing was concurrently performed. A case-control study tested the association of biological and clinical symptoms with the presence of PMMoV in the stool. Twelve (57%) food products were positive for PMMoV RNA sequencing. Stool samples from twenty-two (7.2%) adults and one child (0.7%) were positive for PMMoV by real-time PCR. Positive cases were significantly more likely to have been sampled in Dermatology Units (p<10(-6)), to be seropositive for anti-PMMoV IgM antibodies (p = 0.026) and to be patients who exhibited fever, abdominal pains, and pruritus (p = 0.045, 0.038 and 0.046, respectively). CONCLUSIONS: Our study identified a local source of PMMoV and linked the presence of PMMoV RNA in stool with a specific immune response and clinical symptoms. Although clinical symptoms may be imputable to another cofactor, including spicy food, our data suggest the possibility of a direct or indirect pathogenic role of plant viruses in humans.

NF-1Score: a prediction score for internal neurofibromas in neurofibromatosis-1.

NF-1 is associated with a 15-year decrease in life expectancy. Internal neurofibromas are associated with increased morbidity and mortality through malignant transformation and compression of neighboring organs. Our purpose was to develop and to validate a clinical score for predicting internal neurofibromas in adults. The development sample comprised 208 patients and the validation sample 191 patients. The score was developed using logistic regression. Discrimination and calibration of the model were evaluated. Four variables were independently associated with internal neurofibromas: at least two subcutaneous neurofibromas (odds ratio (OR)=4.7, [2.1-10.5]), age < or =30 years (OR=3.1, [1.4-6.8]), absence of cutaneous neurofibromas (OR=2.6, [0.9-7.5]), and fewer than six café-au-lait spots (OR=2.0 [0.9-4.6]). The score computed by linear combination of the rounded coefficients of these four variables ranged from 0 to 40 (mean, 12.8+/-10.8). The probability of internal neurofibromas was computed as exp (-2.93+0.11Score)/exp (1+(-2.93+0.11Score)). Probabilities agreed well with the observed frequencies indicating good calibration, and discrimination was adequate (AUC-ROC, 0.75) in both data sets. The presence of internal neurofibromas can be accurately predicted using a simple clinical score. Further work will establish the score threshold that identifies patients at high risk for complications.

Evaluation of interleukin 13 polymorphisms in systemic sclerosis.

Systemic sclerosis (SSc) is a multisystem disease of unknown etiology. It is characterized by excessive cutaneous and visceral fibrosis, damage to small blood vessels, and production of autoantibodies. Interleukin-13 (IL-13) has been shown to be involved in abnormal fibrosis in other diseases. Therefore, we have evaluated its possible involvement in SSc. We analyzed four IL13 gene polymorphisms, rs1800925 (IL13-1055), rs20541 (Arg130Gln), rs847, and rs2243204 in 107 unrelated SSc patients (40 patients having diffuse cutaneous form and 67 patients having limited cutaneous form) and in 170 controls. All subjects were Caucasians. In the total patient population and in the diffuse cutaneous subset, we observed an association between two IL13 polymorphisms, IL13 rs1800925 (IL13-1055), and IL13 rs2243204, and disease (p=0.03-0.04). The IL13 rs2243204T allele was more common in SSc patients (p=0.01, OR=2.3 CI 1.21-4.38) and in the diffuse cutaneous form (p=0.01, OR=2.95, CI 1.35-6.49) than in control subjects. Our result supports the suggestion that polymorphisms in IL13 are associated to SSc and skin fibrosis process. However, further studies on larger and independent population and functional analyses are needed to confirm these findings.

IL13RA2 gene polymorphisms are associated with systemic sclerosis.

OBJECTIVE: To investigate the influence of genetic variability on the phenotypic expression of systemic sclerosis (SSc), by testing possible associations between single nucleotide polymorphisms (SNP) in IL13RA1 and IL13RA2 genes and SSc in a Caucasian population. METHODS: As IL13RA1 and IL13RA2 are located on the X chromosome and SSc occurs far more frequently in women than in men, only women were genotyped. The study group comprised 97 women with SSc, 36 with diffuse (dcSSc) and 61 with limited (lcSSc) cutaneous forms of disease, and 109 healthy controls. Patients and controls were Caucasian. We investigated 4 SNP in IL13RA1 and 3 in IL13RA2 by polymerase chain reaction amplifications and enzymatic digestion or primer extension reactions and denaturing high-performance liquid chromatography. RESULTS: We detected an association between IL13RA2 rs638376 and patients with SSc [p = 0.004, odds ratio (OR) = 1.85, confidence interval (CI) 1.22-2.74, p corr = 0.02], as well as with dcSSc in that subgroup of patients (p = 0.01, OR 2.22, 95% CI 1.27-3.89, p corr = 0.05). The IL13RA2 rs638376G allele frequency was higher in patients with SSc (51.6%) than in controls (36.4%, p = 0.003, OR 1.86, 95% CI 1.24-2.79, p corr = 0.015) and in the subgroup with dcSSc (57.6%) than in controls (36.4%, p = 0.003, OR 2.37, 95% CI 1.35-4.15, p corr = 0.015). One other IL13RA2 SNP was only associated with the dcSSc subgroup: the IL13RA2 rs5946040G allele was more common in patients with dcSSc (33.8%) than in controls (17%, p = 0.004, OR 2.5, 95% CI 1.36-4.60, p corr = 0.02). CONCLUSION: Our data suggest that IL13RA2 gene polymorphisms may be involved in susceptibility to SSc. Further studies are under way to show that they contribute to disease.