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PURPOSE: A recent phase II open-label study of the interleukin 1 (IL-1) receptor antagonist (IL-1Ra) anakinra in treating IVIG-resistant Kawasaki disease (KD) patients reported promising results. Here, we aimed to characterize the immunological impact of IL-1 blockade in this unique study population. METHODS: Patients' and control sera and supernatants of cells (whole blood, neutrophils, coronary artery endothelial cells) stimulated with recombinant IL-1ß were analyzed for single or multiple marker (n = 22) expression by ELISA or multiplexed bead array assay. Data were analyzed using unsupervised hierarchical clustering, multiple correlation, and multi-comparison statistics and were compared to retrospective analyses of KD transcriptomics. RESULTS: Inflammation in IVIG-resistant KD (n = 16) is hallmarked by over-expression of innate immune mediators (particularly IL-6 > CXCL10 > S100A12 > IL-1Ra). Those as well as levels of immune or endothelial cell activation markers (sICAM-1, sVCAM-1) declined most significantly in course of anakinra treatment. Prior as well as following IL-1R blockade, over-expression of leucine-rich-α2-glycoprotein 1 (LRG1) associated best with remnant inflammatory activity and the necessity to escalate anakinra dosage and separated inflammatory KD patients from sJIA-MAS (n = 13) and MIS-C (n = 4). Protein as well as retrospective gene expression analyses indicated tight association of LRG1 with IL-1ß signaling and neutrophilia, while particularly neutrophil stimulation with recombinant IL-1ß resulted in concentration-dependent LRG1 release. CONCLUSION: Our study identifies LRG1 as known trigger of endothelial activation and cardiac re-modeling to associate with IL-1ß signaling in KD. Besides a potential patho-mechanistic implication of these findings, our data suggest blood leukocyte and neutrophil counts to best predict response to IL-1Ra treatment in IVIG-resistant KD.
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Síndrome de Linfonodos Mucocutâneos , Biomarcadores , Criança , Células Endoteliais/metabolismo , Glicoproteínas/metabolismo , Glicoproteínas/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta , Interleucina-6/metabolismo , Leucina/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Estudos Retrospectivos , Proteína S100A12RESUMO
OBJECTIVE: To evaluate the ability of neoadjuvant axitinib to reduce the size of T2 renal cell carcinoma (RCC) for shifting from a radical nephrectomy (RN) to a partial nephrectomy (PN) indication, offering preservation of renal function. PATIENTS AND METHODS: Patients with cT2aN0NxM0 clear-cell RCC, considered not suitable for PN, were enrolled in a prospective, multicentre, phase II trial (AXIPAN). Axitinib 5 mg, and up to 7-10 mg, was administered twice daily, for 2-6 months before surgery, depending on the radiological response. The primary outcome was the number of patients receiving PN for a tumour <7 cm in size after neoadjuvant axitinib. RESULTS: Eighteen patients were enrolled. The median (range) tumour size and RENAL nephrometry score were 76.5 (70-98) mm and 11 (7-11), respectively. After axitinib neoadjuvant treatment, 16 tumours decreased in diameter, with a median size reduction of 17% (64.0 vs 76.5 mm; P < 0.001). The primary outcome was considered achieved in 12 patients who underwent PN for tumours <7 cm. Sixteen patients underwent PN. Axitinib was tolerated in the present study, as has been previously shown in the metastatic setting. Five patients had grade 3 adverse events. Five patients experienced Clavien III-V post-surgery complications. At 2-year follow-up, six patients had metastatic progression, and two had a recurrence. CONCLUSION: Neoadjuvant axitinib in cT2 ccRCC is feasible and, even with a modest decrease in size, allowed a tumour shrinkage <7 cm in 12 cases; however, PN procedures remained complex, requiring surgical expertise with possible morbidity.
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Antineoplásicos/uso terapêutico , Axitinibe/uso terapêutico , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Nefrectomia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/terapia , Esquema de Medicação , Feminino , Humanos , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias/métodos , Preservação de Órgãos , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: We aimed to describe the main features of Behçet's disease (BD) in children in the largest prospective cohort to date and to propose a classification. METHODS: An international expert consensus group was formed to define a data set of minimal symptoms for the inclusion of patients. Patients were entered prospectively during 66â months. Experts classified patients on a consensus basis. The concordance of two international classifications was analysed in confirmed patients with BD. Comparisons of subgroups of patients helped define consensus criteria. BD-associated clinical manifestations were also investigated in three control diseases extracted from an independent data set (Eurofever). FINDINGS: In total, 42 centres from 12 countries included 230 patients; data for 219 (M/F ratio=1) could be analysed. The experts classified 156 patients (71.2%) as having confirmed BD. Males more often than females showed cutaneous, ocular and vascular symptoms and females more often genital aphthosis. Age at disease onset and skin and vascular involvement were lower for European than non-European children. Oral aphthosis was the presenting sign for 81% (179/219) of patients. The mean delay to the second symptom was 2.9±2.2â years. International classifications were not concordant with the expert classification. Our paediatric classification contains six categories, a minimum of three signs (each in a distinct category) defining paediatric BD. Three clinical signs discriminated our cohort from the Eurofever cohorts. INTERPRETATION: We present a comprehensive description of a large cohort of patients from both European and non-European countries and propose the first classification of paediatric BD for future therapeutic trials.
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Síndrome de Behçet/classificação , Consenso , Avaliação de Sintomas/classificação , Adolescente , Idade de Início , Síndrome de Behçet/diagnóstico , Criança , Feminino , Humanos , Masculino , Estudos ProspectivosRESUMO
OBJECTIVE: This study aimed to estimate the total healthcare costs associated with elderly chronic pain (CP) patients, define cost-related factors in this population, and examine cost evolution over two years. METHOD: This is an ancillary study from the CP S.AGE subcohort, including non-institutionalized patients aged over 65 suffering from CP. 1190, 1108, 1042, and 950 patients were reviewed with available healthcare data at follow-up visits at 6, 12, 18, and 24 months, respectively. Healthcare components included medical and paramedical visits, medication prescription, and hospitalization. RESULT: The mean total cost in the first semester was estimated at
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Dor Crônica/economia , Custos de Cuidados de Saúde , Idoso , Idoso de 80 Anos ou mais , Dor Crônica/tratamento farmacológico , Feminino , Hospitalização/economia , Humanos , Masculino , Atenção Primária à Saúde/economiaRESUMO
OBJECTIVE: The aim of this study was to identify the relationship between general practitioner (GP) gender and prescribing practice of chronic pain drugs in older adults. DESIGN: Cross-sectional observational study. SETTING: GPs in private practice throughout France. SUBJECTS: Two hundred and sixty GPs (80.8% male and 19.2% female) enrolled 1,379 (28.4% male and 71.6% female) noninstitutionalized patients over 65 years of age, suffering from chronic pain. METHODS: A comparison of prescribing habits between male and female GPs was performed on baseline data with univariate analyses followed by multivariate analyses after taking several confounding factors into account. RESULTS: No significant differences were found when comparing male and female GPs' prescriptions of World Health Organization step 1, step 2, and step 3 analgesics. Male GPs were more likely than female GPs to prescribe antineuropathic pain drugs (11.3% of patients with male GPs versus 4.8% of patients with female GPs, P = 0.004) and less likely to prescribe symptomatic slow-acting drugs for osteoarthritis (SySADOA) (10.2% of male GPs' patients versus 18.8% of female GPs' patients, P = 0.0003). After adjusting for several confounding factors, male GPs were still more likely to prescribe antineuropathic pain drugs (OR 2.43, 95% CI 1.15-5.14, P = 0.02) and less likely to prescribe symptomatic slow-acting drugs (OR 0.64, 95% CI 0.42-0.97, P = 0.03). CONCLUSION: Male and female GPs prescribe analgesics in a similar manner. However, male GPs prescribe more antineuropathic pain drugs, but fewer SySADOA.
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Analgésicos/uso terapêutico , Dor Crônica/tratamento farmacológico , Manejo da Dor/métodos , Padrões de Prática Médica/estatística & dados numéricos , Idoso , Estudos Transversais , Feminino , Clínicos Gerais , Humanos , MasculinoRESUMO
BACKGROUND: The aim was to identify fall predictors in elderly suffering from chronic pain (CP) and to test their applicability among patients with other chronic conditions. METHODS: 1,379 non-institutionalized patients aged 65 years and older who were suffering from CP (S.AGE CP sub-cohort) were monitored every 6 months for 1 year. Socio-demographic, clinical and pain data and medication use were assessed at baseline for the association with falls in the following year. Falls were assessed retrospectively at each study visit. Logistic regression analyses were performed to identify fall predictors. The derived model was applied to two additional S.AGE sub-cohorts: atrial fibrillation (AF) (n = 1,072) and type-2 diabetes mellitus (T2DM) (n = 983). RESULTS: Four factors predicted falls in the CP sub-cohort: fall history (OR: 4.03, 95 % CI 2.79-5.82), dependency in daily activities (OR: 1.81, 95 % CI 1.27-2.59), age ≥75 (OR: 1.53, 95 % CI 1.04-2.25) and living alone (OR: 1.73, 95 % CI 1.24-2.41) (Area Under the Curve: AUC = 0.71, 95 % CI 0.67-0.75). These factors were relevant in AF (AUC = 0.71, 95 % CI 0.66-0.75) and T2DM (AUC = 0.67, 95 % CI 0.59-0.73) sub-cohorts. Fall predicted probability in CP, AF and T2DM sub-cohorts increased from 7, 7 and 6 % in patients with no risk factors to 59, 66 and 45 % respectively, in those with the four predictors. Fall history was the strongest predictor in the three sub-cohorts. CONCLUSION: Fall history, dependency in daily activities, age ≥75 and living alone are independent fall predictors in CP, AF and T2DM patients.
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Acidentes por Quedas , Fibrilação Atrial/epidemiologia , Dor Crônica , Diabetes Mellitus Tipo 2/epidemiologia , Acidentes por Quedas/prevenção & controle , Acidentes por Quedas/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Causalidade , Dor Crônica/diagnóstico , Dor Crônica/epidemiologia , Feminino , Seguimentos , França/epidemiologia , Avaliação Geriátrica/métodos , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de RiscoRESUMO
OBJECTIVE: Describe the consequences of dextropropoxyphene (DXP) market withdrawal on analgesic prescriptions and on the quality of therapeutic management of chronic pain. PATIENTS AND METHODS: From a cohort of non-institutionalised elderly patients with chronic pain recruited by general practitioners, we selected patients who were treated with DXP daily for at least 6 months just prior to DXP market withdrawal and who had an evaluation of pain and its impact on daily activities before and after DXP withdrawal. RESULTS: One hundred three patients took DXP daily for chronic pain. Immediately after DXP market withdrawal, 42 (40.8%), 55 (53.4%) and 3 (2.9%) patients were treated with step 1, 2 and 3 analgesics, respectively, and 3 patients (2.9%) were no longer receiving any analgesic medication. Among the 55 patients who continued on step 2 analgesics, 37 were treated with tramadol, 14 with codeine and 9 with opium. Pain intensity and the impact of pain on daily activities remained stable. CONCLUSION: DXP market withdrawal had no consequences on the intensity or impact of chronic pain in elderly patients.
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Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Dextropropoxifeno/uso terapêutico , Retirada de Medicamento Baseada em Segurança , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Analgésicos/uso terapêutico , Dor Crônica/fisiopatologia , Estudos de Coortes , Feminino , Humanos , Masculino , Estudos ProspectivosRESUMO
BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv) is an adult-onset autosomal dominant disease resulting from TTR gene pathogenic variants. ATTRv often presents as a progressive polyneuropathy, and effective ATTRv treatments are available. METHODS: In this 5 year-long (2017-2021) nationwide prospective study, we systematically analysed the TTR gene in French patients with age >50 years with a progressive idiopathic polyneuropathy. RESULTS: 553 patients (70% males) with a mean age of 70 years were included. A TTR gene pathogenic variant was found in 15 patients (2.7%), including the Val30Met TTR variation in 10 cases. In comparison with patients with no TTR gene pathogenic variants (n = 538), patients with TTR pathogenic variants more often presented with orthostatic hypotension (53 vs. 21%, p = .007), significant weight loss (33 vs 11%, p = .024) and rapidly deteriorating nerve conduction studies (26 vs. 8%, p = .03). ATTRv diagnosis led to amyloid cardiomyopathy diagnosis in 11 cases, ATTRv specific treatment in all cases and identification of 15 additional ATTRv cases among relatives. CONCLUSION: In this nationwide prospective study, we found ATTRv in 2.7% of patients with age >50 years with a progressive polyneuropathy. These results are highly important for the early identification of patients in need of disease-modifying treatments.
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Neuropatias Amiloides Familiares , Polineuropatias , Masculino , Adulto , Pessoa de Meia-Idade , Idoso , Humanos , Feminino , Estudos Prospectivos , Neuropatias Amiloides Familiares/patologia , Polineuropatias/diagnóstico , Polineuropatias/genética , Resultado do Tratamento , Pré-Albumina/genéticaRESUMO
Background: Despite the increasing efficacy of chemotherapy (C), the 5-year survival rate for patients with unresectable colorectal liver metastases (CLM) remains around 10%. Liver transplantation (LT) might offer a curative approach for patients with liver-only disease, yet its superior efficacy compared to C alone remains to be demonstrated. Methods: The TransMet randomised multicentre clinical trial (NCT02597348) compares the curative potential of C followed by LT versus C alone in patients with unresectable CLM despite stable or responding disease on C. Patient eligibility criteria proposed by local tumour boards had to be validated by an independent committee via monthly videoconferences. Outcomes reported here are from a non-specified interim analysis. These include the eligibility of patients to be transplanted for non resectable colorectal liver metastases, as well as the feasibility and the safety of liver transplantation in this indication. Findings: From February 2016 to July 2021, 94 (60%) of 157 patients from 20 centres in 3 countries submitted to the validation committee, were randomised. Reasons for ineligibility were mainly tumour progression in 50 (32%) or potential resectability in 13 (8%). The median delay to LT after randomisation was 51 (IQR 30-65) days. Nine of 47 patients (19%, 95% CI: 9-33) allocated to the LT arm failed to undergo transplantation because of intercurrent disease progression. Three of the 38 transplanted patients (8%) were re-transplanted, one of whom (3%) died post-operatively from multi-organ failure. Interpretation: The selection process of potential candidates for curative intent LT for unresectable CLM in the TransMet trial highlighted the critical role of an independent multidisciplinary validation committee. After stringent selection, the feasibility of LT was 81%, as 19% had disease progression while on the waiting list. These patients should be given high priority for organ allocation to avoid dropout from the transplant strategy. Funding: No source of support or funding from any author to disclose for this work. The trial was supported by the Assistance Publique - Hôpitaux de Paris (AP-HP).
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The primary objective of the S.AGES cohort is to describe the real-life therapeutic care of elderly patients. Patients and methods. This is a prospective observational cohort study of 3 700 non-institutionalized patients over the age of 65 years with either type 2 diabetes mellitus (T2DM), chronic pain or atrial fibrillation (AF) recruited by French general practitioners (GPs). Follow-up is planned for 3 years. Baseline characteristics. In the chronic pain sub-cohort, 33% of patients are treated with only grade 1 analgesics, 29% with grade 2 analgesics and 3% with grade 3 analgesics, and 22% have no pain treatment. In the T2DM sub-cohort, 61% of patients have well-controlled diabetes (Hb1c<7%) and 18% are treated with insulin. In the AF sub-cohort, 65% of patients have a CHADS2 score greater than 2, 77% are treated with oral anticoagulants, 17% with platelet inhibitors, 40% with antiarrhythmic drugs and 56% with rate slowing medications. Conclusion. The S.AGES cohort presents a unique opportunity to clarify the real-life therapeutic management of ambulatory elderly subjects and will help to identify the factors associated with the occurrence of major clinical events.
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Assistência Ambulatorial/estatística & dados numéricos , Fibrilação Atrial/terapia , Dor Crônica/terapia , Diabetes Mellitus Tipo 2/terapia , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial/normas , Fibrilação Atrial/epidemiologia , Dor Crônica/epidemiologia , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , França/epidemiologia , Humanos , Masculino , Características de Residência/estatística & dados numéricosRESUMO
BACKGROUND: Acromegaly is associated with an increased left ventricular (LV) mass, as reported in echo-based and, more recently, in a few cardiac magnetic resonance imaging (MRI) studies. One possible explanation for this increased LV mass could be water retention and subsequent myocardial edema. METHODS: In this prospective cross-sectional study, 26 patients with active acromegaly before and after treatment and 31 controls of comparable age and sex were investigated using cardiac MRI. Cardiac morphology, function, and myocardial tissue characteristics were evaluated. Myocardial T2 relaxation time was used as the main outcome measure of myocardial edema. The study was registered with clinicaltrials.gov (NCT02948322). RESULTS: Patients compared to controls had greater LV mass indexes (58.1 [54.7-68.6] vs 46.0 [41.3-49.8] g/m2; P < .001) and end-diastolic volume (EDV) indexes (97.3 [88-101.2] vs 81.6 [78.1-96.2] mL/m2; P = .0069) and had comparable global contractile function. T2 values were not different between patients and controls. Both intracellular (43.83 [41.0-50.0] vs 34.32 [28.9-38.7] g/m2; P < .001) and extracellular (15.06 [13.5-17.1] vs 11.6 [10.8-12.7] g/m2; P < .001) LV mass indexes were higher in patients compared to controls. Log growth hormone correlated with myocardial mass (r = 0.75; P < .001). Sex, systolic blood pressure (BP), and the presence of acromegaly were predictors of the LV mass index. The extracellular LV mass index was associated with sex and the presence of acromegaly, whereas the intracellular LV mass index was associated with sex, systolic BP, and high-density lipoprotein (HDL) cholesterol. Acromegaly treatment reduced EDV and total and intracellular LV mass indexes without significantly affecting extracellular mass. CONCLUSION: Acromegaly results in a disease-specific form of LV hypertrophic remodeling, characterized by an increase in both intra- and extracellular mass. The LV mass index and intracellular mass were decreased by treatment.
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Acromegalia , Disfunção Ventricular Esquerda , Humanos , Acromegalia/complicações , Acromegalia/diagnóstico por imagem , Estudos Transversais , Estudos Prospectivos , Imageamento por Ressonância Magnética , Edema/complicações , Disfunção Ventricular Esquerda/complicaçõesRESUMO
BACKGROUND: Riociguat and balloon pulmonary angioplasty (BPA) are treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, randomised controlled trials comparing these treatments are lacking. We aimed to evaluate the efficacy and safety of BPA versus riociguat in patients with inoperable CTEPH. METHODS: In this phase 3, multicentre, open-label, parallel-group, randomised controlled trial done in 23 French centres of expertise for pulmonary hypertension, we enrolled treatment-naive patients aged 18-80 years with newly diagnosed, inoperable CTEPH and pulmonary vascular resistance of more than 320 dyn·s/cm5. Patients were randomly assigned (1:1) to BPA or riociguat via a web-based randomisation system, with block randomisation (block sizes of two or four patients) without stratification. The primary endpoint was change in pulmonary vascular resistance at week 26, expressed as percentage of baseline pulmonary vascular resistance in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of riociguat or had at least one BPA session. Patients who completed the RACE trial continued into an ancillary 26-week follow-up during which symptomatic patients with pulmonary vascular resistance of more than 320 dyn·s/cm5 benefited from add-on riociguat after BPA or add-on BPA after riociguat. This trial is registered at ClinicalTrials.gov, NCT02634203, and is completed. FINDINGS: Between Jan 19, 2016, and Jan 18, 2019, 105 patients were randomly assigned to riociguat (n=53) or BPA (n=52). At week 26, the geometric mean pulmonary vascular resistance decreased to 39·9% (95% CI 36·2-44·0) of baseline pulmonary vascular resistance in the BPA group and 66·7% (60·5-73·5) of baseline pulmonary vascular resistance in the riociguat group (ratio of geometric means 0·60, 95% CI 0·52-0·69; p<0·0001). Treatment-related serious adverse events occurred in 22 (42%) of 52 patients in the BPA group and five (9%) of 53 patients in the riociguat group. The most frequent treatment-related serious adverse events were lung injury (18 [35%] of 52 patients) in the BPA group and severe hypotension with syncope (two [4%] of 53 patients) in the riociguat group. There were no treatment-related deaths. At week 52, a similar reduction in pulmonary vascular resistance was observed in patients treated with first-line riociguat or first-line BPA (ratio of geometric means 0·91, 95% CI 0·79-1·04). The incidence of BPA-related serious adverse events was lower in patients who were pretreated with riociguat (five [14%] of 36 patients vs 22 [42%] of 52 patients). INTERPRETATION: At week 26, pulmonary vascular resistance reduction was more pronounced with BPA than with riociguat, but treatment-related serious adverse events were more common with BPA. The finding of fewer BPA-related serious adverse events among patients who were pretreated with riociguat in the follow-up study compared with those who received BPA as first-line treatment points to the potential benefits of a multimodality approach to treatment in patients with inoperable CTEPH. Further studies are needed to explore the effects of sequential treatment combining one or two medications and BPA in patients with inoperable CTEPH. FUNDING: Programme Hospitalier de Recherche Clinique of the French Ministry of Health and Bayer HealthCare. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.
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Angioplastia com Balão , Hipertensão Pulmonar , Embolia Pulmonar , Angioplastia/efeitos adversos , Angioplastia com Balão/efeitos adversos , Doença Crônica , Seguimentos , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Embolia Pulmonar/complicações , Embolia Pulmonar/tratamento farmacológico , Pirazóis , Pirimidinas , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
OBJECTIVE: Measurement of IGF-I is important in the management of patients with growth hormone disorders. Here we aim to establish normative data for two new IGF-I assay kits based on a large random sample of the French general adult population. SUBJECTS AND METHODS: We measured IGF-I in 911 healthy adults (18-90 years) with two immunoassays (ROCHE Elecsys® and IMMULITE-2000 calibrated against the new IS 02/2547). We compared the data with those of the six immunoassays (iSYS, LIAISON XL, IMMULITE-2000 calibrated against the first IS 87/518, IGF-I RIACT, Mediagnost ELISA, and Mediagnost RIA) that we reported previously. The pairwise concordance among the eight assays was assessed with Bland-Altman plots for both the IGF-1 raw data and the standard deviation scores (SDS), as well as with the percentage of observed agreement and the weighted Kappa coefficient for categorizing IGF-I SDS (ClinicalTrials.gov Identifier: NCT01831648). RESULTS: The normative data included the range of values (2.5-97.5 percentiles) given by the two new IGF-I assays according to age group and sex. A formula for the SDS calculation is provided. As for the previous six assays, the lower limits of the reference intervals of the two new assays were similar, but the upper limits varied markedly. The pairwise concordances were only moderate (kappa 0.57). CONCLUSIONS: Data obtained for these two new IGF-I immunoassays confirm that despite being obtained in the same large healthy population, the reference intervals of the eight commercial IGF-1 assay kits showed noteworthy differences. The agreement among the various methods was moderate to good.
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OBJECTIVE: Anakinra has been shown to be successful in preventing and treating cardiovascular lesions both in experimental murine models of Kawasaki disease (KD) and in several studies on intravenous immunoglobulin (IVIG)- and steroid-resistant patients with KD. This study was undertaken to determine the safety of blocking interleukin-1 in patients with IVIG-resistant KD. METHODS: Sixteen patients were included in the present study. Patients with KD who were not responsive to 1 or more courses of 2 mg/kg of IVIG received anakinra by subcutaneous daily injections. Starting doses were 2 mg/kg of IVIG (4 mg/kg in patients who were age <8 months and who weighed ≥5 kilograms), and the dose was increased up to 6 mg/kg every 24 hours if the patient's body temperature remained >38°C, indicative of a fever. Treatment duration was 14 days. The last visit was on day 45. Primary outcome was abatement of fever. Secondary measures included disease activity, coronary artery Z score, and C-reactive protein (CRP) levels. RESULTS: Seventy-five percent of patients in the intention-to-treat group and 87.5% in the per-protocol group became afebrile within 48 hours of the last escalation dose of anakinra. Reduction of disease activity by 50% was indicated on 93.3% (95% confidence interval [95% CI] 68.1-99.8%) of physician evaluations and on 100% (95% CI 73.5-100%) of parent evaluations. CRP values normalized by day 30. At the initial screening, 12 of 16 patients had a maximum coronary artery Z score of >2, and 10 of 16 patients had a maximum Z score of >2.5. At day 45, 5 of 10 patients (50% [95% CI 18.7-81.3%]) and 6 of 12 patients (50% [95% CI 21.1-78.9%]) had achieved coronary artery Z scores of <2.5 and <2, respectively. Five serious adverse events were observed in 3 patients, but no serious infections or deaths occurred. CONCLUSION: Anakinra was well tolerated in the study patients and may have some efficacy in reducing fever, markers of systemic inflammation, and coronary artery dilatation in individuals with IVIG-refractory KD.
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Antirreumáticos/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Proteína C-Reativa/imunologia , Criança , Pré-Escolar , Aneurisma Coronário/diagnóstico por imagem , Ecocardiografia , Feminino , Febre , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/diagnóstico por imagem , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Linfonodos Mucocutâneos/fisiopatologia , Estudo de Prova de Conceito , Falha de Tratamento , Resultado do TratamentoRESUMO
CONTEXT: Cardiovascular disease is the leading cause of death in patients with Cushing syndrome. Cortisol excess and adverse metabolic profile could increase cardiac fat, which can subsequently impair cardiac structure and function. OBJECTIVE: We aimed to evaluate cardiac fat mass and distribution in patients with Cushing syndrome. METHODS: In this prospective, cross-sectional study, 23 patients with Cushing syndrome and 27 control individuals of comparable age, sex, and body mass index were investigated by cardiac magnetic resonance imaging and proton spectroscopy. Patients were explored before and after biochemical disease remission. Myocardial fat measured by the Dixon method was the main outcome measure. The intramyocardial triglyceride/water ratio measured by spectroscopy and epicardial and pericardial fat volumes were secondary outcome measures. RESULTS: No difference was found between patients and controls in intramyocardial lipid content. Epicardial fat mass was increased in patients compared to controls (30.8 g/m2 [20.4-34.8] vs 17.2 g/m2 [13.1-23.5], Pâ <â .001). Similarly, pericardial fat mass was increased in patients compared to controls (28.3 g/m2 [17.9-38.0] vs 11.4 g/m2 [7.5-19.4], Pâ =â .003). Sex, glycated hemoglobin A1c, and the presence of hypercortisolism were independent determinants of epicardial fat. Pericardial fat was associated with sex, impaired glucose homeostasis and left ventricular wall thickness. Disease remission decreased epicardial fat mass without affecting pericardial fat. CONCLUSION: Intramyocardial fat stores are not increased in patients with Cushing syndrome, despite highly prevalent metabolic syndrome, suggesting increased cortisol-mediated lipid consumption. Cushing syndrome is associated with marked accumulation of epicardial and pericardial fat. Epicardial adiposity may exert paracrine proinflammatory effects promoting cardiomyopathy.
Assuntos
Adiposidade , Índice de Massa Corporal , Cardiomiopatias/patologia , Síndrome de Cushing/fisiopatologia , Gordura Intra-Abdominal/patologia , Miocárdio/patologia , Pericárdio/patologia , Adulto , Biomarcadores/análise , Glicemia/análise , Cardiomiopatias/epidemiologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos ProspectivosRESUMO
About 10-20% of patients with Kawasaki disease (KD) are unresponsive to intravenous immunoglobulin (IVIg) and are at increased risk of coronary artery abnormalities (CAAs). Early identification is critical to initiate aggressive therapies, but available scoring systems lack sensitivity in non-Japanese populations. We investigated the accuracy of 3 Japanese scoring systems and studied factors associated with IVIg unresponsiveness in a large multiethnic French population of children with KD to build a new scoring system. Children admitted for KD between 2011-2014 in 65 centers were enrolled. Factors associated with second line-treatment; i.e. unresponsiveness to initial IVIg treatment, were analyzed by multivariate regression analysis. The performance of our score and the Kobayashi, Egami and Sano scores were compared in our population and in ethnic subgroups. Overall, 465 children were reported by 84 physicians; 425 were classified with KD (55% European Caucasian, 12% North African/Middle Eastern, 10% African/Afro-Caribbean, 3% Asian and 11% mixed). Eighty patients (23%) needed second-line treatment. Japanese scores had poor performance in our whole population (sensitivity 14-61%). On multivariate regression analysis, predictors of secondary treatment after initial IVIG were hepatomegaly, ALT level ≥30 IU/L, lymphocyte count <2400/mm3 and time to treatment <5 days. The best sensitivity (77%) and specificity (60%) of this model was with 1 point per variable and cut-off ≥2 points. The sensitivity remained good in our 3 main ethnic subgroups (74-88%). We identified predictors of IVIg resistance and built a new score with good sensitivity and acceptable specificity in a non-Asian population.
Assuntos
Imunoglobulinas Intravenosas/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Linfonodos Mucocutâneos/terapia , Pediatria/normas , Criança , Pré-Escolar , Resistência a Medicamentos , Etnicidade , Feminino , França/etnologia , Humanos , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/etnologia , Análise Multivariada , Estudos Prospectivos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Non-classic 21-hydroxylase deficiency is usually diagnosed in post-pubertal women because of androgen excess. Indication of systematic steroid replacement therapy is controversial because the risk of acute adrenal insufficiency is unknown. In order to specify this risk we evaluated the cortisol and aldosterone secretions in response to appropriate pharmacologic challenges. METHODS: In this prospective case-control non-inferiority study we investigated 20 women with non-classic 21-hydroxylase deficiency carrying biallelic CYP21A2 mutations and with serum 17-hydroxyprogesterone (17OHP) >10 ng/mL after stimulation with Synacthen® (tetracosactrin) and 20 age- and body mass index-matched healthy women with 17OHP after Synacthen® <2 ng/mL. Each participant underwent sequentially an insulin tolerance test to evaluate cortisol secretion and a sodium depletion test, obtained by oral administration of 40 mg of furosemide under low sodium diet (<20 mmol during 24 hours), to evaluate renin and aldosterone secretion. FINDINGS: The peak serum cortisol concentration after insulin hypoglycemia was lower in patients than in controls (mean difference -47 ng/mL, 90% CI, -66, P = 0.0026). A peak serum cortisol above a cutoff value of 170 ng/mL was obtained in all controls but only in 55% of patients (P = 0.0039). Twenty-four hours after sodium depletion, blood pressure, plasma sodium, potassium, and serum aldosterone concentrations were comparable between the two groups, but patients had higher stimulated renin concentrations than controls (P = 0.0044). INTERPRETATION: Patients with non-classic 21-hydroxylase deficiency frequently display partial cortisol insufficiency and compensated defect in aldosterone secretion. Their clinical management should systematically include assessment of adrenal functions.
Assuntos
Hiperplasia Suprarrenal Congênita/fisiopatologia , Aldosterona/sangue , Biomarcadores/sangue , Hidrocortisona/sangue , Hipoglicemia/patologia , Pseudogenes , Sódio/deficiência , Adolescente , Adulto , Estudos de Casos e Controles , Estudos de Equivalência como Asunto , Feminino , Seguimentos , França/epidemiologia , Humanos , Hipoglicemia/sangue , Hipoglicemia/epidemiologia , Incidência , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Adulto JovemRESUMO
Adaptation of drug dosage to kidney function is a common problem in general practice. The aim was to describe adaptation of cardiovascular drugs and metformin according to renal function and its association with mortality with regard to metformin in a cohort of elderly patients. This was an ancillary study to the S.AGES cohort made up of patients over 65 years of age managed by their general practitioner under real-life conditions and followed up prospectively for 3 years. The medications studied were digoxin, spironolactone and metformin. Adaptation of their daily dose according to renal function (eGFR according to CKD/EPI) was compared to that recommended in the summaries of product characteristics (SPCs) or international scientific societies (ISS). A total of 900 patients were included, including 588 on metformin. At baseline, dose adjustment according to renal function was 100% and 87.6% (95% CI: 82.6-92.6) for patients on digoxin and spironolactone respectively. For metformin, only 71.3% (95% CI: 67.6-74.9) or 78.1% (95% CI: 74.7-81.4) of patients had their dosage adapted at inclusion according to their renal function depending on whether the SPCs or ISS recommendations were considered. During the 3-year follow-up period, 42/588 patients died (none from lactic acidosis). At inclusion, a metformin dosage not adapted for renal function according to ISS was not associated with an increase in all-cause mortality (OR 1.7; 95% CI 0.6-5.0, p = 0.32). In conclusion, approximately one-quarter of elderly patients treated with metformin do not have their dosage adapted for renal function according to ISS although there is no increase in mortality after follow-up for 3 years.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Fármacos Cardiovasculares/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Rim/fisiopatologia , Metformina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Fármacos Cardiovasculares/uso terapêutico , Estudos de Coortes , Feminino , Seguimentos , França , Taxa de Filtração Glomerular , Humanos , Masculino , Metformina/uso terapêutico , Estudos Prospectivos , Fatores de RiscoRESUMO
AIM: S.AGES is a multicenter prospective cohort study of non-institutionalized patients aged 65 and over with atrial fibrillation, type 2 diabetes or chronic pain. Its objective is to describe the medical management in primary care. This article presents the baseline characteristics of subjects in the diabetes subcohort and compares the results to those from cohorts of older diabetic patients. METHODS: From April 2009 to June 2011, 983 patients were included in the diabetes subcohort by 213 primary care providers. Demographic data, geriatric parameters and the history, characteristics and treatment of the diabetes were recorded at baseline. RESULTS: The mean age was 76.7 ± 5.9 years. Most patients were living independently, with no cognitive impairment and in relatively good health. The duration of diabetes was 11.3 ± 8.7 years with average HbA1c of 6.9 ± 1.0%. 20% of patients had macrovascular disease, 33% renal failure, 14.6% ocular complication and 7.1% neuropathy. The first-line antidiabetic treatment was metformin (61.2%) and 18% of patients had used insulin. Treatment intensified with the worsening of diabetic symptoms. When compared to those from French and North American cohorts, the results showed increased complications and use of insulin with age, disease duration and severity. CONCLUSION: Due to the method of recruitment, S.AGES patients were generally healthy with well-controlled diabetes. However, the results were consistent with those from other cohorts. Three-year follow-up is expected to study the management of diabetic patients aged 65 and over in primary care.