In vitro development of imipenem/relebactam resistance in KPC-producing Klebsiella pneumoniae involves multiple mutations including OmpK36 disruption and KPC modification.

OBJECTIVES: In order to inform and anticipate potential strategies aimed at combating KPC-producing Klebsiella pneumoniae infections, we analysed imipenem/relebactam and ceftazidime/avibactam single-step mutant frequencies, resistance development trajectories, differentially selected resistance mechanisms and their associated fitness cost using four representative high-risk K. pneumoniae clones. METHODS: Mutant frequencies and mutant preventive concentrations were determined using agar plates containing incremental concentrations of ß-lactam/ß-lactamase inhibitor. Resistance dynamics were determined through incubation for 7 days in 10 mL MH tubes containing incremental concentrations of each antibiotic combination up to their 64 × baseline MIC. Two colonies per strain from each experiment were characterized by antimicrobial susceptibility testing, whole genome sequencing and competitive growth assays (to determine in vitro fitness). KPC variants associated with imipenem/relebactam resistance were characterized by cloning and biochemical experiments, atomic models and molecular dynamics simulation studies. RESULTS: Imipenem/relebactam prevented the emergence of single-step resistance mutants at lower concentrations than ceftazidime/avibactam. In three of the four strains evaluated, imipenem/relebactam resistance development emerged more rapidly, and in the ST512/KPC-3 clone reached higher levels compared to baseline MICs than for ceftazidime/avibactam. Lineages evolved in the presence of ceftazidime/avibactam showed KPC substitutions associated with high-level ceftazidime/avibactam resistance, increased imipenem/relebactam susceptibility and low fitness costs. Lineages that evolved in the presence of imipenem/relebactam showed OmpK36 disruption, KPC modifications (S106L, N132S, L167R) and strain-specific substitutions associated with imipenem/relebactam resistance and high fitness costs. Imipenem/relebactam-selected KPC derivatives demonstrated enhanced relebactam resistance through important changes affecting relebactam recognition and positioning. CONCLUSIONS: Our findings anticipate potential resistance mechanisms affecting imipenem/relebactam during treatment of KPC-producing K. pneumoniae infections.

Therapeutic hypothermia for the management of hypoxic-ischemic encephalopathy in asphyxiated newborns: Clinical, electrographic and radiologic features of newborns treated at Instituto Materno Perinatal / Therapeutic hypothermia for the management of hypoxic-ischemic encephalopathy in asphyxiated newborns: Clinical, electrographic and radiological features of newborns treated at Instituto Materno Perinatal

La encefalopatía hipóxico-isquémica (EHI) es el síndrome neurológico causado por la asfixia perinatal. La hipotermia terapéutica (HT) ha demostrado reducir la mortalidad y morbilidad asociadas a EHI. Se realizó un estudio descriptivo retrospectivo con 30 recién nacidos con EHI moderada y severa que recibieron HT en la Unidad de Cuidados Intensivos del Instituto Materno Perinatal desde setiembre de 2017 a noviembre de 2020. Nueve de los casos fueron severos (30 %). El tiempo promedio de ingreso a HT fue 3.4 horas de vida. No se registraron efectos adversos importantes atribuibles a HT. Todos los pacientes severos tuvieron crisis epilépticas, ecografías cerebrales de ingreso y resonancias con anormalidades. La mortalidad fue de 20.0 %, aunque fue significativamente menor en el grupo con EHI moderada. Se identificaron las características de presentación clínica, electrográfica y radiológica de los neonatos con EHI que recibieron hipotermia terapéutica, la cual se muestra como un procedimiento seguro y efectivo.

Hipotermia terapéutica para tratamiento de encefalopatía hipóxico-isquémica del recién nacido asfixiado: Características clínicas, radiológicas y electrográficas de los neonatos atendidos en el Instituto Nacional Materno Perinatal

La encefalopatía hipóxico-isquémica (EHI) es el síndrome neurológico causado por la asfixia perinatal. La hipotermia terapéutica (HT) ha demostrado reducir la mortalidad y morbilidad asociadas a EHI. Se realizó un estudio descriptivo retrospectivo con 30 recién nacidos con EHI moderada y severa que recibieron HT en la Unidad de Cuidados Intensivos del Instituto Materno Perinatal desde setiembre de 2017 a noviembre de 2020. Nueve de los casos fueron severos (30 %). El tiempo promedio de ingreso a HT fue 3.4 horas de vida. No se registraron efectos adversos importantes atribuibles a HT. Todos los pacientes severos tuvieron crisis epilépticas, ecografías cerebrales de ingreso y resonancias con anormalidades. La mortalidad fue de 20.0 %, aunque fue significativamente menor en el grupo con EHI moderada. Se identificaron las características de presentación clínica, electrográfica y radiológica de los neonatos con EHI que recibieron hipotermia terapéutica, la cual se muestra como un procedimiento seguro y efectivo.

Hypoxic-ischemic encephalopathy (HIE) is the neurological syndrome caused by perinatal asphyxia. Therapeutic hypothermia (TH) has been shown to reduce HIE-associated morbidity and mortality. A descriptive and retrospective study with 30 newborns with moderate and severe HIE who underwent TH in the Intensive Care Unit (ICU) of Instituto Materno Perinatal, from September 2017 until November 2020. Nine patients were severely affected (30%). The average tome for being admitted in the ICU was at 3.4 hours of life. No important adverse effects attributable to TH were observed. All severely affected patients experienced epileptic crises, and abnormal cerebral ultrasonography and magnetic resonance imaging studies on admission. Mortality was 20.0%, but it was significantly lower in the group with moderate HIE. Clinical, electrographic, and radiological characteristics of neonates with HIE who underwent therapeutic hypothermia were identified. This procedure has been shown to be safe and effective.

Medication Optimization Using Pharmacogenomic Testing in a Complex Mental Health Population Prescribed Psychiatric Polypharmacy.

The use of polypharmacy has become significantly more common over the past two decades, increasing the risk of drug-drug interactions and adverse drug reactions. Pharmacogenomic (PGx) assays have the purported benefit of being able to predict an individual's response to a specific medication based on genetic markers, which may facilitate the development of optimized medication regimens for patients prescribed polypharmacy. This 12-week pilot study examined the impact of the PGx results on the clinical management of Veterans who were prescribed psychiatric polypharmacy. Psychiatric medication providers were given access to the PGx assay results, including notification of drug-drug-gene interactions computed from an algorithm decision tool, to assist with medication management decisions. Veteran outpatients (N = 53) prescribed polypharmacy (mean = 13.15 medications) were enrolled into the study. In 92.4% of cases, providers changed medications at baseline, with 83% of providers indicating that they changed their original medication plan based on the PGx results. Clinical improvement over the 12-week treatment phase was seen in depression (F(1.63, 45) = 5.45, P = .01, η2  = .11) and mental health quality of life (F(2.00, 45) = 4.16, P < .05, η2  = .16). Adverse drug effects were unchanged or improved over time. Rates of polypharmacy remained unchanged. The results suggest that medication changes based on the PGx assay may be beneficial in a complex patient population prescribed polypharmacy.

Suitability of strontium and cobalt-free perovskite cathodes with La9.67Si5AlO26 apatite electrolyte for intermediate temperature solid oxide fuel cells.

Aluminium-doped lanthanum silicate (LSAO) apatite-type compounds have been considered as promising candidates for substituting yttria-stabilized zirconia (YSZ) as electrolytes for intermediate temperature solid oxide fuel cells (IT-SOFC). Nevertheless, not many materials have been reported to work as cathodes in a LSAO apatite-based cell. In the present work, eight different strontium and cobalt-free compounds with a perovskite-type structure and the general composition LaM1-xNxO3-δ (where M = Fe, Cr, Mn; N = Cu, Ni; and x = 0.2, 0.3) have been tested. This study includes the synthesis and structural characterization of the compounds, as well as thermomechanical and chemical compatibility tests between them. Functional characterization of the individual components has been performed by electrochemical impedance spectroscopy (EIS). Apatite/perovskite symmetrical cells were used to measure area-specific resistance (ASR) of the half cell in an intermediate temperature range (500-850 °C) both with and without DC bias. According to its electrochemical behaviour, LaFe0.8Cu0.2O3-δ is the most promising material for IT-SOFC among the compositions tested since its ASR is similar to that of the traditional (LaxSr1-x)MnO3 (LSM) cathode.

Measuring Membrane Permeation Rates through the Optical Visualization of a Single Pore.

Membranes are a critical technology for energy-efficient separation processes. The routine method of evaluating membrane performance is a permeation measurement. However, such measurements can be limited in terms of their utility: membrane microstructure is often poorly characterized; membranes or sealants leak; and conditions in the gas phase are poorly controlled and frequently far-removed from the conditions employed in the majority of real processes. Here, we demonstrate a new integrated approach to determine permeation rates, using two novel supported molten-salt membrane geometries. In both cases, the membranes comprise a solid support with laser-drilled pores, which are infiltrated with a highly CO2-selective molten carbonate salt. First, we fabricate an optically transparent single-crystal, single-pore model membrane by local laser drilling. By infiltrating the single pore with molten carbonate, monitoring the gas-liquid interface optically, and using image analysis on gas bubbles within the molten carbonate (because they change volume upon controlled changes in gas composition), we extract CO2 permeation rates with exceptional speed and precision. Additionally, in this arrangement, microstructural characterization is more straightforward and a sealant is not required, eliminating a major source of leakage. Furthermore, we demonstrate that the technique can be used to probe a previously unexplored driving force region, too low to access with conventional methods. Subsequently, we fabricate a leak-free tubular-supported molten-salt membrane with 1000 laser-drilled pores (infiltrated with molten carbonate) and employ a CO2-containing sweep gas to obtain permeation rates in a system that can be described with unprecedented precision. Together, the two approaches provide new ways to measure permeation rates with increased speed and at previously inaccesible conditions.

Síndrome de Pfeiffer tipo 2: diagnóstico prenatal. Reporte de caso y revisión de la literatura / Pfeiffer Syndrome Type 2: Prenatal diagnosis. Case report and literature review

Pfeiffer syndrome is an autosomic dominant disorder characterized by craniosynostosis, midface hypoplasia and syndactyly of the hands and feet. Three different phenotypes have been described, where type 2 is the most severe and the one amenable of prenatal diagnosis. We present the first clinical case reported at Instituto Nacional Materno Perinatal, Lima, Peru, of a fetus with suspicious ultrasound prenatal findings of this syndrome including cloverleaf-shaped skull, severe ventriculomegaly, frontal bossing, ocular proptosis and overlapped fingers, who was born by cesarean section and died at day eight due to progressive respiratory distress.

El síndrome de Pfeiffer es una enfermedad rara de tipo autosómica dominante caracterizada por craneosinostosis bicoronal, hipoplasia medio facial y sindactilia de manos y pies. Se ha descrito 3 fenotipos, siendo el tipo 2 el más severo y que generalmente se diagnostica prenatalmente. Presentamos el primer caso descrito en el Instituto Nacional Materno Perinatal de Lima, Perú, de un feto con hallazgos ultrasonográficos sospechosos de este síndrome, como el cráneo en forma de trébol, ventriculomegalia severa, frente abombada, ojos protruidos y dedos superpuestos, que nació por cesárea y falleció a los 8 días de edad por distrés respiratorio progresivo.

Biallelic loss-of-function LACC1/FAMIN Mutations Presenting as Rheumatoid Factor-Negative Polyarticular Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease with both autoimmune and autoinflammatory components. Recently, familial cases of systemic-onset JIA have been attributed to mutations in LACC1/FAMIN. We describe three affected siblings from a Moroccan consanguineous family with an early-onset chronic, symmetric and erosive arthritis previously diagnosed as rheumatoid factor (RF)-negative polyarticular JIA. Autozygosity mapping identified four homozygous regions shared by all patients, located in chromosomes 3, 6 (n:2) and 13, containing over 330 genes. Subsequent whole exome sequencing identified two potential candidate variants within these regions (in FARS2 and LACC1/FAMIN). Genotyping of a cohort of healthy Moroccan individuals (n: 352) and bioinformatics analyses finally supported the frameshift c.128_129delGT mutation in the LACC1/FAMIN gene, leading to a truncated protein (p.Cys43Tyrfs*6), as the most probable causative gene defect. Additional targeted sequencing studies performed in patients with systemic-onset JIA (n:23) and RF-negative polyarticular JIA (n: 44) revealed no pathogenic LACC1/FAMIN mutations. Our findings support the homozygous genotype in the LACC1/FAMIN gene as the defect underlying the family here described with a recessively inherited severe inflammatory joint disease. Our evidences provide further support to the involvement of LACC1/FAMIN deficiency in different types of JIA in addition to the initially described systemic-onset JIA.

S100A12 and S100A8/9 proteins are biomarkers of articular disease activity in Blau syndrome.

OBJECTIVE: To identify biomarkers of articular and ocular disease activity in patients with Blau syndrome (BS). METHODS: Multiplex plasma protein arrays were performed in five BS patients and eight normal healthy volunteers (NHVs). Plasma S100A12 and S100A8/9 were subsequently measured by ELISA at baseline and 1-year follow-up in all patients from a prospective multicentre cohort study. CRP was measured using Meso Scale Discovery immunoassay. Active joint counts, standardization uveitis nomenclature for anterior uveitis cells and vitreous haze by Nussenblatt scale were the clinical parameters. RESULTS: Multiplex Luminex arrays identified S100A12 as the most significantly elevated protein in five selected BS vs eight NHVs and this was confirmed by ELISA on additional samples from the same five BS patients. In the patient cohort, S100A12 (n = 39) and S100A8/9 (n = 33) were significantly higher compared with NHVs (n = 44 for S100A12, n = 40 for S100A8/9) (P = 0.0000004 and P = 0.0003, respectively). Positive correlations between active joint counts and S100 levels were significant for S100A12 (P = 0.0008) and S100A8/9 (P = 0.015). CRP levels did not correlate with active joint count. Subgroup analysis showed significant association of S100 proteins with active arthritis (S100A12 P = 0.01, S100A8/9 P = 0.008). Active uveitis was not associated with increased S100 levels. CONCLUSION: S100 proteins are biomarkers of articular disease activity in BS and potential outcome measures in future clinical trials. As secreted neutrophil and macrophage products, S100 proteins may reflect the burden of granulomatous tissue in BS.

Blau Syndrome-Associated Uveitis: Preliminary Results From an International Prospective Interventional Case Series.

PURPOSE: Provide baseline and preliminary follow-up results in a 5-year longitudinal study of Blau syndrome. DESIGN: Multicenter, prospective interventional case series. METHODS: Baseline data from 50 patients from 25 centers worldwide, and follow-up data for patients followed 1, 2, or 3 years at the end of study enrollment. Ophthalmic data were collected at baseline and yearly visits by means of a standardized collection form. RESULTS: Median age at onset of eye disease was 60 months and duration of eye disease at baseline 145 months. At baseline 38 patients (78%) had uveitis, which was bilateral in 37 (97%). Eight patients (21%) had moderate to severe visual impairment. Panuveitis was found in 38 eyes (51%), with characteristic multifocal choroidal infiltrates in 29 eyes (39%). Optic disc pallor in 9 eyes (12%) and peripapillary nodules in 9 eyes (12%) were the commonest signs of optic nerve involvement. Active anterior chamber inflammation was noted in 30 eyes (40%) at baseline and in 16 (34%), 17 (57%), and 11 (61%) eyes at 1, 2, and 3 years, respectively. Panuveitis was associated with longer disease duration. At baseline, 56 eyes (75%) were on topical corticosteroids. Twenty-six patients (68%) received a combination of systemic corticosteroids and immunomodulatory therapy. CONCLUSIONS: Blau uveitis is characterized by progressive panuveitis with multifocal choroiditis, resulting in severe ocular morbidity despite continuous systemic and local immunomodulatory therapy. The frequency and severity of Blau uveitis highlight the need for close ophthalmologic surveillance as well as a search for more effective therapies.

Development and Initial Validation of the Macrophage Activation Syndrome/Primary Hemophagocytic Lymphohistiocytosis Score, a Diagnostic Tool that Differentiates Primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome.

OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. RESULTS: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from <1% for a score of <11 to >99% for a score of ≥123. A cutoff value of ≥60 revealed the best performance in discriminating pHLH from MAS. CONCLUSION: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.

Miastenia gravis de tipo bulbar en niños: un caso de difícil diagnóstico / Bulbar Myasthenia Gravis in children: a case of difficult diagnosis

La miastenia gravis (MG) es un trastorno autoinmune caracterizado por debilidad y fatigabilidad de los músculos esqueléticos debida a la disfunción de la unión neuromuscular. Se presenta el caso de una adolescente de 11 años de edad, con diagnóstico de miastenia gravis de tipo bulbar. La paciente presentó dos crisis de MG previamente diagnosticadas de manera equivocada como crisis asmáticas. Recibió tratamiento con inmunoglobulina humana, corticoides, piridostigmina y timectomía. Se discute la evolución clínica y riesgos atribuibles a situaciones sociales que pueden retrasar el diagnóstico y su manejo efectivo.

Myasthenia gravis (MG) is an autoimmune disorder characterized by weakness and fatigability of the skeletal muscles due to dysfunction of the neuromuscular junction. We report the case of an 11-year-old girl diagnosed with bulbar myasthenia gravis. The patient had two previous crises of myasthenia gravis erroneously diagnosed as asthma attacks. She received treatment with human immunoglobulin, corticosteroids, pyridostigmine and thymectomy. We discuss the clinical course and the risks attributable to social situations that can delay the diagnosis and its effective management.

Efficacy and safety of canakinumab in cryopyrin-associated periodic syndromes: results from a Spanish cohort.

OBJECTIVES: Cryopyrin-associated periodic syndromes (CAPS) are dominantly-inherited autoinflammatory diseases. The uncontrolled IL-1ß overproduction observed in these patients is the rational basis to treat them with anti-IL-1 drugs. The objective of this study was to evaluate the efficacy and safety of treatment with the long-lasting fully humanised anti-IL-1ß monoclonal antibody canakinumab in a Spanish cohort of patients with CAPS. METHODS: Clinical and laboratory data of CAPS patients carrying a heterozygous germline NLRP3 mutation were obtained. The initial treatment scheme with canakinumab was 150 mg/8 weeks administered subcutaneously in adult patients and 2 mg/kg/8 weeks in paediatric patients. RESULTS: Eight unrelated patients were enrolled. Canakinumab was the first anti-IL-1 drug used in three of them; five were already receiving anakinra. The clinical response to the initial canakinumab scheme was positive in all patients, and was quickly observed in the first 24-72 hours. Four required increasing the frequency and/or dose of canakinumab. A limited or no efficacy in those symptoms related to consequence of the deforming arthropathy and neurosensorial deafness was observed. The adverse side effects were restricted to infectious complications in a small percentage of patients. The treatment was well tolerated by all patients, with no reactions at drug site injections. CONCLUSIONS: Canakinumab caused fast and sustained remissions in most clinical and biochemical manifestations in all enrolled patients, with a limited efficacy in the structural lesions. Dose adjustments seem to be necessary for children and/or for patients with the most severe CAPS phenotypes. Treatment was well tolerated with a low incidence of adverse effects.

Consensus of the Spanish society of pediatric rheumatology for transition management from pediatric to adult care in rheumatic patients with childhood onset.

To develop recommendations on the transition from pediatric care to adult care in patients with chronic inflammatory rheumatic diseases with childhood onset based. Recommendations were generated following nominal group methodology and Delphi technique. A panel of 16 experts was established. A systematic literature review (on transitional care) and a narrative review were performed and presented to the panel in the first panel meeting to be discussed. A first draft of recommendations was generated and circulated. Focal groups with adolescents, young adults and parents were organized. In a second meeting, the focus group results along with the input from invited psychologist were used to establish definitive recommendations. Then, a Delphi process (two rounds) was carried out. A group of 72 pediatric and adult rheumatologists took part. Recommendations were voted from 1 (total disagreement) to 10 (total agreement). We defined agreement if at least 70 % voted ≥7. The level of evidence and grade or recommendation was assessed using the Oxford center for evidence-based medicine levels of evidence. Transition care was defined as a purposeful, planned process that addresses the medical, psychosocial and educational/vocational needs of adolescents and young adults with chronic inflammatory rheumatic diseases with childhood onset as they move from child-centered to adult-oriented healthcare systems. The consensus covers: transition needs, barriers and facilitators, transitional issues (objectives, participants, content, phases, timing, plans, documentation and responsibilities), physicians' and other health professionals' knowledge and skill requirements, models/programs, and strategies and guideline for implementation. Preliminary recommendations and agreement grade are shown in the Table (first Delphi round). These recommendations are intended to provide health professionals, patients, families and other stakeholders with a consensus on the transition process from pediatric to adult care.

Clinical management algorithm of uveitis associated with juvenile idiopathic arthritis: interdisciplinary panel consensus.

Uveitis associated with juvenile idiopathic arthritis (JIA) typically involves the anterior chamber segment, follows an indolent chronic course, and presents a high rate of uveitic complications and a worse outcome as compared to other aetiologies of uveitis. Disease assessment, treatment, and outcome measures have not been standardized. Collaboration between pediatric rheumatologists and ophthalmologists is critical for effective management and prevention of morbidity, impaired vision, and irreparable visual loss. Although the Standardization of Uveitis Nomenclature Working Group recommendations have been a great advance to help clinicians to improve consistency in grading and reporting data, difficulties arise at the time of deciding the best treatment approach in the individual patient in routine daily practice. For this reason, recommendations for a systematized control and treatment strategies according to clinical characteristics and disease severity in children with JIA-related uveitis were developed by a panel of experts with special interest in uveitis associated with JIA. A clinical management algorithm organized in a stepwise regimen is here presented.

Blau syndrome: cross-sectional data from a multicentre study of clinical, radiological and functional outcomes.

OBJECTIVE: To report baseline articular, functional and ocular findings of the first international prospective cohort study of Blau syndrome (BS). METHODS: Three-year, multicentre, observational study on articular, functional (HAQ, Childhood HAQ and VAS global and pain), ophthalmological, therapeutic and radiological data in BS patients. RESULTS: Baseline data on the first 31 recruited patients (12 females and 19 males) from 18 centres in 11 countries are presented. Of the 31 patients, 11 carried the p.R334W NOD2 mutation, 9 the p.R334Q and 11 various other NOD2 missense mutations; 20 patients were sporadic and 11 from five BS pedigrees. Median disease duration was 12.8 years (1.1-57). Arthritis, documented in all but one patient, was oligoarticular in 7, polyarticular in 23. The median active joint count was 21. Functional capacity was normal in 41%, mildly impaired in 31% and moderate-severe in 28% of patients. The most frequently involved joints at presentation were wrists, ankles, knees and PIPs. On radiographs, a symmetrical non-erosive arthropathy was shown. Previously unknown dysplastic bony changes were found in two-thirds of patients. Ocular disease was documented in 25 of 31 patients, with vitreous inflammation in 64% and moderate-severe visual loss in 33%. Expanded manifestations (visceral, vascular) beyond the classic clinical triad were seen in 52%. CONCLUSION: BS is associated with severe ocular and articular morbidity. Visceral involvement is common and may be life-threatening. Bone dysplastic changes may show diagnostic value and suggest a previously unknown role of NOD2 in bone morphogenesis. BS is resistant to current drugs, suggesting the need for novel targeted therapies.

Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients.

OBJECTIVE: To describe the clinical, laboratory, and histopathologic features, current treatment, and outcome of patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA). METHODS: In this multinational, multicenter study, pediatric rheumatologists and hemato-oncologists entered patient data collected retrospectively into a web-based database. RESULTS: A total of 362 patients, 22% of whom had MAS at the onset of systemic JIA, were included in the study by 95 investigators from 33 countries. The most frequent clinical manifestations were fever (96%), hepatomegaly (70%), and splenomegaly (58%). Central nervous system dysfunction and hemorrhages were recorded in 35% and 20% of the patients, respectively. Platelet count and liver transaminase, ferritin, lactate dehydrogenase, triglyceride, and d-dimer levels were the sole laboratory biomarkers showing a percentage change of >50% between the pre-MAS visit and MAS onset. Evidence of macrophage hemophagocytosis was found in 60% of the patients who underwent bone marrow aspiration. MAS occurred most frequently in the setting of active underlying disease, in the absence of a specific trigger. Nearly all patients were given corticosteroids, and 61% received cyclosporine. Biologic medications and etoposide were given to 15% and 12% of the patients, respectively. Approximately one-third of the patients required admission to the intensive care unit (ICU), and the mortality rate was 8%. CONCLUSION: This study provides information on the clinical spectrum and current management of systemic JIA-associated MAS through the analysis of a very large patient sample. MAS remains a serious condition, as a sizeable proportion of patients required admission to the ICU or died.

Detection of synovitis by ultrasonography in clinically inactive juvenile idiopathic arthritis on and off medication.

OBJECTIVES: To determine the prevalence of abnormalities detected by ultrasonography (US) in children with juvenile idiopathic arthritis (JIA) showing clinically inactive disease (ID) on medication and off medication. INCLUSION CRITERIA: 1) JIA patients, 2) clinician-determined ID, 3) JIA drugs withdrawal or stably dosed modified anti-rheumatic drugs (DMARDs) therapy for at least 6 months prior to inclusion, 4) biologics naïve patients. Clinical and US assessments were performed on 44 joints, which were scored for grey-scale (GS) synovitis and Power Doppler (PD) signal. PD signal inside intra-articular synovium or tendon sheath was considered as inflammatory activity. RESULTS: Thirty-four patients were included, of whom 23 patients were labelled as ID on medication and 11 patients without medication. The duration of the current episode of ID at the inclusion time was 9.5 months. Although it was longer for the group off medication there was no significant difference between the two groups (p=0.06). Thirteen patients presented US findings. Number of US-detected synovial abnormalities was higher in patients on medication, but there were no significant differences between both groups in the detection of GS synovitis (p=0.86), GS tenosynovitis (p=0.78) and PD signal (p=0.38). Out of 37 joints presenting US-determined GS-synovitis, 18 joints showed PD signal. CONCLUSIONS: Our study provides evidence of synovitis and tenosynovitis on B-mode US in JIA patients with clinical inactivity. In addition, inflammatory activity upheld by power-Doppler has been shown in a few joints from patients on medication.