Population Pharmacodynamic Modelling of the CD19+ Suppression Effects of Rituximab in Paediatric Patients with Neurological and Autoimmune Diseases

Background: Limited pharmacotherapy and the failure of conventional treatments in complex pathologies in children lead to increased off-label use of rituximab. We aimed to characterize the time course of CD19+ B lymphocytes (CD19+) under treatment with intravenous rituximab in children with neurologic and autoimmune diseases and to evaluate the impact of covariates (i.e., demographics, diagnosis and substitution between innovator and biosimilar product) on rituximab pharmacodynamics and disease activity. Methods: Pre- and post-drug infusion CD19+ in peripheral blood were prospectively registered. A population pharmacodynamic model describing the time course of CD19+ was developed with NONMEM v7.4. Simulations of three different rituximab regimens were performed to assess the impact on CD19+. Logistic regression analysis was performed to identify predictors of clinical response recorded through disease activity scores. Results: 281 measurements of CD19+ lymphocyte counts obtained from 63 children with neurologic (n = 36) and autoimmune (n = 27) diseases were available. The time course of CD19+ was described with a turn-over model in which the balance between synthesis and degradation rates is disrupted by rituximab, increasing the latter process. The model predicts half-lives (percent coefficient of variation, CV(%)) of rituximab and CD19+ of 11.6 days (17%) and 173.3 days (22%), respectively. No statistically significant effect was found between any of the studied covariates and model parameters (p > 0.05). Simulations of different regimens showed no clinically significant differences in terms of CD19+ repopulation times. A trend towards a lack of clinical response was observed in patients with lower CD19+ repopulation times and higher areas under the CD19+ versus time curve. Conclusions: Rituximab pharmacodynamics was described in a real-world setting in children suffering from autoimmune and neurologic diseases. Diagnosis, substitution between innovator rituximab and its biosimilars or type of regimen did not affect rituximab-induced depletion of CD19+ nor the clinical response in this cohort of patients. According to this study, rituximab frequency and dosage may be chosen based on clinical convenience or safety reasons without affecting CD19+ repopulation times. Further studies in larger populations are required to confirm these results.Fil: Riva, Natalia. Universidad de Navarra; España. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Brstilo, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Sancho Araiz, Aymara. Universidad de Navarra; España. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Molina, Manuel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Savransky, Andrea. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Roffé, Georgina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Sanz, Marianela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Tenembaum, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Katsicas, Maria M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Trocóniz, Iñaki F.. Universidad de Navarra; EspañaFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentin

The Argentinian Spanish version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR)

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Argentinian Spanish language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach\u2019s alpha, interscale correlations, test\u2013retest reliability, and construct validity (convergent and discriminant validity). A total of 373 JIA patients (23.1% systemic, 30.8% oligoarticular, 28.1% RF negative polyarthritis, 18% other categories) and 100 healthy children were enrolled in five centres. The JAMAR components discriminated well healthy subjects from JIA patients. Notably, there was no significant difference between healthy subjects and their affected peers in the school-related item. All JAMAR components revealed good psychometric performances. In conclusion, the Argentinian Spanish version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research

Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience

CARD11-associated diseases are monogenic inborn errors of immunity involving immunodeficiency, predisposition to malignancy and immune dysregulation such as lymphoproliferation, inflammation, atopic and autoimmune manifestations. Defects in CARD11 can present as mutations that confer a complete or a partial loss of function (LOF) or contrarily, a gain of function (GOF) of the affected gene product. We report clinical characteristics, immunophenotypes and genotypes of 15 patients from our center presenting with CARD11-associated diseases. Index cases are pediatric patients followed in our immunology division who had access to next generation sequencing studies. Variant significance was defined by functional analysis in cultured cells transfected with a wild type and/or with mutated hCARD11 constructs. Cytoplasmic aggregation of CARD11 products was evaluated by immunofluorescence. Nine index patients with 9 unique heterozygous CARD11 variants were identified. At the time of the identification, 7 variants previously unreported required functional validation. Altogether, four variants showed a GOF effect as well a spontaneous aggregation in the cytoplasm, leading to B cell expansion with NF-κB and T cell anergy (BENTA) diagnosis. Additional four variants showing a LOF activity were considered as causative of CARD11-associated atopy with dominant interference of NF-kB signaling (CADINS). The remaining variant exhibited a neutral functional assay excluding its carrier from further analysis. Family segregation studies expanded to 15 individuals the number of patients presenting CARD11-associated disease. A thorough clinical, immunophenotypical, and therapeutic management evaluation was performed on these patients (5 BENTA and 10 CADINS). A remarkable variability of disease expression was clearly noted among BENTA as well as in CADINS patients, even within multiplex families. Identification of novel CARD11 variants required functional studies to validate their pathogenic activity. In our cohort BENTA phenotype exhibited a more severe and expanded clinical spectrum than previously reported, e.g., severe hematological and extra hematological autoimmunity and 3 fatal outcomes. The growing number of patients with dysmorphic facial features strengthen the inclusion of extra-immune characteristics as part of the CADINS spectrum. CARD11-associated diseases represent a challenging group of disorders from the diagnostic and therapeutic standpoint, especially BENTA cases that can undergo a more severe progression than previously described.Fil: Urdinez, Luciano. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Erra, Lorenzo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Palma, Alejandro Martín. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Mercogliano, María Florencia. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; ArgentinaFil: Fernández, Julieta Belén. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; ArgentinaFil: Prieto, Emma. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatria "juan P.garrahan". Laboratorio de Biología Molecular y Cultivo Celular; ArgentinaFil: Goris, Verónica. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatria "juan P.garrahan". Laboratorio de Biología Molecular y Cultivo Celular; ArgentinaFil: Bernasconi, Andrea Raquel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Sanz, Marianela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Villa, Mariana Natalia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Bouzo, Carolina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Caputi, Lucía. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Quesada, Belén. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Solís, Daniel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatria "juan P.garrahan". Laboratorio de Biología Molecular y Cultivo Celular; ArgentinaFil: Aguirre Bruzzo, Anabel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Katsicas, Maria Martha. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Galluzzo, Laura. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Weyersberg, Christian. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Bocian, Marcela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Bujan, Maria Marta. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Oleastro Matías. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Almejún, María Belén. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; ArgentinaFil: Danielian, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatria "juan P.garrahan". Laboratorio de Biología Molecular y Cultivo Celular; Argentin

Application and performance of disease activity indices proposed for patients with systemic sclerosis in an international cohort of patients with juvenile systemic sclerosis

Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: the inception cohort project is supported by an unrestricted grant from the Joachim Herz Stiftung, Hamburg, Germany. Publisher Copyright: © The Author(s) 2023.Objectives: Juvenile systemic sclerosis is a rare childhood disease. Three disease activity indices have been published for adult patients with systemic sclerosis: the European Scleroderma Study Group Index, a modified version of the European Scleroderma Study Group Index and the revised European Scleroderma Trials and Research index. The objective of this study was to determine the feasibility and performance of the three disease activity indices in a prospectively followed cohort of patients with juvenile systemic sclerosis. Methods: The analysis cohort was selected from the prospective international inception cohort enrolling juvenile systemic sclerosis patients. The correlation of the disease activity indices with the physicians’ and the patients’ global assessment of disease activity was determined. The disease activity indices were compared between patients with active and inactive disease. Sensitivity to change between 6- and 12-month follow-up was investigated by mixed models. Results: Eighty percent of the 70 patients had a diffuse cutaneous subtype. The revised European Scleroderma Trials and Research index was highly correlated with the physician-reported global disease activity/parents-reported global disease activity (r = 0.74/0.64), followed by the European Scleroderma Study Group activity index (r = 0.61/0.55) and the modified version of the European Scleroderma Study Group activity index (r = 0.51/0.43). The disease activity indices significantly differed between active and inactive patients. The disease activity indices showed sensitivity to change between 6- and 12-month follow-up among patients who improved or worsened according to the physician-reported global disease activity and the parents-reported global disease activity. Conclusion: Overall, no disease activity score is superior to the other, and all three scores have limitations in the application in juvenile systemic sclerosis patients. Furthermore, research on the concept of disease activity and suitable scores to measure disease activity in patients with juvenile systemic sclerosis is necessary in future.Peer reviewe

Defining criteria for disease activity states in systemic juvenile idiopathic arthritis based on the systemic Juvenile Arthritis Disease Activity Score

Objective To develop and validate cutoff values in the systemic Juvenile Arthritis Disease Activity Score 10 (sJADAS10) that distinguish the states of inactive disease (ID), minimal disease activity (MiDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with systemic juvenile idiopathic arthritis (sJIA), based on subjective disease state assessment by the treating pediatric rheumatologist. Methods The cutoffs definition cohort was composed of 400 patients enrolled at 30 pediatric rheumatology centers in 11 countries. Using the subjective physician rating as an external criterion, 6 methods were applied to identify the cutoffs: mapping, calculation of percentiles of cumulative score distribution, Youden index, 90% specificity, maximum agreement, and ROC curve analysis. Sixty percent of the patients were assigned to the definition cohort and 40% to the validation cohort. Cutoff validation was conducted by assessing discriminative ability. Results The sJADAS10 cutoffs that separated ID from MiDA, MiDA from MoDA, and MoDA from HDA were ≤ 2.9, ≤ 10, and > 20.6. The cutoffs discriminated strongly among different levels of pain, between patients with or without morning stiffness, and between patients whose parents judged their disease status as remission or persistent activity/flare or were satisfied or not satisfied with current illness outcome. Conclusion The sJADAS cutoffs revealed good metrologic properties in both definition and validation cohorts, and are therefore suitable for use in clinical trials and routine practice

Cleantech insinöörikoulutuksessa

Cleantech-insinoorit -projekti on Lahden ammattikorkeakoulun tekniikan alan hallinnoima ja Hameen ELY-keskuksen osarahoittama Euroopan Sosiaalirahaston hanke, jonka tavoitteena on parantaa Paijat-Hameen cleantech-osaamista seka insinoorikoulutuksen tyoelamavastaavuutta. Projektin tavoitteena on tuottaa uudenlainen koulutuksen toimintamalli, joka luo aitoja edellytyksia cleantech-innovaatioiden syntymiselle seka uusille tuotteille ja palveluille ymparistoliiketoiminnan alueella. Uuden yhteistyo- ja toimintamallin kehittaminen tekniikan alan koulutukseen perustuu yhteistyohon yrityselaman ja muiden toimijoiden kanssa. Yhteistyota on toteutettu erilaisissa opiskelija- ja T&K-projekteissa, opinnaytetoissa, koulutuksissa, tyopajoissa, seminaareissa, opintomatkoilla ja benchmarkkaamalla erilaisia kaytantoja koti- ja ulkomailla. Uusi yhteistyo- ja toimintamalli kasittaa lisaksi CDIO-/PBL-pedagogiikkaan (CDIO = Conceive – Design – Implement – Operate- / PBL = Problem Based Learning) perustuvan oppimismallin tuomisen tekniikan alan koulutukseen perinteisten insinooritietojen ja -taitojen ohella seka cleantech-osaamisen sisallyttamisen opintosuunnitelmiin. Myos tyoelamalta saadut tiedot tyoelamaosaamisen osaamis- ja muista tarpeista sisallytetaan opintosuunnitelmiin. Lahden ammattikorkeakoulu haluaa osaltaan seka kehittaa insinoorikoulutusta vastaamaan alueen cleantech-yritysten osaamistarpeita etta osallistua alueen yritysten tuotteiden, palvelujen ja prosessien kehittamiseen. Cleantech-insinoorit -projektin tarkoituksena on tunnistaa puhtaan teknologian suunnittelemisessa ja hyodyntamisessa tarvittavia tietoja ja taitoja ja integroida ne insinoorien koulutukseen. Lahden ammattikorkeakoulun tekniikan alalla on viisi koulutusohjelmaa, joista jokaisen cleantech-tarpeita on projektissa tarkasteltu. Lisaksi projektissa selvitettiin olemassa olevan tiedon avulla cleantech-sektorin tarpeita. Cleantech-osaamisen koulutustarvekartoitus tehtiin syksylla 2011, josta tarkempi koulutussuunnitelma cleantech-osaamisen parantamiseksi Paijat-Hameessa valmistui joulukuussa 2011. Kartoituksen ja yritysten haastattelujen pohjalta projektissa toteutettiin cleantech-osaamisen parantamiseksi koulutuksia vuosina 2012 – 2013. Koulutukset pureutuivat ajankohtaisiin teemoihin, kuten vihreaan ICT:hen, energia- ja materiaalitehokkuuteen, kestaviin hankintoihin seka ajankohtaisiin lainsaadannon vaatimuksiin. Tassa artikkelikokoelmassa kerrotaan Lahden ammattikorkeakoulun tekniikan alan koulutusohjelmien toimenpiteista, joilla alueen ja insinoorikoulutuksen cleantech-osaamista ja tyoelamavastaavuutta on parannettu. Raportin suomenkielisessa osassa on tarkasteltu cleantech-liiketoiminnan globaaleja markkinoita ja tulevaisuuden nakymia seka Suomen ja Lahden seudun cleantech-osaamista ja osaamistarpeita. Materiaalitekniikan koulutusohjelman artikkeleissa on kasitelty opintosuunnitelman muutostyota, joka kasittaa myos cleantech-nakokulman ja CDIO- / PBL-pedagogiikan sisallyttamisen opintosuunnitelmaan. Mekatroniikan koulutusohjelman artikkelissa on kasitelty CDIO- / PBL-pedagogiikan lahestymistapaa ja toteutumista kone- ja tuotantotekniikan koulutusohjelmassa. Raportin englanninkielinen osuus kasittelee ymparistoteknologian koulutusohjelman opintosuunnitelman muutosta, joka sisaltaa myos englanninkielisen ylemman ammattikorkeakoulututkinnon. Lisaksi englanninkieliset artikkelit kasittelevat tietotekniikan koulutusohjelman cleantech-nakokulmaa Green ICT -moduuleissa

Juvenile arthritis management in less resourced countries (JAMLess): consensus recommendations from the Cradle of Humankind

Juvenile idiopathic arthritis (JIA) is the most prevalent chronic rheumatic disease in children and young people (CYP) and a major cause of pain and disability. The vast majority of the world's children and their families live in less resourced countries (LRCs) and face significant socioeconomic and healthcare challenges. Current recommendations for standards of care and treatment for children with JIA do not consider children living in less resourced countries. In order to develop appropriate recommendations for the care of CYP with JIA in less resourced countries a meeting of experienced pediatric rheumatologists from less resourced countries was convened with additional input from a steering group of international pediatric rheumatologists with experience in developing recommendations and standards of care for JIA. Following a needs assessment survey of healthcare workers caring for CYP with JIA in LRC, a literature review was carried out and management recommendations formulated using Delphi technique and a final consensus conference. Responses from the needs assessment were received from 121/483 (25%) practitioners from 25/49 (51%) less resourced countries. From these responses, the initial 84 recommendations were refined and expanded through a series of 3 online Delphi rounds. A final list of 90 recommendations was proposed for evaluation. Evidence for each statement was reviewed, graded, and presented to the consensus group. The degree of consensus, level of agreement, and level of evidence for these recommendations are reported. Recommendations arrived at by consensus for CYP with JIA in less resourced countries cover 5 themes: (1) diagnosis, (2) referral and monitoring, (3) education and training, (4) advocacy and networks, and (5) research. Thirty-five statements were drafted. All but one statement achieved 100% consensus. The body of published evidence was small and the quality of evidence available for critical appraisal was low. Our recommendations offer novel insights and present consensus-based strategies for the management of JIA in less resourced countries. The emphasis on communicable and endemic diseases influencing the diagnosis and treatment of JIA serves as a valuable addition to existing JIA guidelines. With increasing globalization, these recommendations as a whole provide educational and clinical utility for clinicians worldwide. The low evidence base for our recommendations reflects a shortage of research specific to less resourced countries and serves as an impetus for further inquiry towards optimizing care for children with JIA around the world.status: publishe