This prospective, long-term observational study, initiated in 2002, aimed to characterize clinical and laboratory data, whole body MRI detected lesions, and treatment responses in 37 juvenile patients with chronic non-bacterial osteomyelitis at a time when biological DMARDs were not yet standard therapy. Patients were assessed at baseline and at 1 (without MRI), 3, 6, 12, 18, 24, 36, 48, 60 months. All patients received naproxen as first-line therapy. Clinical management allowed for escalation to sulfasalazine, pamidronate, and glucocorticoids as needed. Treatment response was evaluated using the pedCNO disease activity score (30/50/70/90

OBJECTIVE:Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease with no validated criteria for assessing disease activity (DA), inactive disease, or remission. To date, DA assessment has relied on subjective judgments from patients, rheumatologists, and/or radiologists. Evaluations based on composite DA measures are emerging. The Pediatric CNO (PedCNO) response score documents relative DA changes during follow-up in analogy to the Pediatric American College of Rheumatology score for juvenile idiopathic arthritis. The international Childhood Arthritis and Rheumatology Research Alliance (CARRA) CNO initiative proposed a numeric composite DA score (CDAS) on the basis of the patient global assessment of DA (PAG), patient assessment of pain (PAP), and clinically active CNO lesions. We aim to propose different composite scores for assessment of DA, including physician assessment of DA and magnetic resonance imaging (MRI) findings; to evaluate the previously published CNO CDAS and the PedCNO response score using established registry data; and to suggest a PedCNO 90% improvement (PedCNO90) category. METHODS:Newly diagnosed patients with CNO were enrolled between 2015 and 2020 and analyzed for clinical course and DA measures (physician global assessment of DA [PGDA]/PAG and pain scores) for up to 4 years of follow-up (YFU) in the National Pediatric Rheumatologic Database. RESULTS:A total of 400 patients were enrolled. In single numeric scores only, clinical and MRI lesion scores reached significant changes (from baseline to 3 YFU: P = 0.003/P = 0.004). Composite scores, which include MRI DA scores consisting of one clinical patient-based assessment parameter (PAG/PAP of DA), the PGDA and MRI lesion count are less dependent on subjective measures and demonstrate more pronounced changes over time of supposed CNO DA compared with the CNO CDAS. A PedCNO90 response score gradually increased during follow-up, ultimately reaching a PedCNO90 in half of the remaining patients after 4 years. CONCLUSION:Composite scores, including MRI lesions and PGDA, seem to be promising tools for describing the activity of CNO and are proposed. The composition of DA scores seems essential for future studies.

BACKGROUND Antibiotic-Refractory Lyme Arthritis (ARLA) involves a complex interplay of T cell responses targeting Borrelia burgdorferi antigens progressing toward autoantigens by epitope spreading. However, the precise molecular mechanisms driving the pathogenic T cell response in ARLA remain unclear. Our aim was to elucidate the molecular program of disease-specific Th cells.METHODS Using flow cytometry, high-throughput T cell receptor (TCR) sequencing, and scRNA-Seq of CD4+ Th cells isolated from the joints of patients with ARLA living in Europe, we aimed to infer antigen specificity through unbiased analysis of TCR repertoire patterns, identifying surrogate markers for disease-specific TCRs, and connecting TCR specificity to transcriptional patterns.RESULTS PD-1hiHLA-DR+CD4+ effector T cells were clonally expanded within the inflamed joints and persisted throughout disease course. Among these cells, we identified a distinct TCR-β motif restricted to HLA-DRB1*11 or *13 alleles. These alleles, being underrepresented in patients with ARLA living in North America, were unexpectedly prevalent in our European cohort. The identified TCR-β motif served as surrogate marker for a convergent TCR response specific to ARLA, distinguishing it from other rheumatic diseases. In the scRNA-Seq data set, the TCR-β motif particularly mapped to peripheral T helper (TPH) cells displaying signs of sustained proliferation, continuous TCR signaling, and expressing CXCL13 and IFN-γ.CONCLUSION By inferring disease-specific TCRs from synovial T cells we identified a convergent TCR response in the joints of patients with ARLA that continuously fueled the expansion of TPH cells expressing a pathogenic cytokine effector program. The identified TCRs will aid in uncovering the major antigen targets of the maladaptive immune response.FUNDING Supported by the German Research Foundation (DFG) MO 2160/4-1; the Federal Ministry of Education and Research (BMBF; Advanced Clinician Scientist-Program INTERACT; 01EO2108) embedded in the Interdisciplinary Center for Clinical Research (IZKF) of the University Hospital Würzburg; the German Center for Infection Research (DZIF; Clinical Leave Program; TI07.001_007) and the Interdisciplinary Center for Clinical Research (IZKF) Würzburg (Clinician Scientist Program, Z-2/CSP-30).

ZUSAMMENFASSUNG Die Hypophosphatasie (HPP) ist eine seltene genetische Erkrankung, welche infolge einer verminderten Alkalischen Phosphatase-Aktivität zu Problemen an Knochen, Muskeln, Zähnen, aber auch zahlreichen weiteren Organsystemen führen kann. Letztlich handelt es sich um eine metabolische Multisystemerkrankung mit sehr variablem klinischem Phänotyp bzw. Schweregrad, die alle Altersgruppen betreffen kann und zu einer signifikanten Mortalität und Morbidität bei den betroffenen Familien führt. Die klinische Verdachtsdiagnose kann durch laborchemische Untersuchungen (insbesondere die Bestimmung der AP-Aktivität), bildgebende Maßnahmen und eine humangenetische Testung erhärtet werden. Eine Anbindung betroffener Familien an ein erfahrenes Zentrum mit multidisziplinärer Betreuung erscheint sinnvoll. Die Enzymersatztherapie mit Asfotase alfa stellt eine zugelassene effektive und gut verträgliche Therapie zur Behandlung des „Knochenphänotyps“ dar. Langzeitdaten zu Wirksamkeit und Verträglichkeit sollen im Rahmen eines internationalen Registers erfasst werden.

Background The safe treatment of polytrauma patients requires effective and highly coordinated team-based strategies. Simulation-based team training helps to establish crisis resource management (CRM) in emergency medicine. This study analyzes the successful implementation of an interdisciplinary and interprofessional in situ team training in the trauma room of a level I trauma center.Methods The Advanced Trauma Life Support (R) (ATLS (R))-based training was developed by an interdisciplinary team comprised of all specialties involved in trauma room management. A week of training included 5 days with two groups per day, each consisting of eight participants for 4 h in the trauma room. The training included two interactive discussions on CRM and ATLS (R) principles, familiarization with the simulation environment, and two scenarios (20 min each) followed by debriefings. After the training, participants were asked to evaluate the training concept and their self-assessment regarding CRM principles using anonymized questionnaires.Results In summary, 167 physicians, nurses, and technicians from anesthesiology, trauma surgery, general surgery, and radiology attended the trainings. Junior physicians represented the largest group of participants (47.6%). The training concept was positively evaluated. All participants assessed an increased acceptability regarding CRM principles. More than 95% of the participants wished to repeat the training at least once a year.Conclusion The training enables subjective improvement of knowledge of all staff members regarding CRM principles, increases comprehension about the importance of these principles and, therefore, has the potential to improve communication and processes in the trauma room.Graphic abstract

Zusammenfassung Hintergrund Eine effektive Schockraumversorgung polytraumatisierter Patienten erfordert professionelle interdisziplinäre Teamarbeit. Simulationsgestützte Teamtrainings können es ermöglichen, die Grundprinzipien des Crisis Resource Management (CRM) auch in der Akut- und Notfallmedizin zu etablieren. Diese Arbeit präsentiert die erfolgreiche Implementierung eines interdisziplinären, interprofessionellen In-situ-Schockraumsimulationstrainings (iSRST) in einem überregionalen Traumazentrum. Methodik Das iSRST wurde durch Vertretende aller an der Schockraumversorgung beteiligten Fachdisziplinen Advanced-Trauma-Life-Support®(ATLS®)-basiert entwickelt. Pro Trainingswoche wurde an fünf aufeinanderfolgenden Tagen mit jeweils zwei Gruppen zu je acht Teilnehmenden für vier Stunden im traumatologischen Schockraum trainiert. Das Training bestand aus zwei interaktiven Diskussionen zu CRM und ATLS®, einer Einführung in die Simulationstechnik und zwei Szenarien (ca. 20 min) mit darauffolgenden Debriefings. Alle Teilnehmenden wurden nach dem Training anhand anonymisierter Fragebögen zur Evaluation des Trainings inklusive Selbsteinschätzung in Bezug auf die Leitsätze des CRM befragt. Ergebnisse Insgesamt beantworteten 167 Ärzt*innen, Pflegekräfte und technisches Assistenzpersonal aus Anästhesiologie, Unfallchirurgie, Allgemeinchirurgie und Radiologie die Fragebögen. Die größte Berufsgruppe stellten mit 47,6 % Assistenzärzt*innen dar. Das Trainingskonzept wurde durchweg sehr gut bewertet. Der Lernzuwachs hinsichtlich der befragten CRM-Prinzipien war bei allen Aspekten signifikant. Über 95 % der Teilnehmenden wünschten eine mindestens jährliche Wiederholung des Trainings. Diskussion Das iSRST führt aus Teilnehmendensicht zu einem relevanten subjektiven Wissenszuwachs hinsichtlich CRM, steigert das Verständnis für die Bedeutung dieser Prinzipien und hat somit das Potenzial, die Kommunikation und Handlungsabläufe im chirurgischen Schockraum zu verbessern.

ObjectiveAntinuclear antibody (ANA)–positive juvenile idiopathic arthritis (JIA) is characterized by synovial B cell hyperactivity, but the precise role of CD4+ T cells in promoting local B cell activation is unknown. This study was undertaken to determine the phenotype and function of synovial CD4+ T cells that promote aberrant B cell activation in JIA.MethodsFlow cytometry was performed to compare the phenotype and cytokine patterns of PD‐1highCD4+ T cells in the synovial fluid (SF) of patients with JIA and T follicular helper cells in the tonsils of control individuals. TCRVB next‐generation sequencing was used to analyze T cell subsets for signs of clonal expansion. The functional impact of these T cell subsets on B cells was examined in cocultures in vitro.ResultsMultidimensional flow cytometry revealed the expansion of interleukin‐21 (IL‐21) and interferon‐γ (IFNγ)–coexpressing PD‐1highCXCR5–HLA–DR+CD4+ T cells that accumulate in the joints of ANA‐positive JIA patients. These T cells exhibited signs of clonal expansion with restricted T cell receptor clonotypes. The phenotype resembled peripheral T helper (Tph) cells with an extrafollicular chemokine receptor pattern and high T‐bet and B lymphocyte–induced maturation protein 1 expression, but low B cell lymphoma 6 expression. SF Tph cells, by provision of IL‐21 and IFNy, skewed B cell differentiation toward a CD21low/–CD11c+ phenotype in vitro. Additionally, SF Tph cell frequencies correlated with the appearance of SF CD21low/–CD11c+CD27–IgM– double‐negative (DN) B cells in situ.ConclusionClonally expanded CD4+ Tph cells accumulate in the joints of ANA‐positive JIA patients and, in particular, promote CD21low/–CD11c+ DN B cell differentiation. The expansion of Tph cells and DN B cells might reflect the autoimmune response in the joints of ANA‐positive JIA patients.

Juvenile idiopathic arthritis (JIA) encompasses a heterogeneous group of diseases. The appearance of antinuclear antibodies (ANAs) in almost half of the patients suggests B cell dysregulation as a distinct pathomechanism in these patients. Additionally, ANAs were considered potential biomarkers encompassing a clinically homogenous subgroup of JIA patients. However, in ANA+ JIA patients, the site of dysregulated B cell activation as well as the B cell subsets involved in this process is still unknown. Hence, in this cross-sectional study, we aimed in an explorative approach at characterizing potential divergences in B cell differentiation in ANA+ JIA patients by assessing the distribution of peripheral blood (PB) and synovial fluid (SF) B cell subpopulations using flow cytometry. The frequency of transitional as well as switched-memory B cells was higher in PB of JIA patients than in healthy controls. There were no differences in the distribution of B cell subsets between ANA- and ANA+ patients in PB. However, the composition of SF B cells was different between ANA- and ANA+ patients with increased frequencies of CD21lo/−CD27−IgM− “double negative” (DN) B cells in the latter. DN B cells might be a characteristic subset expanding in the joints of ANA+ JIA patients and are potentially involved in the antinuclear immune response in these patients. The results of our explorative study might foster further research dissecting the pathogenesis of ANA+ JIA patients.

This article provides an overview of the current knowledge on hypophosphatasia-a rare genetic disease of very variable presentation and severity-with a special focus on adolescents and adults. It summarizes the available information on the many known mutations of tissue-nonspecific alkaline phosphatase (TNSALP), the epidemiology and clinical presentation of the disease in adolescents and adults, and the essential diagnostic clues. The last section reviews the therapeutic approaches, including recent reports on enzyme replacement therapy (EnzRT).

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme’s role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish.

Following publication of the original article [1], we have been notified that the authors' first names and last names are presented in wrong order. The presentation of names, thus, should be as follows.

The pediatric musculoskeletal system undergoes a high growth velocity in childhood and adolescence until the final height is reached. Additionally, the musculoskeletal system must continuously adapt to the current physical strains acting on the muscles and bones. The bone modelling and remodelling processes are adapted in the sense of a feedback regulatory system via the functional muscle-bone unit. In chronic diseases (e.g. neurological diseases, bone metabolism disorders, inflammatory rheumatic diseases) and also in temporary periods of immobilization, alterations of the functional integrity of the muscle-bone unit, the joints or the movement pattern occur directly or indirectly, ultimately leading to a movement disorder or altered movement patterns. Independent of the underlying cause, the reduced mobility, the altered movement pattern and the partially resulting immobility seem to clearly reduce the participation of affected persons. Therefore, this symptom is of great importance from the perspective of the patient. Targeted diagnostics with a functional analysis of the movement disorder present appear to be indispensable to be able to provide an interdisciplinary individual treatment concept based on the underlying disease and to assess the effectiveness as well as the quality of life and social participation

ypophosphatasia is a systemic metabolic disorder due to genetically determined deficient activity of the tissue non-specific alkaline phosphatase (TNAP). The phenotypic presentation is characterized by a wide spectrum of clinical manifestations regarding both, affected body systems and organs as well as the severity of associated deficits. Appropriate treatment strategies thus have to be multimodal in order to cover individual disease manifestation. For patients with disease onset before adulthood, enzyme replacement therapy with asfotase alfa is approved in Europe to treat the bone manifestations of the disease. Available data from clinical trials as well as real-word evidence confirm encouraging results of this treatment in severely affected children with substantial improvement regarding radiographic and functional outcome parameters as well as overall survival. In adult patients with disease manifestation pursuant to the label, published results also report substantial amelioration of disease-specific deficits along with functional improvements. Meanwhile, there is are also data supporting the safety and efficacy of long-term treatment with asfotase alfa over several years. While inflammatory muskuloskeletal pain - seemingly the most prevalent clinical manifestation along with exhaustion - can transiently be mitigated with on-demand NSARs, essential treatment options to causatively overcome that issue are still lacking. Accordingly, maintenance of musculoskeletal health and functionality requires sustained supportive treatment including physiotherapy and individually adjusted technical orthopedic support. The use and potential clinical impact of phosphate and vitamin B6 on the course of the disease requires further investigation. Current data regarding the use of bone-targeted compounds established for osteoporosis is critical in terms of antiresorptive, while osteoanabolic treatment strategies appear feasible. Considering further organ manifestation including orodental, gastrointestinal and neurological symptoms etc., the entirety of therapeutic measures should be coordinated among a multidisciplinary team and overlooked at an experienced center, while individual tasks can preferably be accomplished at local facilities near the patient’s home.

Juvenile Idiopathic Arthritis (JIA) is currently classified into seven subgroups. Recently, antinuclear antibody (ANA) positive JIA patients were suggested to encompass a clinically homogenous new subgroup. CD4+ T helper (Th) cells play an essential role in JIA pathogenesis. Herein, we analyzed cytokine expression in synovial fluid (SF) CD4+ Th cells of JIA patients by using flow cytometry and compared cytokine patterns between JIA subgroups. We could show increased frequencies of IL-21 expressing CD4+ Th cells in the joints of ANA+ Oligo-/Poly-JIA patients, which co-expressed the Th-1 cytokines IFN-γ/TNF-α. In contrast, frequencies of IL-17 expressing cells were lowest in the joints of ANA+ Oligo-/Poly-JIA but enriched in that of ERA-JIA patients. This is the first description of a diverse SF Th cell cytokine pattern in different JIA subgroups. Additionally, we could define IL-21 as an effector cytokine expressed in SF Th cell in a significant proportion of ANA+ JIA patients.

Hypophosphatasia due to genetically determined deficient activity of the tissue non-specific alkaline phosphatase (TNAP) is characterized by a wide spectrum of potential clinical manifestations, both, regarding the type of symptoms, as well as the severity of associated deficits. Appropriate treatment strategies should be built on a multimodal approach specifically considering individual disease manifestation. For patients with disease onset before adulthood, enzyme replacement therapy with Asfotase alfa (Strensiq) is approved in Europe to treat the bone manifestation of the disease. Both, available data from clinical trials as well as clinical routine experience confirm basically encouraging results of that treatment in severely affected children with substantial improvement regarding radiographic and functional outcome parameters as well as overall survival. Even in adult patients with severe disease manifestation pursuant to the approval, first results confirm substantial amelioration of disease-specific deficits and functional improvements. Meanwhile, there is also data supporting safety and efficacy of long-term treatment Asfotase alfa over several years. While inflammatory pain, which is typically perceived as being burdensome, can commonly be addressed successfully with NSAIDs on-demand, overall musculoskeletal health requires sustained, multimodal, supportive treatment strategies including exercise interventions as well as age and health state adjusted technical orthopedic support. The use and potential clinical impact of Phosphate and Vitamin B6 on the course of the disease requires further investigation. Current data regarding the use of bone-targeted compounds is critical in terms of antiresorptives while osteoanabolic treatment strategies appear feasible. Ideally, the entirety of therapeutic measures should be coordinated and overlooked at an experienced center while individual tasks can preferably be accomplished at local facilities near the patient’s home.

Das muskuloskeletale System unterliegt in Kindheit und Jugend bis zum Erreichen der Endgröße einem ausgeprägten Längenwachstum. Zusätzlich muss sich das muskuloskeletale System kontinuierlich an die aktuellen auf Muskel und Knochen einwirkenden Beanspruchungen adaptieren. Über die funktionelle Muskel-Knochen-Einheit wird im Sinne eines Regelkreises der Knochenaufbau und -abbau angepasst. Im Rahmen chronischer Erkrankungen (neurologische Erkrankungen, Knochenstoffwechselstörungen, rheumatisch-entzündliche Erkrankungen) aber auch im Rahmen einer kurzfristigen Immobilität kommt es häufig direkt oder indirekt zu Veränderungen der funktionellen Muskel-Knochen-Einheit, der Gelenke oder der Bewegungsmuster, was letztlich in einer „Bewegungsstörung“ bzw. in veränderten Bewegungsmustern mündet. Unabhängig von der zugrunde liegenden Ursache scheinen die reduzierte Beweglichkeit, das veränderte Bewegungsmuster und die teilweise resultierende Immobilität die Teilhabe der Betroffenen am Leben deutlich zu reduzieren, weswegen diesem Symptom eine hohe Wichtigkeit aus Sicht der Patienten zugeschrieben wird. Eine gezielte Diagnostik mit funktioneller Analyse der vorliegenden Bewegungsstörung erscheint unabdingbar, um ein interdisziplinär individuelles Betreuungskonzept, basierend auf der zugrunde liegenden Erkrankung, anbieten und dessen Wirksamkeit beurteilen zu können sowie die Lebensqualität und Teilhabe der Betroffenen zu erhalten.

A significant proportion of rare diseases affect the musculoskeletal system. Due to growing disease awareness, increasingly individualized medicine and the availability of new innovative drugs an expanding need for expert knowledge and networking in the field of rare osteological diseases has arisen. In Europe, the European Reference Networks (ERN) were established in 2017 to address these tasks in a patient centered way. In the same year the German Society for Osteology (DGO) started an initiative to synergize and develop existing activities in the field of Rare Bone Diseases in German-speaking countries. As a result, the Network on Rare Osteopathologies (NetsOs) was founded in November 2018 with specialists from a wide range of disciplines from Germany, Austria and Switzerland. NetsOs encompasses both, an expert-network with clinical and scientific experts from Austria, Germany and Switzerland as well as an expert-center based network in Germany. The latter connects clinical centers with special expertise, so-called B-centers, for rare osteological diseases. NetsOs aims to improve and support diagnostic procedures, lifelong care and monitoring for patients who are affected by a rare bone and mineral condition together with the patient associations. Additional focus lies on training and education in the field of rare osteological diseases. In order to achieve these goals, members of the network are involved in clinical care, clinical and basic research and teaching for rare bone and skeletal diseases and are available for consutls for colleagues. Involvement in national, European and international clinical and scientific networking, interaction with centers for rare diseases, scientific societies, ERNs and European registers is established through the involvement of the members of NetsOs in these structures.

Seltene Erkrankungen des muskuloskelettalen Systems stellen einen wesentlichen Anteil der Seltenen Erkrankungen dar. Die Bildung der europaischen Referenznetzwerke (ERNs) hat die Deutsche Gesellschaft fur Osteologie (DGO) 2017 zum Anlass genommen, bestehende Aktivitaten im Bereich der Seltenen Knochenerkrankungen im deutschsprachigen Raum zu bundeln und weiterzuentwickeln. Aus dieser DGO-Initiative heraus grundete sich im November 2018 das Netzwerk Seltene Osteopathien (NetsOs). NetsOs verbindet als deutschsprachiges Netzwerk fur seltene osteologische Erkrankungen ExpertInnen aus Osterreich, Deutschland und der Schweiz sowie als krankheitsspezifisches Netzwerk die Zentren mit besonderer Expertise sog. B-Zentren fur seltene osteologische Erkrankungen. Im Fokus des Netzwerkes steht die Verbesserung der Diagnostik, Therapie und Versorgung von PatientInnen, die von einer seltenen Erkrankung des Knochens betroffen sind. Daruber hinaus soll eine Verbesserung der Ausbildung und Weiterbildung im Themengebiet seltene osteologische Erkrankungen erreicht werden. Die uberregionale und internationale klinische und wissenschaftliche Vernetzung zu den Patientenverbanden, Zentren fur Seltene Erkrankungen, Fachgesellschaften, ERNs und europaischen Registern wird durch die Einbindung der Mitglieder von NetsOs in diese Strukturen gewahrleistet.

ZusammenfassungIn Anbetracht des breiten Spektrums klinischer Manifestationen der HPP erfordert eine umfassende Behandlung stets einen multimodalen, interdisziplinären Ansatz. Eine kurative Therapie der genetisch determinierten Erkrankung ist auf absehbare Zeit nicht verfügbar. Insofern fokussieren alle therapeutischen Bemühungen auf eine Verbesserung der krankheitsassoziierten Symptome und Einschränkungen sowie die Vermeidung krankheitsassoziierter Komplikationen. Mit Asfotase alfa steht seit September 2015 ein in der EU zugelassenes Enzymersatztherapiepräparat (rekombinante TNAP, Strensiq®) zur Langzeitbehandlung der Knochenmanifestation bei Patienten mit ersten HPP-Symptomen im Kindesalter zur Verfügung. In den Zulassungsstudien bei schwer betroffenen Kindern zeigte sich ein erfreuliches muskuläres und radiologisches Ansprechen, eine respiratorische Verbesserung sowie ein verbessertes Gesamtüberleben im Vergleich zum natürlichen Verlauf der Erkrankung. In Zukunft ist das Erfassen von weiteren klinischen Daten, insbesondere zur Langzeittherapie im Hinblick auf Sicherheit und Wirksamkeit zu Asfotase alfa, erforderlich. Sinnvollerweise sollte die Gesamtheit aller therapeutischen Maßnahmen an einem Zentrum mit entsprechender Erfahrung koordiniert und überblickt werden. Dies beinhaltet stets auch eine Betreuung der gesamten Familie als wesentliches Grundprinzip der Therapie.

Asfotase alfa (AA), an enzyme replacement therapy, is the only approved medical treatment for pediatric-onset hypophosphatasia (HPP). We report the safety profile of AA in patients from the clinical trial program. Safety data were pooled from 4 open-label, multicenter studies in children age ≤3 years (study 002/003 [NCT00744042/NCT01205152]; n=11) and age ≤5 years (study 010-10 [NCT01176266]; n=69) with onset of HPP symptoms before age 6 months, children age 5-12 years with HPP and open growth plates (study 006/008 [NCT00952484/NCT01203826]; n=13), and adolescents and adults age 13-65 years with onset of HPP at any age (study 009 [NCT01163149]; n=19). AA doses varied between studies; data were available for up to 7 years from studies 002/003, 010-10, and 006/008 and for up to 5 years from study 009. Safety events after the studies ended were not included. In total, data were available for 112 patients (median [min, max] age at enrollment: 3.2 [0, 66.5] y; female: 51%; white: 84%). Median (min, max) treatment duration was 2.7 years (1 d, 7.5 y). The average weekly total dose ranged from 2.1 to 11.9 mg/kg. All patients experienced adverse events (AEs); 26% of events were considered related to treatment and were mild (74%) or moderate (21%) in severity. Serious treatment-related AEs were reported in 10 (9%) patients. Serious AEs of special interest were craniosynostosis (25%; including increased intracranial pressure), injection-associated reactions (5%; including hypersensitivity), injection site reactions (ISRs) (2%; including erythema), ectopic calcifications (2%; including nephrolithiasis), and liver abnormalities or disease (2%; including chronic hepatitis). Overall, ISRs were the most common treatment-related AEs (73%). Ten deaths occurred among patients with severe HPP who entered the studies as infants (1 day to 20 months). Four of these deaths were attributed to pneumonia/sepsis, and 1 death each was attributed to respiratory failure and cerebral death; HPP-related complications; severe respiratory failure; cardiopulmonary arrest; severe cardiopulmonary insufficiency; and transtentorial and cerebellar tonsillar herniation due to cerebral edema. The majority of deaths were considered related to underlying HPP; one of the deaths, attributed to pneumonia, was reported by the investigator as being possibly related to AA. AEs leading to AA withdrawal were reported in 11 (10%) patients; those reported in ≥2 patients included pneumonia and respiratory failure. Anti-AA antibody data were available for 109 patients; 97 (89%) tested positive, and 55 (57%) of these showed presence of neutralizing antibodies at some time during the studies. In this pooled analysis of mostly prepubescent children (84%) treated with AA for up to 7 years, ISRs were the most frequently reported treatment-related AEs. Funding: This study was sponsored by Alexion Pharmaceuticals, Inc.