•The type of genetic variant is a predictive biomarker for disease severity and survival in WAS.•Less severe variants entail a later onset of disease-related complications but patients remain prone ...to morbidity and premature mortality.
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Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.
Wiskott-Aldrich syndrome (WAS) is an X-linked monogenic inborn error of immunity characterized by thrombocytopenia, eczema, recurrent infections, autoimmunity, and cancer risk. In a tour de force, Vallée and colleagues describe the genetic landscape affecting the WAS gene across 577 patients and resolve the associations between specific gain- or loss-of-function mutations and the severity of clinical phenotype. Class I mutations portended less severe disease while class II mutations predicted earlier onset and more severe disease with worse survival, allowing personalized prognostic advice and informing tailored care.
Aim. This paper reports a study to assess stress, well‐being and supportive resources experienced by mothers and fathers of children with rare disabilities, and how these variables were affected by ...an intensive family competence intervention.
Background. Despite diagnosis‐specific studies, little overall knowledge exists about life‐consequences for families of children with rare disorders.
Method. We used a prospective design with baseline data and two follow‐ups (at 6 and 12 months) after an intervention. The intervention aimed at empowering parents in managing their child's disability. Parents from all parts of Sweden visiting a national centre for families of children with rare disabilities were consecutively selected (n = 136 mothers, 108 fathers). Instruments of parental stress, social support, self‐rated health, optimism and life satisfaction and perceived physical or psychological strain were used. Stratified analyses were carried out for mothers and fathers, and related to parental demands: single mothers, full‐time employment, participation in a parent association, child's age and type of disability.
Results. We found high parental stress, physical and emotional strain among mothers, especially among single mothers. Fathers showed high stress related to incompetence, which decreased after the intervention. Decreased strain was found among full‐time working mothers and fathers after the intervention. Parents’ perceived knowledge and active coping and mothers’ perceived social support were increased at follow‐up. Factors related to parents’ overall life satisfaction (57–70% explained variance) changed after the intervention, from being more related to internal demands (perceived strain, incompetence and social isolation) to other conditions, such as problems related to spouse, paid work and social network.
Conclusion. Parents, especially fathers and full‐time working parents, may benefit from an intensive family competence programme.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK, VSZLJ
The aim of the study was to describe school attendance and participation in physical education in school among children with juvenile idiopathic arthritis (JIA).
Consecutive cases of JIA from defined ...geographical areas of Finland, Sweden and Norway with disease onset in 1997 to 2000 were followed for 8 years in a multi-center cohort study, aimed to be as close to population-based as possible. Clinical characteristics and information on school attendance and participation in physical education (PE) were registered.
Participation in school and in PE was lowest initially and increased during the disease course. Eight years after disease onset 228/274 (83.2%) of the children reported no school absence due to JIA, while 16.8% reported absence during the last 2 months due to JIA. Full participation in PE was reported by 194/242 (80.2%), partly by 16.9%, and none by 2.9%. Lowest participation in PE was found among children with ERA and the undifferentiated categories. Absence in school and PE was associated with higher disease activity measures at the 8-year visit. School absence > 1 day at baseline predicted use of disease-modifying anti-rheumatic drugs, including biologics (DMARDs) (OR 1.2 (1.1-1.5)), and non-remission off medication (OR 1.4 (1.1-1.7) 8 years after disease onset.
School absence at baseline predicted adverse long-term outcome. In children and adolescents with JIA participation in school activities is mostly high after 8 years of disease. For the minority with low participation, special attention is warranted to promote their full potential of social interaction and improve long-term outcome.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Objectives To analyze available evidence on vaccinations in paediatric patients with rheumatic and autoinflammatory diseases. This evidence formed the basis of the recently constructed ...European League against Rheumatism (EULAR) recommendations for vaccination of these patients. Methods A systematic literature review in the MEDLINE and EMBASE databases was conducted using various terms for vaccinations, paediatric rheumatic and autoinflammatory diseases and immunosuppressive drugs. Only papers on paediatric patients (< 18 years of age) were selected. A panel of 13 experts in the field graded methodological quality and extracted data using predefined criteria. Results 27 papers were available. No studies were found on autoinflammatory diseases. 14 studies considered live-attenuated vaccines. Evidence so far supports the safety and immunogenicity of non-live composite vaccines, although studies were underpowered to accurately assess safety. Live-attenuated vaccines did not cause disease flares or severe adverse events, not even in patients on methotrexate and low dose glucocorticosteroids. Seven patients on anti-TNFalpha therapy were described receiving the live-attenuated measles, mumps, rubella ( n = 5) or varicella ( n = 2) booster without severe adverse events. Conclusions Data on safety and efficacy of vaccinations in paediatric patients with rheumatic diseases is reassuring, but too limited to draw definite conclusions. More research is needed on the safety and efficacy of especially live-attenuated vaccines in patients with rheumatic and autoinflammatory diseases using high dose immunosuppressive drugs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background and objectiveUmbilical cord blood (UCB) is a valuable stem cell source used for transplantation. Immediate umbilical cord (UC) clamping is widely practised, but delayed UC clamping is ...increasingly advocated to reduce possible infant anaemia. The aim of this study was to investigate an intermediate UC clamping time point and to evaluate iron status at the age of 4 months in infants who had the UC clamped after 60 s and compare the results with immediate and late UC clamping.DesignProspective observational study with two historical controls.SettingA university hospital in Stockholm, Sweden, and a county hospital in Halland, Sweden.MethodsIron status was assessed at 4 months in 200 prospectively recruited term infants whose UC was clamped 60 s after birth. The newborn baby was held below the uterine level for the first 30 s before placing the infant on the mother’s abdomen for additional 30 s. The results were compared with data from a previously conducted randomised controlled trial including infants subjected to UC clamping at ≤10 s (n=200) or ≥180 s (n=200) after delivery.ResultsAfter adjustment for age differences at the time of follow-up, serum ferritin concentrations were 77, 103 and 114 µg/L in the 10, 60 and 180 s groups, respectively. The adjusted ferritin concentration was significantly higher in the 60 s group compared with the 10 s group (P=0.002), while the difference between the 60 and 180 s groups was not significant (P=0.29).ConclusionIn this study of healthy term infants, 60 s UC clamping with 30 s lowering of the baby below the uterine level resulted in higher serum ferritin concentrations at 4 months compared with 10 s UC clamping. The results suggest that delaying the UC clamping for 60 s reduces the risk for iron deficiency.Trial registration number NCT01245296.
Objective
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an autoinflammatory disease of unknown etiology that primarily affects preschool‐aged children. ...PFAPA syndrome is characterized by recurrent attacks of fever and symptoms of inflammation consistent with the disease acronym. Since autoinflammatory diseases are, by definition, mediated by cells of the innate immune system, the aim of this study was to evaluate the functional features of neutrophils, the most abundant innate immune cell in the circulation, in children with PFAPA syndrome.
Methods
Blood polymorphonuclear leukocytes (PMNs), obtained from patients with PFAPA syndrome during both febrile and asymptomatic, afebrile phases of the disease, as well as from healthy children (afebrile controls) and children with fever and abdominal pain (febrile controls), were analyzed for 3 key neutrophil characteristics: 1) apoptosis (measured by annexin V/7‐aminoactinomycin D staining), 2) production of reactive oxygen species (ROS) (measured by luminol/isoluminol‐amplified chemiluminescence), and 3) priming status (measured as responsiveness to galectin‐3 and up‐regulation of CD11b).
Results
Compared to PMNs obtained from patients with PFAPA syndrome during an afebrile interval and those from febrile controls, PMNs obtained from patients during a PFAPA syndrome flare produced elevated levels of intracellular NADPH oxidase–derived ROS, had significantly diminished rates of spontaneous apoptosis, and displayed signatures of priming. In contrast, PMNs from afebrile patients with PFAPA syndrome had a significantly elevated rate of spontaneous apoptosis compared to PMNs from afebrile controls.
Conclusion
These findings demonstrate that 3 key aspects of neutrophil innate immune function, namely, apoptosis, priming, and generation of an intracellular oxidative burst, are altered, most prominently during febrile attacks, in children with PFAPA syndrome.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Nineteen lightly sleep-deprived healthy volunteers were examined with H2(15)O and positron emission tomography (PET). Scanning was performed during wakefulness and after the subjects had fallen ...asleep. Sleep stage was graded retrospectively from electroencephalogram (EEG) recordings, and scans were divided into two groups: wakefulness or synchronized sleep. Global flow was quantified, revealing no difference between sleep and wakefulness. A pixel-by-pixel-blocked one-way analysis of variance (ANOVA) was performed after correcting for differences in anatomy and global flow. The sum of squares of the z-score distribution showed a highly significant (P < 0.00001) omnibus difference between sleep and wakefulness. The z-score images indicated decreased flow in the thalamus and the frontal and parietal association cortices and increased flow in the cerebellum during sleep. A principal component (PC) analysis was performed on data after correction for global flow and block effects, and a multivariate analysis of variance (MANOVA) on all PC scores revealed significant (P = 0.00004) differences between sleep and wakefulness. Principal component's 2 and 5 correlated to sleep and revealed distinct networks consisting of PC 2, cerebellum and frontal and parietal association cortices, and PC 5, thalamus.
Early therapeutic intervention and use of new highly efficacious treatments have improved the outcome in many patients with juvenile idiopathic arthritis (JIA), but have also led to the need for more ...precise methods to evaluate disease activity. In adult rheumatology, numerous studies have established the importance of magnetic resonance imaging (MRI) and ultrasonography (US), and MRI is considered the reference standard. Nevertheless, due to differences in disease characteristics and the unique features of the growing skeleton, the findings obtained in adults are not directly applicable to children and adolescents. For paediatric patients, US offers specific advantages over MRI, because it is non-invasive, does not require sedation or general anesthesia (which facilitates repeated examinations for follow-up), is quickly accessible bedside, and is easy to combine with clinical assessment (interactivity). Agitation of the patient is rarely a problem, and hence young children can be seated on a parent's lap or play while being examined, and multiple locations can be assessed during a single session. Furthermore, modern high-frequency US transducers used by experienced US examiners can provide unsurpassed resolution of the superficial musculoskeletal structures in children. US is also the best available technique for imaging guidance of steroid injections. Unfortunately, there are still no validated MRI or US scoring systems for evaluating inflammatory and joint damage abnormalities in JIA, and few US studies have been conducted. Sonographic assessment of disease activity has, however, been proven to be more informative than clinical examination and is also readily available at points of care. This review summarises the literature on imaging in JIA, focusing on US and the important role this technique will play in JIA in the future.
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