Search

Background: Physical active lifestyles are essential throughout growth and maturation and may offer potential preventive and therapeutic benefit in patients with juvenile idiopathic arthritis (JIA). Insufficient physical activity (PA), in contrast, can lead to aggravation of disease-related symptoms. This study aimed to i) examine PA levels in children and adolescents with JIA compared to general population controls and ii) investigate correlates of pronounced physical inactivity in order to identify risk groups for sedentary behaviour., Methods: Data from children and adolescents with JIA and population controls aged 3 to 17 years documented in the National Pediatric Rheumatologic Database (NPRD) and the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) were used. Self-reported PA was collected from parents/guardians of children up to 11 years of age or adolescents 12 years of age and older. To compare PA-related data, age- and sex-specific pairwise analyses were conducted considering NPRD/KiGGS participants' data from 2017. Correlates of physical inactivity among patients were identified using a linear regression model., Results: Data of 6,297 matched-pairs (mean age 11.2 ± 4.2 years, female 67%, patients' disease duration 4.5 ± 3.7 years, persistent oligoarthritis 43%) were available for evaluation. Almost 36% of patients aged 3-17 years (vs. 20% of controls) achieved the WHO recommended amount of PA, while PA steadily decreased with age (18% of patients aged ≥ 12 years) and varied between JIA categories. Female adolescents and patients with enthesitis-related arthritis were least likely to achieve the minimum recommended level of PA. Physical inactivity was associated with female sex, higher age at disease onset, longer disease duration, more functional disability (C-HAQ) and higher disease activity (cJADAS-10)., Conclusions: Depending on JIA category, children and adolescents with JIA were similarly or even more likely to achieve the WHO recommended minimum level of PA compared to general population controls. However, since a large proportion of young JIA patients appear to be insufficiently physically active, engagement in targeted efforts to promote PA is urgently needed., (© 2024. The Author(s).)

Objectives: To describe the clinical phenotype and response to treatment of autoinflammatory disease (AID) patients with the TNFRSF1A-pR92Q variant compared to patients with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) due to pathogenic mutations in the same gene and patients diagnosed with other recurrent fever syndromes including periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) and syndrome of undefined recurrent fever (SURF)., Methods: Clinical data from pR92Q variant associated AID, classical TRAPS, PFAPA and SURF patients were obtained from the Eurofever registry, an international, multicentre registry enabling retrospective collection of data on AID patients., Results: In this study, 361 patients were enrolled, including 77 pR92Q variant, 72 classical TRAPS, 152 PFAPA and 60 SURF patients. pR92Q carriers had an older age of disease onset than classical TRAPS and PFAPA patients. Compared to pR92Q variant patients, classical TRAPS patients had more relatives affected and were more likely to have migratory rash and AA-amyloidosis. Despite several differences in disease characteristics and symptoms between pR92Q variant and PFAPA patients, part of the pR92Q variant patients experienced PFAPA-like symptoms. pR92Q variant and SURF patients showed a comparable clinical phenotype. No major differences were observed in response to treatment between the four patient groups. Steroids were most often prescribed and effective in the majority of patients., Conclusions: Patients with AID carrying the TNFRSF1A-pR92Q variant behave more like SURF patients and differ from patients diagnosed with classical TRAPS and PFAPA in clinical phenotype. Hence, they should no longer be diagnosed as having TRAPS and management should differ accordingly.

Objectives: Animal assisted intervention is an increasingly accepted tool to improve human well-being. The present study was performed to assess whether dog assisted education has a positive effect on children suffering from rheumatic disorders with pain and adolescents with chronic pain syndrome., Design: Two groups of juvenile patients were recruited: 7-17-year-old children in children with rheumatic diseases and adolescents with chronic pain syndromes. Overall, n=26 participated in the intervention, and n=29 in the control group., Setting: The intervention group met once a month, 12 times overall, for working with man trailing dogs in various locations., Main Outcome Measures: The influence of dog assisted education on quality of life (PedsQL TM Scoring Algorithm), pain intensity, perception, coping (Paediatric Pain Coping Inventory-Revised), and state anxiety (State Trait Anxiety Inventory) was assessed., Results: The quality of life increased significantly in the investigated period, but for both, the intervention and the control group. The state anxiety of children was lower after the dog assisted education than before. After the dog training sessions, state anxiety was 18% to 30% lower than before the intervention. Some participants noted subjectively improved pain coping and changes in pain perception, which were not found in the data., Conclusion: Our results indicate that for children with rheumatic diseases and adolescents with chronic pain syndromes dog assisted education (1) might lead to an increase of the quality of life, (2) leads to decreased state anxiety from pre to post intervention and (3) does not influence pain perception, frequency and intensity., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023 Kiesewetter et al.)

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease that primarily affects children and adolescents. CNO is associated with pain, bone swelling, deformity, and fractures. Its pathophysiology is characterized by increased inflammasome assembly and imbalanced expression of cytokines. Treatment is currently based on personal experience, case series and resulting expert recommendations. Randomized controlled trials (RCTs) have not been initiated because of the rarity of CNO, expired patent protection of some medications, and the absence of agreed outcome measures. An international group of fourteen CNO experts and two patient/parent representatives was assembled to generate consensus to inform and conduct future RCTs. The exercise delivered consensus inclusion and exclusion criteria, patent protected (excludes TNF inhibitors) treatments of immediate interest (biological DMARDs targeting IL-1 and IL-17), primary (improvement of pain; physician global assessment) and secondary endpoints (improved MRI; improved PedCNO score which includes physician and patient global scores) for future RCTs in CNO., Competing Interests: Declaration of Competing Interest In the past, CMH received research funding from Novartis for research in psoriasis (secukinumab programme, 2017–2019). In the past 5 years, CMH received speaker's honoraria from Roche, and was involved in advisory boards hosted by Novartis and Cancer Research UK (CRUK). CMH, PJF, HJG, and YZ participated in advisory boards on the use of canakinumab in inflammatory bone disease hosted by Novartis. RML is a consultant to Novartis and SOBI., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Differential diagnosis in children with prolonged fever is challenging. In particular, differentiating systemic-onset JIA (SJIA) from infectious diseases is difficult. Biomarkers are needed that support the diagnostic work-up. The aim of this study was to validate the usefulness of Myeloid-related protein 8/14 (MRP8/14) measurements in the diagnostic work-up of febrile children and to transfer it to clinical practice., Methods: Data for 1110 paediatric patients were included and divided into two cohorts: (cohort A) for validation of MRP8/14 test performance with three different testing systems: the experimental ELISA, commercial ELISA and an innovative (point-of-care test) lateral flow immunoassay (LFIA); (cohort B) to validate the diagnostic accuracy with the two latter assays., Results: In cohort A (n = 940), MRP8/14 was elevated in SJIA (12 110 ± 2650 ng/ml mean ± 95% CI) compared with other diagnoses (including infections and autoinflammatory diseases; 2980 ± 510 ng/ml) irrespective of fever and anti-inflammatory treatment (P < 0.001). In untreated patients with fever (n = 195) MRP8/14 levels in SJIA (19 740 ± 5080 ng/ml) were even higher compared with other diagnoses (4590 ± 1160 ng/ml) (P < 0.001, sensitivity 73%, specificity 90%). In group B1, the performance of the tests was confirmed in untreated patients with fever (n = 170): commercial ELISA (sensitivity 79%, specificity 89%) and LFIA (sensitivity 84%, specificity 81%). Compared with ferritin, IL-18, ESR, soluble IL-2 receptor and procalcitonin, MRP8/14 showed the best accuracy., Conclusion: MRP8/14 serum analyses have been validated as a helpful tool supporting the diagnosis of SJIA in febrile children. The results could be confirmed with commercial ELISA and LFIA enabling a rapid diagnostic point-of-care screening test., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To assess the first-year features of patients with chronic nonbacterial osteomyelitis (CNO)., Methods: Patients with a diagnosis of CNO, disease duration of under 13 months, and first registration in the German National Pediatric Rheumatologic Database (NPRD) between 2009 and 2018 were included in this cross-sectional analysis., Results: Of 774 documented patients, 62.8% were female, and all patients had a median age of 11 years. The most affected clinical sites were the tibia (29.7%), pelvis (28.0%), and femur (27.8%). HLA-B27 was positive in 48 of 314 analyzed patients (15.3%). In 406 patients, an X-ray was performed at the first visit; X-ray results showed osteosclerosis/-lysis in 34.0% and hyperostosis in 14.5% of the patients. MRI scans (focal and whole-body scans) were performed in 648 patients, and 81.5% showed a positive TIRM/STIR signal. A total of 84.7% of the patients were administered nonsteroidal anti-inflammatory drugs, 9.6% were administered oral glucocorticoids, 10.8% were administered disease-modifying anti-rheumatic drugs (DMARDs), and 6.1% were administered bisphosphonates. An evaluation of the patient's questionnaire showed an overall well-being (NRS 0-10) of 2.0. The PedCNO disease "activity" score revealed a 70% improvement in variables in 43% of patients in the initial 1-year follow-up. Copresentation with diagnostic criteria of pediatric enthesitis-related arthritis was rare., Conclusion: To our knowledge, the NPRD cohort seemed to be the largest cohort of children and adolescents suffering from CNO worldwide. Most patients were treated effectively with NSAIDs, and only a small group of patients was administered additional medication. The patient-defined measures of disease activity had a moderate impact on patients' daily lives., Trial Registration: Not applicable., (© 2021. The Author(s).)

Background: Rare autoinflammatory diseases (AIDs) including Cryopyrin-Associated Periodic Syndrome (CAPS), Tumor Necrosis Receptor-Associated Periodic Syndrome (TRAPS) and Mevalonate Kinase Deficiency Syndrome (MKD)/ Hyper-IgD Syndrome (HIDS) are genetically defined and characterized by recurrent fever episodes and inflammatory organ manifestations. Early diagnosis and early start of effective therapies control the inflammation and prevent organ damage. The PRO-KIND initiative of the German Society of Pediatric Rheumatology (GKJR) aims to harmonize the diagnosis and management of children with rheumatic diseases nationally. The task of the PRO-KIND CAPS/TRAPS/MKD/HIDS working group was to develop evidence-based, consensus diagnosis and management protocols including the first AID treat-to-target strategies., Methods: The national CAPS/TRAPS/MKD/HIDS expert working group was established, defined its aims and conducted a comprehensive literature review synthesising the recent (2013 to 2018) published evidence including all available recommendations for diagnosis and management. General and disease-specific statements were anchored in the 2015 SHARE recommendations. An iterative expert review process discussed, adapted and refined these statements. Ultimately the GKJR membership vetted the proposed consensus statements, agreement of 80% was mandatory for inclusion. The approved statements were integrated into three disease specific consensus treatment plans (CTPs). These were developed to enable the implementation of evidence-based, standardized care into clinical practice., Results: The CAPS/TRAPS/MKD/HIDS expert working group of 12 German and Austrian paediatric rheumatologists completed the evidence synthesis and modified a total of 38 statements based on the SHARE recommendation framework. In iterative reviews 36 reached the mandatory agreement threshold of 80% in the final GKJR member survey. These included 9 overarching principles and 27 disease-specific statements (7 for CAPS, 11 TRAPS, 9 MKD/HIDS). A diagnostic algorithm was established based on the synthesized evidence. Statements were integrated into diagnosis- and disease activity specific treat-to-target CTPs for CAPS, TRAPS and MKD/HIDS., Conclusions: The PRO-KIND CAPS/TRAPS/MKD/HIDS working group established the first evidence-based, actionable treat-to-target consensus treatment plans for three rare hereditary autoinflammatory diseases. These provide a path to a rapid evaluation, effective control of disease activity and tailored adjustment of therapies. Their implementation will decrease variation in care and optimize health outcomes for children with AID.

Introduction: Autoinflammatory diseases can cause irreversible tissue damage due to systemic inflammation. Recently, the Autoinflammatory Disease Damage Index (ADDI) was developed. The ADDI is the first instrument to quantify damage in familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency and tumour necrosis factor receptor-associated periodic syndrome. The aim of this study was to validate this tool for its intended use in a clinical/research setting., Methods: The ADDI was scored on paper clinical cases by at least three physicians per case, independently of each other. Face and content validity were assessed by requesting comments on the ADDI. Reliability was tested by calculating the intraclass correlation coefficient (ICC) using an 'observer-nested-within-subject' design. Construct validity was determined by correlating the ADDI score to the Physician Global Assessment (PGA) of damage and disease activity. Redundancy of individual items was determined with Cronbach's alpha., Results: The ADDI was validated on a total of 110 paper clinical cases by 37 experts in autoinflammatory diseases. This yielded an ICC of 0.84 (95% CI 0.78 to 0.89). The ADDI score correlated strongly with PGA-damage (r=0.92, 95% CI 0.88 to 0.95) and was not strongly influenced by disease activity (r=0.395, 95% CI 0.21 to 0.55). After comments from disease experts, some item definitions were refined. The interitem correlation in all different categories was lower than 0.7, indicating that there was no redundancy between individual damage items., Conclusion: The ADDI is a reliable and valid instrument to quantify damage in individual patients and can be used to compare disease outcomes in clinical studies., Competing Interests: Competing interests: Novartis Pharma financially supported meetings with the methodologist. PAB: consultancy/speaking fees from Novartis, Roche, SOBI, UCB. FdB: Novartis, Novimmune, Hoffmann-La Roche, SOBI, AbbVie. LC: speaker’s fee from Novartis and SOBI. MC: consultancy fees for Novartis, SOBI and Abbvie. KLD: consultancy work for SOBI and Novartis; donations, honorariums and unrestricted grants have been received by the Autoinflammatory Alliance from SOBI, Novartis and Regeneron. RG: consultant for Abbvie. RGM: study support from SOBI, Novartis, Regeneron. VH: honorariums and educational grants from Novartis; honorariums from SOBI. MH: consultant for Novartis. HMH: consultant for Novartis and SOBI; speaker for Novartis. TK: research grant by Novartis; speaker’s bureau by Roche, BMS, Novartis and SOBI. JKD: consultant/speaker for Novartis and SOBI, and has received grant support from SOBI and Novartis. RML: ad board and consultant for Abbvie and Novartis. PQ: investigator, consultant and speaker’s bureau for Novartis and SOBI. MG: consultant for and unrestricted grants to Eurofever and speaker’s fee from SOBI and Novartis. YU: grant/research support from Novartis; consultant for Novartis; speaker’s bureau of Abbvie, Neopharm, Novartis, Roche. JF: consultant for Novartis. GS: consulting fees for Novartis. FD: attended to Novartis advisory board meeting., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Systemic juvenile idiopathic arthritis (SJIA) is an autoinflammatory disease associated with chronic arthritis. Early diagnosis and effective therapy of SJIA is desirable, so that complications are avoided. The PRO-KIND initiative of the German Society for Pediatric Rheumatology (GKJR) aims to define consensus-based strategies to harmonize diagnostic and therapeutic approaches in Germany., Methods: We analyzed data on patients diagnosed with SJIA from 3 national registries in Germany. Subsequently, via online surveys and teleconferences among pediatric rheumatologists with a special expertise in the treatment of SJIA, we identified current diagnostic and treatment approaches in Germany. Those were harmonized via the formulation of statements and, supported by findings from a literature search. Finally, an in-person consensus conference using nominal group technique was held to further modify and consent the statements., Results: Up to 50% of patients diagnosed with SJIA in Germany do not fulfill the International League of Associations for Rheumatology (ILAR) classification criteria, mostly due to the absence of chronic arthritis. Our findings suggest that chronic arthritis is not obligatory for the diagnosis and treatment of SJIA, allowing a diagnosis of probable SJIA. Malignant, infectious and hereditary autoinflammatory diseases should be considered before rendering a diagnosis of probable SJIA. There is substantial variability in the initial treatment of SJIA. Based on registry data, most patients initially receive systemic glucocorticoids, however, increasingly substituted or accompanied by biological agents, i.e. interleukin (IL)-1 and IL-6 blockade (up to 27.2% of patients). We identified preferred initial therapies for probable and definitive SJIA, including step-up patterns and treatment targets for the short-term (resolution of fever, decrease in C-reactive protein by 50% within 7 days), the mid-term (improvement in physician global and active joint count by at least 50% or a JADAS-10 score of maximally 5.4 within 4 weeks) and the long-term (glucocorticoid-free clinically inactive disease within 6 to 12 months), and an explicit treat-to-target strategy., Conclusions: We developed consensus-based strategies regarding the diagnosis and treatment of probable or definitive SJIA in Germany.

Objective: Although chronic non-bacterial osteitis (CNO) is an ever-increasingly recognised illness in the paediatric community and the adult healthcare community, a study to assess diagnosing, treatment and the psychosocial aspect of CNO from a large population pool was not available. We aimed to investigate CNO from the patient perspective., Design: Health services research, patient survey., Setting: Ludwig-Maximilians-University (LMU) Pediatric Rheumatology Department CNO Conferences held in June 2013 and June 2015., Participants: Using a patient survey developed by the LMU Pediatric Rheumatology Department, 105 patients from ages 5 to 63 years were assessed regarding CNO to include epidemiological data, medical history and treatment, initial symptoms, diagnostic procedures, current symptoms, associated diseases, current treating physicians, absences in school and work due to illness and the impact of illness on patient, family and friends., Results: Active CNO was reported in 90% of patients present, with 73% being women and 27% being men. An overwhelming majority (70%) reported being diagnosed within 18 months of onset of symptoms; however, the initial diagnoses were wide-ranged to include malignancies in 36% to bacterial osteomyelitis in 30%, where the majority were treated with an antibiotic and/or were biopsied. When asked about the psychosocial aspect of this illness, 83% reported that non-bacterial osteitis (NBO) negatively impacted the family, 79% reported that NBO has negatively affected either school or work and 56% reported a negative impact on friendships., Conclusion: Delay of diagnosis, living with differential diagnoses like malignancies and finding specialists for medical care are a few examples of what leads patients into searching for more information. The negative impact on daily life including family relationships, friendships and work/school highlights a need for better psychosocial support such as guidance counselling or psychological support due to three-quarters of patients receiving no such said support., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: The aim was to analyse factors influencing the individual colchicine dose in children with FMF, to evaluate the impact of dose adjustment on the clinical course and inflammation and to identify clinical parameters and biomarkers that predict dose increase in the near future., Methods: Data from 409 paediatric FMF patients (4566 visits) derived from the national auto-inflammatory diseases registry were analysed. Serum concentrations of S100 molecules were determined by ELISA., Results: The age-dependent colchicine dose is influenced by the present genotype. The body surface area is the anthropometric parameter that correlates best with the applied dosages. Colchicine introduction and dose increase lead to significant reduction of clinical symptoms and inflammation. During established colchicine therapy, an increase of one single biomarker increases the likelihood of a dose increment in the next 12 months with a factor of 1.62-1.94. A combination of biomarkers including S100 molecules increases this odds ratio up to 4.66 when analysing all patients and up to 7.27 when analysing patients with a high risk of severe disease., Conclusion: Colchicine therapy is currently guided mainly by the occurrence of clinical symptoms and serological inflammation. Other factors, such as the genotype, the body surface area and biomarkers, will help to manage colchicine therapy in a more individualized fashion. The additional analysis of S100 molecules as sensitive biomarkers will help to identify patients at risk for dose increases in the near future., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objectives: To correlate clinical findings of Non-bacterial Osteitis (NBO) with whole-body MRI (WB-MRI) findings and determine a radiologic index for NBO (RINBO) which allows standardized reporting of WB-MRI., Methods and Materials: In a prospective study, 40 patients with diagnosis of NBO underwent clinical examination and WB-MRI in which STIR- and T1- weighted images were assessed for NBO-typical lesions. Parameters of interest for RINBO were: number of radiologically active lesions (RAL), size of the patients' maximum RAL presence of extramedullary and spinal involvement. Results were tested for statistical agreement of clinical and MR-based lesion detection. RINBO was tested for correlation with clinical activity., Results: 62/95 clinically/radiologically active lesions were found in 30/33 patients. In 45 % of the cohort, more active lesions were detected by WB-MRI than by clinical examination. RINBO was a significant predictor for the presence of clinically active lesions., Conclusion: WB-MRI is a powerful diagnostic tool for patients with NBO which can reveal asymptomatic disease activity. With RINBO a standardized evaluation approach is proposed which helps assessing radiologic disease burden and predicts clinical disease activity., Key Points: • Whole body MRI is a powerful diagnostic tool for patients with non-bacterial Osteitis. • Whole body MRI can reveal asymptomatic disease activity. • The radiologic index RINBO offers a standardized evaluation approach.

Background: Although bacterial osteomyelitis (BO) is a commonly recognized diagnosis in pediatrics, it is often difficult to distinguish from nonbacterial osteitis (NBO). The goal of our study was to distinguish between the 2 disease entities and better define NBO., Methods: Using the German Surveillance Unit for Rare Diseases in Childhood (Erhebungseinheit für Seltene Paediatrische Erkrankungen in Deutschland), this prospective study during a 5-year period captured 657 patients at first diagnosis of either BO (n = 378) or NBO (n = 279) while analyzing epidemiologic, clinical and radiologic data., Results: BO was reported in 1.2 per 100,000 children with a higher prevalence in younger male patients (58%), and NBO was reported in 0.45 per 100,000 children. BO patients tended to present with fevers (68%), elevated inflammation markers (82%) and local swelling (62%) but a shorter course of symptoms than NBO patients. NBO patients presented in good general health (86%) and were more likely to have multifocal lesions (66%). Staphylococcus aureus was the most prominent pathogen (83%), with only one methicillin-resistant S. aureus reported. Complications ranged from arthritis adjacent to the lesion to hyperostosis and vertebral fractures., Conclusions: BO and NBO can be distinguished based on symptoms, associated diseases and inflammation markers. NBO should always be considered in pediatric patients presenting with bone lesions and pain, especially in young female patients presenting with good general health, minimal inflammation markers and multifocal lesions in the vertebrae, clavicle and sternum.

Objectives: Autoinflammatory diseases cause systemic inflammation that can result in damage to multiple organs. A validated instrument is essential to quantify damage in individual patients and to compare disease outcomes in clinical studies. Currently, there is no such tool. Our objective was to develop a common autoinflammatory disease damage index (ADDI) for familial Mediterranean fever, cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic fever syndrome and mevalonate kinase deficiency., Methods: We developed the ADDI by consensus building. The top 40 enrollers of patients in the Eurofever Registry and 9 experts from the Americas participated in multiple rounds of online surveys to select items and definitions. Further, 22 (parents of) patients rated damage items and suggested new items. A consensus meeting was held to refine the items and definitions, which were then formally weighted in a scoring system derived using decision-making software, known as 1000minds., Results: More than 80% of the experts and patients completed the online surveys. The preliminary ADDI contains 18 items, categorised in the following eight organ systems: reproductive, renal/amyloidosis, developmental, serosal, neurological, ears, ocular and musculoskeletal damage. The categories renal/amyloidosis and neurological damage were assigned the highest number of points, serosal damage the lowest number of points. The involvement of (parents of) patients resulted in the inclusion of, for example, chronic musculoskeletal pain., Conclusions: An instrument to measure damage caused by autoinflammatory diseases is developed based on consensus building. Patients fulfilled a significant role in this process., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by elevated serum IgE, eczema, and recurrent infections. Despite the availability of confirmatory molecular diagnosis of several distinct HIES entities, the differentiation of HIES particularly from severe forms of atopic dermatitis remains a challenge. The two most common forms of HIES are caused by mutations in the genes STAT3 and DOCK8., Methods: Here, we assess the clinical and immunologic phenotype of DOCK8- and STAT3-HIES patients including the cell activation, proliferation, and cytokine release after stimulation., Results: Existing HIES scoring systems are helpful to identify HIES patients. However, those scores may fail in infants and young children due to the age-related lack of clinical symptoms. Furthermore, our long-term observations showed a striking variation of laboratory results over time in the individual patient. Reduced memory B-cell counts in concert with low specific antibody production are the most consistent findings likely contributing to the high susceptibility to bacterial and fungal infection. In DOCK8-HIES, T-cell lymphopenia and low IFN-gamma secretion after stimulation were common, likely promoting viral infections. In contrast to STAT3-HIES, DOCK8-HIES patients showed more severe inflammation with regard to allergic manifestations, elevated activation markers (HLA-DR, CD69, CD86, and CD154), and significantly increased inflammatory cytokines (IL1-beta, IL4, IL6, and IFN-gamma)., Conclusion: Differentiating HIES from other diseases such as atopic dermatitis early in life is essential for patients because treatment modalities differ. To expedite the diagnosis process, we propose here a diagnostic workflow., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: (1) To examine how many patients have clinically and/or radiologically active chronic recurrent multifocal osteomyelitis (CRMO) ≥ 10 years after first onset of symptoms, and (2) to compare clinical and whole-body magnetic resonance imaging (WB-MRI) findings., Methods: Seventeen patients (82% women) who were diagnosed with childhood-onset CRMO at least 10 years (average 12) before reexamination were reevaluated. Patients completed a standardized questionnaire, and underwent clinical and laboratory investigation and WB-MRI. Clinical features were compared with imaging findings., Results: Five patients were found to be in clinical and radiological remission. One of these patients demonstrated 1 radiologically inactive lesion on WB-MRI. Four patients showed radiologically active lesions despite full clinical remission, 2 of them in 3 vertebral bodies. Spinal involvement in 6 patients (35%) caused vertebral compression fractures, vertebra plana, or vertebral hemifusion. Eight patients presented with ongoing clinical disease activity. When applying a CRMO activity score based on clinical and imaging findings, 2 patients were identified as having pain amplification. Overall, 22/55 known CRMO lesions were identified; 11 of them were radiologically active lesions. Additionally, 14 so far unknown clinically silent lesions were detected: 8 radiologically active lesions and 6 radiologically inactive lesions., Conclusion: CRMO activity on longterm followup might have been underestimated. Our study demonstrates that clinical remission does not necessarily mean radiological remission. We therefore propose that all patients with CRMO, including patients in clinical remission, require longterm clinical followup and should undergo evaluation with WB-MRI on a regular basis until radiological remission or a steady state of disease is achieved.

Moving from child- to adult-centred services (transition) is a challenge for patients and health care professionals. Every second adolescent with a rheumatic disease will still have active disease that requires treatment when they are adults. A third of these patients do not arrive in adult-centered care, a consequence that is accompanied by negative consequences on the individual course of disease and contributes to socioeconomical costs. The present article describes the current situation: barriers for successful transfer and transition models are discussed. Transitional care and research must be improved in Germany.

Aim: To analyse the incidence, clinical presentation, laboratory and radiological findings, as well as diagnostic approaches and therapeutic procedures in paediatric patients suffering from nonbacterial osteitis., Methods: A nationwide incidence survey was conducted from 2006 to 2008 through monthly contacts with all German paediatric and paediatric-orthopaedic hospitals. Children with osteomyelitic bone lesions newly diagnosed as suffering from nonbacterial osteitis were identified. Cases were assessed using a questionnaire to be filled in by the treating physician containing information on time since first symptoms, associated diseases, diagnostic procedures, localization of lesions, complications, laboratory and histological results, and treatment., Results: Nonbacterial osteitis was newly reported in 148 children. The annual incidence was estimated at 0.4 per 100,000 children. Mean manifestation age was 11.4 years (SD 3.2); 99 children (67%) were girls. Palmoplantar pustulosis was observed in 8 (6%). Unifocal manifestations were seen in 50 (34%) patients. Of all patients with vertebral involvement (15%), 9% suffered from vertebral fractures. Bone biopsies were taken in 79 (53%) patients., Conclusions: Nonbacterial osteitis is an auto-inflammatory disorder resulting in at least 60 new paediatric cases/year in Germany. Spinal lesions and complications are frequently observed, even at first diagnosis., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.

Data on B cell depletion therapy in severe autoimmune diseases in paediatric patients are very limited. We conducted a retrospective cohort study and recruited patients who were treated with rituximab (RTX) and followed up for at least 6 months through the German societies of paediatric rheumatology and nephrology. The aim was to describe the spectrum of autoimmune disorders for which RTX was used and to describe the applied therapeutic regimens, the observed efficacy, as well as potential immunological side effects. The need to develop standard treatment guidelines for future trials should be discussed. Sixty-five patients were included. Nineteen patients suffered from systemic lupus erythematosus, 13 from vasculitic disorders, 12 from hematological autoimmune diseases, 5 from mixed connective tissue disorders, 4 from juvenile idiopathic arthritis, and 9 had other autoimmune diseases. Adverse, infusion-related events were reported in 12/65 (18%) patients. Considering laboratory and clinical parameters, 13 patients (22%) were in complete remission, 31 (52%) were in partial remission, 6 (10%) were unchanged and 10 (17%) had progressed after 6 months. In 46% of the patients, the steroid dose could be more than halved. IgG, IgM and IgA decreased from normal levels prior to RTX therapy to below normal levels at 6 months in 2/22 (9%), 10/21 (48%), and 4/22 (18%) patients, respectively. Immunoglobulin deficiency or prolonged CD20 depletion was reported in eight patients after an observation period longer than 12 months. RTX therapy led to a perceivable reduction in disease activity. However, long-term immunological alterations may occur in more than 10% of the patients. Guidelines and protocols for off-label therapy are desirable to document reasonable follow-up data. Controlled prospective studies for RTX therapies in children with standardised therapeutic and diagnostic protocols are urgently needed.

Background: Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by Staphylococcus aureus abscesses, recurrent pneumonia, increased serum IgE levels, and eczema. The association of heterozygous signal transducer and activator of transcription 3 (STAT3) mutations with autosomal dominant (AD)-HIES allows the differentiation of AD-HIES from disorders associated with eczema and increased serum IgE levels, such as other primary immunodeficiencies and atopic dermatitis., Objective: To facilitate early diagnosis of AD-HIES to initiate appropriate therapy., Methods: The clinical phenotype (suggested by a National Institutes of Health [NIH] score of >or=40 points), STAT3 genotype, and T(H)17 cell counts were compared in a cohort of 78 patients suspected of having HIES., Results: Heterozygous STAT3 missense mutations and in-frame deletions were identified in 48 patients, all but 2 with an NIH score >or=40 points. Patients with STAT3 mutations with HIES showed significantly lower T(H)17 cell counts compared with patients with wild-type STAT3 and control subjects. Only 1 patient with wild-type STAT3 had both an NIH score >or=40 points and abnormal T(H)17 cell counts (

Objective: To accurately differentiate nonbacterial osteitis (NBO) from other bone lesions by applying a clinical score through the use of validated diagnostic criteria., Methods: A retrospective study was conducted to assess data on patients from a pediatric clinic and an orthopedic tertiary care clinic, using administrative International Classification of Diseases codes as well as laboratory and department records from 1996 to 2006. Two hundred twenty-four patients older than age 3 years who had either NBO (n = 102), proven bacterial osteomyelitis (n = 22), malignant bone tumors (n = 48), or benign bone tumors (n = 52) were identified by chart review. Univariate logistic regression was used to determine associations of single risk factors with a diagnosis of NBO, and multivariable logistic regression was used to assess simultaneous risk factor associations with NBO., Results: NBO was best predicted by a normal blood cell count (odds ratio [OR] 81.5), symmetric bone lesions (OR 30.0), lesions with marginal sclerosis (OR 26.8), normal body temperature (OR 20.3) a vertebral, clavicular, or sternal location of lesions (OR 13.9), presence of >1 radiologically proven lesion (OR 10.9), and C-reactive protein level > or =1 mg/dl (OR 6.9). The clinical score for a diagnosis of NBO based on these predictors ranged from 0 to 63. A score for NBO of > or =39 had a positive predictive value of 97% and a sensitivity of 68%., Conclusion: The proposed scoring system helps to facilitate the diagnostic process in patients with suspected NBO. Use of this system might spare unnecessary invasive diagnostic and therapeutic procedures.

Background: Hyper-IgE syndrome (HIES) is a rare, autosomal-dominant immunodeficiency characterized by eczema, Staphylococcus aureus skin abscesses, pneumonia with pneumatocele formation, Candida infections, and skeletal/connective tissue abnormalities. Recently it was shown that heterozygous signal transducer and activator of transcription 3 (STAT3) mutations cause autosomal-dominant HIES., Objective: To determine the spectrum and functional consequences of heterozygous STAT3 mutations in a cohort of patients with HIES., Methods: We sequenced the STAT3 gene in 38 patients with HIES (National Institutes of Health score >40 points) from 35 families, quantified T(H)17 cells in peripheral blood, and evaluated tyrosine phosphorylation of STAT3., Results: Most STAT3 mutations in our cohort were in the DNA-binding domain (DBD; 22/35 families) or Src homology 2 (SH2) domain (10/35) and were missense mutations. We identified 2 intronic mutations resulting in exon skipping and in-frame deletions within the DBD. In addition, we identified 2 mutations located in the transactivation domain downstream of the SH2 domain: a 10-amino acid deletion and an amino acid substitution. In 1 patient, we were unable to identify a STAT3 mutation. T(H)17 cells were absent or low in the peripheral blood of all patients who were evaluated (n = 17). IL-6-induced STAT3-phosphorylation was consistently reduced in patients with SH2 domain mutations but comparable to normal controls in patients with mutations in the DBD., Conclusion: Heterozygous STAT3 mutations were identified in 34 of 35 unrelated HIES families. Patients had impaired T(H)17 cell development, and those with SH2 domain mutations had reduced STAT3 phosphorylation.