[Mentalisation in Dog-Assisted Psychotherapy for Children and Adolescents]. / Mentalisieren in der hundegestützten Psychotherapie für Kinder und Jugendliche.

The article describes how a dog can be integrated into a psychotherapeutic process. Dogs react to momentary moods and functional abilities of patients and therapists and help shape an emerging "scene" according to their assessment if they are free to express themselves and are not reduced to a function.The therapist can verbalize the patient's way of shaping the interactions and use it to promote the ability tomentalize. Central therapeutic techniques are "reflective seeing", reflection on the scene and the therapist's attitude. After the general description of the concept, the special features of therapy with children and their caregivers are presented.

Update of evidence- and consensus-based guidelines for the treatment of juvenile idiopathic arthritis (JIA) by the German Society of Pediatric and Juvenile Rheumatic Diseases (GKJR): New perspectives on interdisciplinary care.

BACKGROUND: New therapeutic strategies for juvenile idiopathic arthritis (JIA) have evolved within the past ten years, and as a result, an update of the 2011 recommendations of the German management guidelines was initiated. METHODS: A systemic literature review was performed, overarching principles were proposed and pre-selected via an online survey followed by two multidisciplinary consensus conferences. Pharmacological and non-pharmacological treatments were discussed, statements were proposed and ultimately agreed upon by nominal group technique (NGT). RESULTS: 12 overarching therapeutic principles, as well as 9 recommendations on pharmacological and 5 on non-pharmacological treatments for JIA were agreed upon. CONCLUSION: This report summarizes the recent update of the interdisciplinary, consensus-based German guidelines on the management of JIA. The multi- and interdisciplinary participation of all caregivers was central for this patient-focused update. With these guidelines, physicians can choose an evidence-based approach, which allows better tailored treatment in this vulnerable cohort of children and adolescents.

MRP8/14 serum levels as diagnostic markers for systemic juvenile idiopathic arthritis in children with prolonged fever.

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.

Age dependent ultrasound B-mode findings of the elbow joint in healthy children and adolescents.

Due to maturation of joints, various changes take place, not only in the field of paediatric rheumatology but also in paediatric orthopaedics musculoskeletal ultrasound plays an important role in both the diagnosis and the follow-up of diseases in this field. To differentiate between physiological and pathological findings, the knowledge of reference values of joint structures is indispensable. The objective was to define B-mode ultrasound age- and sex-related reference values for the elbow joint in healthy children and adolescents during maturation. In a cross-sectional, multicentre ultrasound study we examined both sides of the elbow joints of 437 healthy children and adolescents (194 boys/243 girls) being between one and less than 18 years old. The children were classified into six equal age groups and divided according to their gender. We measured the distance between the outer margin of the joint capsule and the bone surface to define the bone-capsule distance (BCD), the thickness of the joint cartilage as well as the thickness of the joint capsule. The bone-capsule junction zone and the shape of the joint capsule were analysed qualitatively. The bone capsule distance and the capsule thickness increased with age. In contrast, the joint cartilage thickness decreased. In most cases the junction zone was peaked. The joint capsule showed mostly a concave shape. Intra- and interobserver reliabilities were good. We propose B-mode ultrasound age- and sex-related reference values for the elbow joint in a large number of healthy children and adolescents for the first time. By applying these standard values to the ultrasound examination of the elbow joint, it may be possible to achieve greater certainty in the diagnosis of pathological processes.

Correction to: Age dependent ultrasound B-mode findings of the elbow joint in healthy children and adolescents.

The Second author's name was incorrectly published in the original article. The correct name is Hartwig Wilhelm Lehmann.

The multifaceted presentation of chronic recurrent multifocal osteomyelitis: a series of 486 cases from the Eurofever international registry.

OBJECTIVES: Chronic non-bacterial osteomyelitis (CNO) or chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disorder characterized by sterile bone osteolytic lesions. The aim of this study was to evaluate the demographic data and clinical, instrumental and therapeutic features at baseline in a large series of CNO/CRMO patients enrolled in the Eurofever registry. METHODS: A web-based registry collected retrospective data on patients affected by CRMO/CNO. Both paediatric and adult centres were involved. RESULTS: Complete baseline information on 486 patients was available (176 male, 310 female). The mean age of onset was 9.9 years. Adult onset (>18 years of age) was observed in 31 (6.3%) patients. The mean time from disease onset to final diagnosis was 1 year (range 0-15). MRI was performed at baseline in 426 patients (88%), revealing a mean number of 4.1 lesions. More frequent manifestations not directly related to bone involvement were myalgia (12%), mucocutaneous manifestations (5% acne, 5% palmoplantar pustulosis, 4% psoriasis, 3% papulopustular lesions, 2% urticarial rash) and gastrointestinal symptoms (8%). A total of 361 patients have been treated with NSAIDs, 112 with glucocorticoids, 61 with bisphosphonates, 58 with MTX, 47 with SSZ, 26 with anti-TNF and 4 with anakinra, with a variable response. CONCLUSION: This is the largest reported case series of CNO patients, showing that the range of associated clinical manifestations is rather heterogeneous. The study confirms that the disease usually presents with an early teenage onset, but it may also occur in adults, even in the absence of mucocutaneous manifestations.

The German 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 German language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. The participating centres were asked to collect demographic and clinical data along the JAMAR questionnaire 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's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 319 JIA patients (2.8% systemic, 36.7% oligoarticular, 23.5% RF negative polyarthritis, and 37% other categories) and 100 healthy children were enrolled in eight centres. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the German 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 in clinical research.

Discontinuation of long-term adalimumab treatment in patients with juvenile idiopathic arthritis-associated uveitis.

PURPOSE: The purpose of this study was to evaluate the discontinuation of adalimumab (ADA) treatment in patients with juvenile idiopathic arthritis-associated uveitis (JIAU). METHODS: Patients in whom ADA treatment was initiated for JIAU were included in this retrospective analysis. Reasons for discontinuing ADA treatment in patients with primary treatment response were analysed. RESULTS: Within a group of 387 JIAU patients, 59 of 68 patients who were treated with ADA achieved a sufficient response to treatment within 6 months. Here, 39 patients (66.1 %) were still on therapy at their last follow-up visit (mean treatment duration of 38.3 months, range 12-91). In another 20 patients, ADA had been discontinued after 1 or 2 years or later, in 10 % (n = 2), 45 % (n = 9) and 45 % (n = 9) of patients, respectively (mean 30.6 months; range 10-65). Reasons for discontinuing ADA were reactivation of uveitis (n = 8, 3.93 per 100 patient-years) or arthritis (n = 4; 1.97 per 100 patient-years), or ≥2 years of complete disease inactivity (n = 3, 1.47 per 100 patient-years), adverse events (n = 4; 1.89 per 100 patient-years), or other (n = 1; 0.47 per 100 patient-years). CONCLUSIONS: The data show a good primary response to ADA in patients with refractory JIAU. Due to the increasing rate of adalimumab failure or adverse events during long-term treatment, further treatment options may be required.

Arthrosonographic Reference Values of the Shoulder Joint in Healthy Children and Adolescents: A Cross-Sectional Multicentre Ultrasound Study.

Background Defining of gray scale ultrasound standard reference values of the shoulder joint in childhood and adolescence during maturation. PATIENTS: We examined 445 healthy girls and boys between 1 year and 18 years of age. Method A cross-sectional multicentre grey-scale ultrasound study was performed to examine the shoulder joint on both sides. The children were divided according to their gender and were further classified into six age groups, which constituted three-year age ranges, to record anatomical development changes. We measured the capsule-bone distance (BCD) as a representation of the intracapsular cavity, as well as the thickness of the joint capsule and joint cartilage. Values were expressed in mean±standard deviation (SD) and minimum-maximum (min-max). The shape of the joint capsule and capsule-bone junction zone was qualitatively analysed. Results The joint cartilage thickness decreased with increasing age in all joints independently from sex and body side. However, the BCD and the capsule thickness increased with age. There was no intraarticular fluid visible. The joint capsule had a predominantly concave form, whereas the capsule-bone junction was mostly sharp. Discussion This study is the first describing age-related normal values of the intracapsular cavity, joint capsule and cartilage thickness as well as their respective shape in a large cohort of healthy children. Conclusion The findings could be helpful to differentiate between physiological and pathological joint conditions and thereby distinguishing age-related variations from alterations caused by inflammation.

Age-dependent arthrosonographic reference values of the hip joint in healthy children and adolescents - a cross-sectional multicenter ultrasound study.

BACKGROUND: Musculoskeletal US is a noninvasive imaging method for diagnosing and monitoring inflammatory rheumatic diseases. OBJECTIVES: To develop age- and gender-related arthrosonographic reference intervals for the hip joint of healthy children and adolescents. MATERIALS AND METHODS: In a cross-sectional US study, we examined both hip joints of 445 children and adolescents with an age range of 1 year to 18 years. We measured the distance between the bone surface and the outer margin of the joint capsule to define the bone-capsule distance, the joint capsule and cartilage thickness, and the capsule layer thickness. Reference values were calculated. The shape of the joint capsule and bone-capsule junction zone were analyzed qualitatively. An intraobserver analysis was performed. RESULTS: Bone-capsule distance, capsule thickness and the anterior capsule layer increase with age. In contrast, joint cartilage decreases. The posterior capsule layer exhibited constant thickness across all age groups. The difference between both body sides and gender was collectively less than 0.5 mm. The intraobserver variations were within the calculated reference intervals. The insertion of the capsule to the bone was mostly a peaked one. The capsule shape had a convex or straight configuration in a neutral position and a concave position during outward rotation. The intraobserver analysis revealed good to very good concordance. CONCLUSION: We propose age- and gender-related reference intervals for the bone-capsule distance, joint capsule and cartilage thickness of the hip.

Methotrexate intolerance in oral and subcutaneous administration in patients with juvenile idiopathic arthritis: a cross-sectional, observational study.

OBJECTIVES: Methotrexate (MTX) is the cornerstone disease-modifying anti-rheumatic drug (DMARD) in juvenile idiopathic arthritis (JIA). In Dutch patients, MTX intolerance occurred frequently and was associated with subcutaneous (SC) administration. The aim of this study was to assess the prevalence of MTX intolerance and its association with the route of administration in a German cohort of JIA patients. METHODS: A cross-sectional study of JIA patients on MTX was performed. Primary outcome was MTX intolerance, which was determined using the validated Methotrexate Intolerance Severity Score (MISS) questionnaire. The prevalence of gastrointestinal adverse effects and MTX intolerance was compared between patients on MTX SC and MTX administered orally (PO). RESULTS: Of 179 JIA patients on MTX, 73 (40.8%) were intolerant. The odds of MTX intolerance were higher in patients using MTX exclusively SC compared to exclusively PO (adjusted odds ratio 3.37 [95% confidence interval 1.19-10.0]). There was strong evidence that the former experienced more behavioural complaints (76.1% vs. 47.4%, p=0.001) and weak evidence that they experienced more abdominal pain after MTX intake (43.5% vs. 27.4%, p=0.056). CONCLUSIONS: The prevalence of MTX intolerance was high and exclusively SC administration of MTX was associated with MTX intolerance and behavioural adverse effects. The prevalence of gastrointestinal adverse effects was at least as high as in patients on MTX PO. The frequently held assumption that SC causes fewer side effects than PO seems unwarranted. Definite answers about the differences between SC and PO administration with respect to safety and efficacy should be obtained by randomised trials.

Human procaspase-1 variants with decreased enzymatic activity are associated with febrile episodes and may contribute to inflammation via RIP2 and NF-κB signaling.

The proinflammatory enzyme caspase-1 plays an important role in the innate immune system and is involved in a variety of inflammatory conditions. Rare naturally occurring human variants of the caspase-1 gene (CASP1) lead to different protein expression and structure and to decreased or absent enzymatic activity. Paradoxically, a significant number of patients with such variants suffer from febrile episodes despite decreased IL-1ß production and secretion. In this study, we investigate how variant (pro)caspase-1 can possibly contribute to inflammation. In a transfection model, such variant procaspase-1 binds receptor interacting protein kinase 2 (RIP2) via Caspase activation and recruitment domain (CARD)/CARD interaction and thereby activates NF-κB, whereas wild-type procaspase-1 reduces intracellular RIP2 levels by enzymatic cleavage and release into the supernatant. We approach the protein interactions by coimmunoprecipitation and confocal microscopy and show that NF-κB activation is inhibited by anti-RIP2-short hairpin RNA and by the expression of a RIP2 CARD-only protein. In conclusion, variant procaspase-1 binds RIP2 and thereby activates NF-κB. This pathway could possibly contribute to proinflammatory signaling.

Pediatric musculoskeletal ultrasound: age- and sex-related normal B-mode findings of the knee.

Musculoskeletal ultrasound (MSUS) is an important tool for evaluating disease activity, therapeutic progress, and remission status of rheumatic diseases in children. Knowledge of age-related normal findings is essential when interpreting pathological findings such as those seen in juvenile idiopathic arthritis. To evaluate normal findings of the knee joint, we recorded age-related stages of musculoskeletal development in the knee of 435 healthy children between 1 and 18 years of age using high-resolution B-mode MSUS. We determined approximate age- and sex-related norms for the suprapatellar recess size, ossified patella size, and distal femoral intercondylar cartilage thickness. In almost all age-groups, over 64 % of children had visible fluid accumulation in the suprapatellar recess. Significant correlations were found between chronological age and the suprapatellar recess size and ossified patella length (p < 0.05). An age-dependent decrease in intercondylar cartilage thickness of the distal femoral epiphysis was found in children between 10 and 18 years of age. High-resolution B-mode MSUS is an excellent tool for assessing joint and skeletal development in children. Our reference data can be used to discriminate better between normal physiological findings and pathological abnormalities.

Naturally occurring genetic variants of human caspase-1 differ considerably in structure and the ability to activate interleukin-1ß.

Caspase-1 (Interleukin-1 Converting Enzyme, ICE) is a proinflammatory enzyme that plays pivotal roles in innate immunity and many inflammatory conditions such as periodic fever syndromes and gout. Inflammation is often mediated by enzymatic activation of interleukin (IL)-1ß and IL-18. We detected seven naturally occurring human CASP1 variants with different effects on protein structure, expression, and enzymatic activity. Most mutations destabilized the caspase-1 dimer interface as revealed by crystal structure analysis and homology modeling followed by molecular dynamics simulations. All variants demonstrated decreased or absent enzymatic and IL-1ß releasing activity in vitro, in a cell transfection model, and as low as 25% of normal ex vivo in a whole blood assay of samples taken from subjects with variant CASP1, a subset of whom suffered from unclassified autoinflammation. We conclude that decreased enzymatic activity of caspase-1 is compatible with normal life and does not prevent moderate and severe autoinflammation.

The PRINTO criteria for clinically inactive disease in juvenile dermatomyositis.

OBJECTIVES: To develop data-driven criteria for clinically inactive disease on and off therapy for juvenile dermatomyositis (JDM). METHODS: The Paediatric Rheumatology International Trials Organisation (PRINTO) database contains 275 patients with active JDM evaluated prospectively up to 24 months. Thirty-eight patients off therapy at 24 months were defined as clinically inactive and included in the reference group. These were compared with a random sample of 76 patients who had active disease at study baseline. Individual measures of muscle strength/endurance, muscle enzymes, physician's and parent's global disease activity/damage evaluations, inactive disease criteria derived from the literature and other ad hoc criteria were evaluated for sensitivity, specificity and Cohen's κ agreement. RESULTS: The individual measures that best characterised inactive disease (sensitivity and specificity >0.8 and Cohen's κ >0.8) were manual muscle testing (MMT) ≥78, physician global assessment of muscle activity=0, physician global assessment of overall disease activity (PhyGloVAS) ≤0.2, Childhood Myositis Assessment Scale (CMAS) ≥48, Disease Activity Score ≤3 and Myositis Disease Activity Assessment Visual Analogue Scale ≤0.2. The best combination of variables to classify a patient as being in a state of inactive disease on or off therapy is at least three of four of the following criteria: creatine kinase ≤150, CMAS ≥48, MMT ≥78 and PhyGloVAS ≤0.2. After 24 months, 30/31 patients (96.8%) were inactive off therapy and 69/145 (47.6%) were inactive on therapy. CONCLUSION: PRINTO established data-driven criteria with clearly evidence-based cut-off values to identify JDM patients with clinically inactive disease. These criteria can be used in clinical trials, in research and in clinical practice.

Evidence and consensus based GKJR guidelines for the treatment of juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and adolescents. Immunomodulatory drugs are used frequently in its treatment. Using the nominal group technique (NGT) and Delphi method, we created a multidisciplinary, evidence- and consensus-based treatment guideline for JIA based on a systematic literature analysis and three consensus conferences. Conferences were headed by a professional moderator and were attended by representatives who had been nominated by their scientific societies or organizations. 15 statements regarding drug therapy, symptomatic and surgical management were generated. It is recommended that initially JIA is treated with NSAID followed by local glucocorticoids and/or methotrexate if unresponsive. Complementing literature evidence with long-standing experience of caregivers allows creating guidelines that may potentially improve the quality of care for children and adolescents with JIA.

Long-term outcome of patients with JIA treated with etanercept, results of the biologic register JuMBO.

OBJECTIVE: To assess the outcome of adult patients with JIA who received etanercept (ETA) during childhood. METHODS: JuMBO (Juvenile arthritis MTX/Biologics long-term Observation) is an ongoing prospective cohort study. It follows adult JIA patients who were formerly included in the national JIA biologic register. In JuMBO, clinical status, therapy and the occurrence of adverse events are documented every 6 months by physicians; additionally, patient-derived data are included [e.g. functional capacity and health-related quality of life (HRQoL)]. Here, data from the last available visit of patients were analysed. RESULTS: Until December 2010, 346 patients with a median age of 21 years were included in JuMBO. The majority of them had polyarthritis. Seventy-eight per cent of them were still on DMARDs, 45% on ETA. The disease was inactive in about one in five patients. A restricted functional capacity was reported by 51% of participants and fatigue by 76%. The patients judged their HRQoL to be lower than a reference group from the general population, but only with regard to physical health. HRQoL correlated with the patient's perceived fatigue. Most frequently observed comorbidities in the young adults with JIA were disease related and included uveitis, IBDs and psoriasis. During the observation period, 2.1 severe infections and 1.5 new-onset autoimmune events per 100 patient-years were reported in patients on ETA, respectively. CONCLUSION: The first data from the JuMBO register indicate an improved long-term outcome of patients with severe JIA treated in the biologic era and an acceptable safety profile of ETA.

Phenotype of Innate Immune Cells in Uveitis Associated with Axial Spondyloarthritis- and Juvenile Idiopathic Arthritis-associated Uveitis.

Purpose: To analyze circulating immune cells in patients with anterior uveitis (AU) associated to axial spondyloarthritis (SpA), or juvenile idiopathic arthritis (JIA).Methods: Venous blood samples were collected from healthy controls (n = 16), and either SpA (n = 19) or JIA (n = 23) patients with associated anterior uveitis (AU) during active flare, or after ≥3 months of inactivity. Frequencies of CD56+, MHC-I+, and S100A9+ monocytes, CCR7+ dendritic cells, CD56+dim natural killer (NK) cells and CD3+CD56bright T-cells were analyzed via flow cytometry. Serum S100A8/A9 levels were determined via ELISA.Results: SpA patients showed a reduced frequency of CD56+dim NK cells during uveitis activity, a constitutively activated monocyte phenotype, and elevated S100A8/A9 serum levels. In contrast, JIAU patients showed elevated frequencies of CD56+ monocytes and CCR7+ DC.Conclusion: Phenotype of peripheral immune cells differ between patients, probably contributing to different courses of acute onset AU in SpA and insidious onset AU in JIAU patients.Abbreviations: AU: anterior uveitis, AR: arthritis, JIA: juvenile idiopathic arthritis, SpA: axial spondyloarthritis.

Similarities in clinical course and outcome between juvenile idiopathic arthritis (JIA)-associated and ANA-positive idiopathic anterior uveitis: data from a population-based nationwide study in Germany.

BACKGROUND: To analyze whether ANA-positive idiopathic anterior uveitis differs from JIA-associated uveitis concerning clinical course, response to treatment, and disease outcome. METHODS: Prospective study of the National Paediatric Rheumatological Database (NPRD) including its uveitis add-on module from the years 2002 to 2016. Cross-sectional data from the years 2002 to 2016 were analyzed. Patients with JIA-associated uveitis and with ANA-positive idiopathic anterior uveitis were included and the disease manifestation investigated in terms of uveitis characteristics and disease course. RESULTS: Of the total cohort of 34,458 patients enrolled in the NPRD, including 3551 patients with uveitis, those with detailed uveitis documentation were taken into account: 62 ANA-positive patients with idiopathic anterior uveitis (group 1), 688 patients with initial uveitis diagnosis after JIA onset (group 2), and 61 JIA patients with initial uveitis diagnosis before arthritis onset (group 3). Anterior uveitis was documented in 100%, 94%, and 80% of patients and with insidious onset of uveitis flare in 50%, 70.9%, and 56.1% each in groups 1, 2, and 3, respectively. Use of topical or systemic corticosteroids and conventional synthetic or biological DMARDs did not significantly differ between the patient groups, either at the initial or the 2-year follow-up (2-FU) visits (mean 2 years, each p > 0.05). At 2-FU, uveitis inactivity was achieved in 64.7%, 55.8%, and 61.5% of patients in groups 1, 2, and 3 (p > 0.05). Uveitis-related complications were more frequent at the initial visit and at 2-FU in groups 1 and 3, as compared to group 2. CONCLUSIONS: ANA-positive idiopathic uveitis and JIA-associated uveitis do not significantly differ concerning clinical course of uveitis, treatment, and response to corticosteroids and DMARDs.