[Advances in the diagnostics and treatment of juvenile dermatomyositis]. / Fortschritte in der Diagnostik und Therapie der juvenilen Dermatomyositis.

Juvenile dermatomyositis (JDM) is by far the most frequent inflammatory myopathy in childhood and adolescence. It is clinically characterized by inflammatory changes of the skin and muscles but as a multisystemic disease can also affect the skeletal system, the gastrointestinal tract, lungs and heart. Intrinsic (multigenetic risk) and extrinsic factors (triggers) are involved in the pathogenesis resulting in endothelial damage, involvement of fascies, activation of the interferon system and autoimmune reactions including formation of myositis-specific autoantibodies (MSA). In contrast to dermatomyositis in adults, in children and adolescents there are no associations with malignant diseases. The variable expression, the rarity of the disease and the risk of long-term damage and complications necessitate pediatric rheumatological experience in the diagnostics and treatment. Recently, new approaches in drug treatment have substantially improved the outcome and prognosis but a multidisciplinary treatment (including physicians, physiotherapists, psychologists, social workers) is mandatory, especially in the first phases of the disease. Particularly important is a professionally correct treatment of the functional sequelae, which are a particular focus of this article.

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.

Myositis-specific autoantibodies and their associated phenotypes in juvenile dermatomyositis: data from a German cohort.

OBJECTIVES: To describe a German cohort of patients with juvenile dermatomyositis (JDM) and to evaluate clinical manifestations, disease course and prognosis in JDM patients with a certain myositis-specific autoantibody. METHODS: Cross-sectional data on patients with JDM documented in the National Paediatric Rheumatologic Database in Germany between 2014 and 2016 were analysed. In a subgroup of the cohort, MSAs were determined with a commercial multiplex array, and a retrospective chart review was conducted to specify the clinical phenotype and patient outcome. RESULTS: The total cohort consisted of 196 patients with JDM (mean age 12.2±4.0 years, mean disease duration 5.1±3.8 years, 70% female). Apart from typical skin changes and muscle weakness, 41% of patients also had arthritis and/or contractures, 27% had calcinosis and approximately 10% had interstitial lung disease. Immunoblot testing was performed on the sera of 91 (46%) patients, detecting MSAs in 44% of patients. Patient groups with specific MSAs differed in clinical characteristics such as calcinosis, dysphagia, and lung and joint involvement. The extent of muscle weakness evaluated by the Childhood Myositis Assessment Scale was significantly associated with an increased level of creatine kinase. Patients with anti-MDA5 were particularly affected by polyarthritis of the small joints. After 5 years, 51 patients of the MSA cohort (56.0%) achieved an inactive disease state, 12/51 (23.5%) were off therapy. CONCLUSIONS: Patients with JDM in Germany show a broad spectrum of clinical manifestations that can be grouped into homogeneous groups using MSA, which also helps to predict the course and prognosis of the disease.

[Polyarticular juvenile idiopathic arthritis and rheumatoid arthritis : Common features and differences]. / Polyartikuläre juvenile idiopathische Arthritis und rheumatoide Arthritis : Gemeinsamkeiten und Unterschiede.

The spectrum of polyarthritic diseases in childhood as well as in adulthood is wide. In the differential diagnostics different age-related diseases must be taken into consideration. Although, a clear similarity is obvious in all age groups for the classical diseases of polyarticular juvenile idiopathic arthritis and rheumatoid arthritis with respect to the pathogenesis, clinical manifestation and treatment options, this review points to specific differences. The prognosis of polyarthritis in children mainly depends on the joint manifestation, whereas extra-articular comorbidities play a predominant role in the older adult population.

Consumer perspective on healthcare services for juvenile idiopathic arthritis: results of a multicentre JIA inception cohort study.

OBJECTIVES: To evaluate healthcare services for patients with juvenile idiopathic arthritis (JIA) from the parent-proxy perspective and to identify factors associated with perceived deficits in care. METHODS: Patients with JIA from 11 paediatric rheumatology units were enrolled in an inception cohort within the first 12 months after diagnosis. Healthcare services were assessed using The Child Healthcare Questionnaire on satisfaction, utilisation and needs. Factors associated with deficits in care were identified by logistic regression analysis. RESULTS: Data from parents of 835 JIA-patients were included in the analysis. At the assessment (4.7 months after diagnosis), 85% of the patients received drug treatment, and 50% had received multi-professional care. The most frequently used services were physiotherapy (84%), occupational therapy (23%), and telephone counselling (17%). Almost one-third of families reported that they had not received the services that they needed, with health education being the most frequently reported need. Most parents (93%) were satisfied with the overall healthcare provided for their children, especially regarding doctors' behaviour. However, approximately 1 in 3 consumers were dissatisfied with the time to JIA diagnosis and the school services. The lower the child's quality of life, the higher the chance was that the child and the family received multi-professional care, perceived unmet needs, and were dissatisfied with care. CONCLUSIONS: According to parents' experience and satisfaction with their child's care, performance at the system level can be further improved by diagnosing JIA earlier, providing additional information at disease onset, and ensuring that the child's social environment is taken into account.

[Medical pain care for children and adolescents with chronic pain in Germany : An inventory]. / Schmerzmedizinische Versorgung chronisch schmerzkranker Kinder und Jugendlicher in Deutschland : Eine Bestandsaufnahme.

Chronic pain in children and adolescents is increasing in prevalence, affects the quality of life, predisposes to pain in adulthood and causes numerous contacts to the healthcare system. In contrast, the number of therapeutic offers tailored to the special needs of this age group is insufficient and confusing. The working group on pain in children and adolescents of the German Pain Society therefore documented appropriate facilities in a questionnaire survey carried out using a snowball system. The response rate of 27/109 questionnaires was low. Thus, the results may not be entirely representative. Nevertheless, the heterogeneity of the offers and in total an undersupply became very clear. In order to improve the care situation, joint efforts by the various pediatric subdisciplines dealing with pain, an increase in the number of child pain treatment centers and a better networking are necessary.

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.

HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis.

Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 × 10(-17), odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 × 10(-5), OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 × 10(-16), OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11-HLA-DQA1*05-HLA-DQB1*03 haplotype [6.4 × 10(-17), OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.

Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA. METHODS: We performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes. RESULTS: The major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes. CONCLUSIONS: The lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways.

Countermeasures against methotrexate intolerance in juvenile idiopathic arthritis instituted by parents show no effect.

Objectives: A high proportion of children with JIA will develop intolerance to MTX with anticipatory and associative gastrointestinal adverse effects. Parents and physicians frequently try to alleviate these symptoms with a variety of countermeasures. The objective of this study was to investigate the course of MTX intolerance within a 6 month period, and the effects of countermeasures on MTX intolerance severity. Methods: We performed a prospective study of 196 consecutive JIA patients treated with MTX. Intolerance was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire. MISS and countermeasures instituted by parents or physicians were determined at four time points, each 2 months apart. Countermeasures, classified into four types (antiemetic drugs, covert dosing, taste masking and complementary medicine), were analysed using non-parametric statistics and mixed linear modelling, adjusted by propensity scoring for use of countermeasures. Results: Ninety patients (46%) showed MTX intolerance, with 58 (64%) using countermeasures at time of inclusion. Median MISS at inclusion was 11 (interquartile range = 8.0-14.25), and did not change significantly over time. No significant difference in MISS score was observed between patients receiving countermeasures and those who did not. For specific countermeasures, MISS did not change significantly after introduction. Sensitivity analysis adjusting for propensity score indicated no significant association of MISS severity on parents' decision to implement any countermeasures. Conclusion: MTX intolerance was present in many children with JIA and symptoms decreased little in the short term. Various modalities used as countermeasures against nausea by parents showed no discernible effect.

Excellent balance skills despite active and inactive juvenile idiopathic arthritis - unexpected results of a cross-sectional study.

OBJECTIVES: Postural control (PC) is fundamental for human movements. Different factors, such as injuries or diseases, can adversely affect PC. The purpose of this study was to evaluate PC in juvenile idiopathic arthritis (JIA) patients with different disease activity levels in comparison to healthy peers. METHODS: JIA patients with active and inactive lower limb joints (n=36 each group) were examined. Both groups have been on medication and have had physiotherapy for at least 5 years. For comparison, an age- and gender-matched healthy control group (CG; n=36) participated. PC was measured bipedal on a balance-board (S3-Check, TST, Großhoeflein), with an instable tilting between left and right. The parameters of interest were the best results of Stability Index (STI), Sensorimotor Index (SMI) and Symmetry Index (SYI) out of 4 test trials as well as JIA disease-related variables. Data were analysed with descriptive statistics, comparison of averages, linear regression and correlations (p<0.05). RESULTS: The three groups showed no differences in anthropometric characteristics and SYI (p>0.05). In both JIA groups, STI and SMI were lower than indices of CG (p<0.05), indicating better stability and motor control. Balance indices did not differ between active and inactive JIA patients (p>0.05). CONCLUSIONS: JIA patients showed better PC than CG. Possible explanations are an increased body-awareness due to long-term physiotherapy and daily coordination training due to compensatory movements. The positive results highlight the success of individual, interdisciplinary treatment in JIA and can be used to promote recommendations for safe sport participation.

Incidence of malignancies in patients with juvenile idiopathic arthritis: A retrospective single-center cohort study in Germany.

OBJECTIVES: In recent years, concern has been raised about Juvenile Idiopathic Arthritis (JIA) that it could be associated with an increased risk for malignancies. Therefore, the cancer incidence in the JIA patients was evaluated and compared to the cancer incidence in the German population. METHODS: A retrospective single-center hospital-based cohort study was performed using data on the JIA patients treated between 1952 and 2010 at the German Center for Pediatric and Adolescent Rheumatology (GCPAR) (Garmisch-Partenkirchen, Germany). Self-administered standardized questionnaires were sent out in 2012. Standardized incidence ratios (SIRs) and their corresponding 95% confidence intervals (95%CIs) were calculated. RESULTS: The study cohort consisted of 3691 JIA patients, and the response rate was 66%. Patients age ranged from 3 to 73 years of which 64% were female. Total follow-up time was 60,075 person-years; a history of malignancy was reported by 47 patients. Most common types of cancer were melanoma (n = 11), cervical cancer (n = 8) and breast cancer (n = 7). The overall SIR for women was 1.19 (95%CI: 0.77; 1.60) and for men was 0.67 (95%CI: 0.27; 1.07). The SIR for melanoma was 3.21 (95%CI: 1.60; 5.73) in women, whereas in men no melanoma cases were observed. CONCLUSION: Although no overall increased cancer risk was found, results suggest that the risk of melanoma might be increased in female JIA patients.

Long-term safety of etanercept and adalimumab compared to methotrexate in patients with juvenile idiopathic arthritis (JIA).

IMPORTANCE: Published evidence on the long-term safety of etanercept (ETA) and adalimumab (ADA) in patients with polyarticular juvenile idiopathic arthritis (pJIA) is still limited. OBJECTIVES: To investigate the rates of serious adverse events (SAE) and of events of special interest (ESI) under ETA and ADA treatment. DESIGN, SETTING AND PARTICIPANTS: Patients with pJIA were prospectively observed in the national JIA biological register, Biologika in der Kinderrheumatologie, and its follow-up register, Juvenile arthritis Methotrexate/Biologics long-term Observation. MAIN OUTCOMES AND MEASURES: We calculated the relative risks of SAE and ESI for ETA and ADA compared with methotrexate (MTX). RESULTS: Among the 1414 patients treated with ETA (n=1414; 4461 exposure years (EY)) and ADA (n=320; 493 EY), significantly more SAE, infections and medically important infections were observed (ETA: 4.5, 5.7, 0.9; ADA: 4.7, 11.4, 0.4 per 100 EY) compared with those treated with MTX alone (n=1455; 2.907 EY; 2.6, 5.5, 0.5 per 100 EY). The risk for malignancies was not significantly increased for ETA and ADA compared with MTX (0.09, 0.27 and 0.07/100 person-years). Patients under ETA monotherapy developed more frequently incident inflammatory bowel disease (IBD) and incident uveitis (0.5 and 0.8/100 EY) than patients treated by ETA in combination with MTX (0.1 and 0.2/100 EY) or MTX alone (0.03 and 0.1/100 EY). CONCLUSIONS AND RELEVANCE: Our data confirm the acceptable long-term tolerability of ETA and ADA in pJIA. However, whether the onset of IBD and uveitis during ETA monotherapy is a paradoxical effect or an inadequate response to therapy remains unclear and requires further investigation in this growing cohort.

Functional limitations in children and adolescents suffering from chronic pain: validation and psychometric properties of the German Functional Disability Inventory (FDI-G).

Our objective was to translate the Functional Disability Inventory (FDI) into German, to evaluate its validity and to assess functional limitation in a large cohort of children and adolescents with juvenile fibromyalgia syndrome (jFMS). We administered several questions (e.g., sociodemographics, school-related issues) and questionnaires to 329 patients and one parent. The questionnaires included, among others, a German version of the FDI, the CHAQ (parent report), KIDSCREEN, tender point score (TPS), Depression Inventory for Children and Adolescents (DIKJ) and others. Patients were asked about the severity of pain today (NRS = numerical rating scale) and other symptoms. Internal consistency was evaluated with Cronbach's alpha. Construct validity of the FDI was evaluated by correlating the FDI with the questionnaires as well as with the pain and other variables, e.g., days missed school. An exploratory factor analysis (EFA) was also performed. Mean age was 13.9 years (SD ±2.48). Means were for pain today 5.37 (±2.39) and for the TPS 39.71 (±21.56). Internal consistency was α = .90. Low-to-moderate correlations were obtained between the FDI and the CHAQ (ρ = .51**), KIDSCREEN (e.g., physical well-being ρ = -.62**; peers and social support ρ = -.28**) as well as the pain variables (NRS ρ = .24**; TPS ρ = .38**). Psychological variables were also correlated with the FDI (e.g., DIJK ρ = .28**). An EFA suggested a two-factor solution. The FDI is a valid instrument for measuring functional limitations in German children and adolescents with jFMS.

Chronic diseases in pregnant women: prevalence and birth outcomes based on the SNiP-study.

BACKGROUND: The subject of "pregnancy and disease" is of particular importance for maternal well-being and neonatal outcomes. The international literature has focused on acute diseases during pregnancy; however, there are only a few studies investigating chronic diseases in pregnant women. The focus of this study is on diseases of women in childbearing age that are not related to the pregnancy. The objective of the paper is to deliver population based prevalences of chronic dieases in childbearing women and compare the two groups of chronically ill women and healthy women in detail regarding sociodemography, peri- and prenatal parameters and birth outcomes. METHODS: Data of n = 5320 childbearing women were evaluated in the context of the population-based Survey of Neonates in Pomerania (SNiP). Data were obtained via face-to-face interviews, self-applied questionnaires, and abstraction from medical records at the time of giving birth. Sociodemographic and health status data were assessed, including chronic diseases that were taken out of medical records. A comprehensive set of pre- and perinatal varaiables were assessed. RESULTS: In the SNiP, every fifth pregnant woman suffers from at least one chronic disease, and higher prevalence rates have been reported in the literature. There was a significant difference between chronically ill women and healthy women in age, education and income. Prenatal complications were more frequent in the healthy group than in the chronic disease group. Women with chronic diseases delivered by Cesarean section more frequently than women in the healthy group. Every tenth woman with at least one chronic disease gave birth to a premature infant, while only one in every 13 woman in the healthy control group gave birth to a premature infant. CONCLUSIONS: This analysis is the first population-based study in which all chronic diseases could be taken into consideration. The population-based prevalences rates in the SNiP data are consistently lower than those found in the literature. There are differences between chronically ill women and healthy women in peri- and prenatal variables as well as birth outcome on the population level. However, they are less frequent than expected and further analyses are need focusing on specific diseases.