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Background Flares of juvenile idiopathic arthritis (JIA) have been described in the context of various infections. Flares of rheumatic diseases in adults have been described following infection with SARS-CoV-2 in several cohorts. So far, the effect of infection with SARS-CoV-2 on the course of JIA is unknown. Methods The database of the German Center for Pediatric and Adolescent Rheumatology was searched for patients with confirmed infection with SARS-CoV-2 and subsequent disease flare, admitted from July 2020 until June 2021. cJADAS-27, ESR and C-reactive protein, as well as uveitis activity, medication at the time of flare and treatment of flare was extracted. Patient cases were described individually. Results Out of 988 patients admitted, five patients with remission off medication (n = 2) or inactive disease on medication (n = 3) were identified, with flare symptoms up to four weeks after infection with SARS-CoV-2. Conclusions Flares can occur after infection with SARS-CoV-2 in patients with JIA in remission or inactive disease on medication. Treating physicians need to be aware of this fact, especially when counseling patients with rheumatic diseases about the respective dangers of COVID-19 and vaccination against SARS-CoV-2.

ZUSAMMENFASSUNGDie Therapie kindlicher rheumatischer Erkrankungen hat sich über die letzten dreißig Jahre entschieden verbessert durch die Einführung von wirksamen Medikamenten einschließlich biologischer DMARDS. Trotzdem ist die nächste Neuerung bereits in Sicht: ‚small molecules‘ in Tablettenform, die unterhalb der Ebene der Zytokin-Rezeptor-Interaktion mehrere Signalwege gleichzeitig hemmen können. In der Erwachsenenheilkunde haben diese Medikamente schon Einzug gehalten und sind inzwischen ein unverzichtbarer Bestandteil der rheumatologischen Behandlung. Für Kinder wird die Einführung des ersten Medikaments dieser Art noch in diesem Jahr erwartet. Nicht nur die in Studien gezeigte gute Wirksamkeit weckt hohe Erwartungen, auch die für Kinder nicht zu vernachlässigende Verbesserung durch die orale Gabe wird von Kinderrheumatologen dankbar angenommen werden. Weitere Verbesserungen des Wirkmechanismus dieser Medikamente haben dazu geführt, dass sich aktuell mehr als ein Dutzend Wirkstoffe in der ‚Pipeline‘ befinden; einschneidende Änderungen in der Therapie der rheumatoiden Arthritis und der juvenilen Arthritiden sind hier auf Jahre hinaus zu erwarten.

Introduction: Due to potentially severe sequelae (impaired growth, condylar resorption, and ankylosis) early diagnosis of chronic rheumatic arthritis of the temporomandibular joint (TMJ) and timely onset of therapy are essential. Aim: Owing to very limited evidence the aim of the study was to identify and discuss controversial topics in the guideline development to promote further focused research. Methods: Through a systematic literature search, 394 out of 3771 publications were included in a German interdisciplinary guideline draft. Two workgroups (1: oral and maxillofacial surgery, 2: interdisciplinary) voted on 77 recommendations/statements, in 2 independent anonymized and blinded consensus phases (Delphi process). Results: The voting results were relatively homogenous, except for a greater proportion of abstentions amongst the interdisciplinary group (p < 0.001). Eighty-four percent of recommendations/statements were approved in the first round, 89% with strong consensus. Fourteen recommendations/statements (18.2%) required a prolonged consensus phase and further discussion. Discussion: Contrast-enhanced MRI was confirmed as the method of choice for the diagnosis of TMJ arthritis. Intraarticular corticosteroid injection is to be limited to therapy-refractory cases and single injection only. In adults, alloplastic joint replacement is preferable to autologous replacement. In children/adolescents, autologous reconstruction may be performed lacking viable alternatives. Alloplastic options are currently still considered experimental.

Objective Using data from the German Biologics JIA Registry (BIKER), long-term safety of biologics for systemic-onset JIA with regard to adverse events of special interest was assessed. Methods Safety assessments were based on adverse event reports after first dose through 90 days after last dose. Rates of adverse event, serious adverse event and 25 predefined adverse events of special interest were analysed. Incidence rates were compared for each biologic against all other biologics combined applying a mixed-effect Poisson model. Results Of 260 systemic-onset JIA patients in this analysis, 151 patients received etanercept, 109 tocilizumab, 71 anakinra and 51 canakinumab. Patients with etanercept had higher clinical Juvenile Arthritis Disease Activity Score 10 scores, active joint counts and steroid use at therapy start. Serious adverse events were reported with higher frequency in patients receiving canakinumab [20/100 patient years (PY)] and tocilizumab (21/100 PY). Cytopenia and hepatic events occurred with a higher frequency with tocilizumab and canakinumab. Medically important infections were seen more often in patients with IL-6 or IL-1 inhibition. Macrophage activation syndrome occurred in all cohorts with a higher frequency in patients with canakinumab (3.2/100 PY) and tocilizumab (2.5/100 PY) vs anakinra (0.83/100 PY) and etanercept (0.5/100 PY). After adjustment only an elevated risk for infections in anakinra-treated patients remained significant. Three definite malignancies were reported in patients ever exposed to biologics. Two deaths occurred in patients treated with etanercept. Conclusion Surveillance of pharmacotherapy as provided by BIKER is an import approach especially for patients on long-term treatment. Overall, tolerance was acceptable. Differences between several biologics were noted and should be considered in daily patient care.

ZusammenfassungMuskuloskelettale Symptome der Gelenke sind ein häufiger Grund für Vorstellungen beim Kinderarzt, für die betroffenen Kinder jedoch nicht selten schwer zu beschreiben. Der untersuchende Arzt muss dann erkennen, ob die Gelenkschmerzen durch eine entzündliche oder nicht-entzündliche Erkrankung verursacht werden. Eine sorgfältige Anamnese kann wertvolle Hinweise auf die zugrundeliegende Ursache geben, die durch die körperliche Untersuchung weiter eingeengt werden kann. Insbesondere das Alter, das Schmerzmuster mit Tagesrhythmik und die Begleitsymptome sowie der Allgemeinzustand des Kindes helfen dem geübten Untersucher rasch weiter. Auch wenn das Spektrum der nicht-entzündlichen Gelenkerkrankungen weit und die Liste v. a. seltener Differenzialdiagnosen lang ist, lohnt es sich, einen Überblick über die häufigsten Ursachen zu behalten, um rasch zielgerichtete Untersuchungen zu veranlassen und überflüssige Diagnostik zu vermeiden. Wichtige Bereiche, die in die differenzialdiagnostischen Überlegungen einbezogen werden, sind v. a. maligne Erkrankungen, orthopädische Erkrankungen und chronische Schmerzstörungen. Aber auch alimentäre und andere Erkrankungen können im Kindesalter zu Gelenk- und Muskelschmerzen führen.

MTX is the medication most commonly used for antirheumatic treatment in juvenile idiopathic arthritis. It has high efficacy, is usually well tolerated and has an excellent safety profile. However, frequently intolerance symptoms develop that manifest as nausea, feelings of disgust or abdominal complaints prior to or directly after administration of the medication. No obvious toxicity is causing these intolerance symptoms, but symptoms are strictly limited to MTX and not transferred to other medications. MTX intolerance causes a significant reduction of quality of life in affected patients, frequently puts the treating physician in difficult situations regarding treatment choice, and may lead to uncomfortable decisions whether or not to stop an otherwise effective drug. Conventional countermeasures such as antiemetics, change of route from subcutaneous to oral or vice versa, or taste masking usually have only a limited effect. In this review, we present the current knowledge on MTX intolerance, its clinical picture and commonly employed strategies. We also consider newer behavioural treatment strategies that may offer a more effective symptom control.

B cell development is a highly regulated process involving multiple differentiation steps, yet many details regarding this pathway remain unknown. Sequencing of patients with B cell-restricted immunodeficiency reveals autosomal dominant mutations in TOP2B. TOP2B encodes a type II topoisomerase, an essential gene required to alleviate topological stress during DNA replication and gene transcription, with no previously known role in B cell development. We use Saccharomyces cerevisiae, and knockin and knockout murine models, to demonstrate that patient mutations in TOP2B have a dominant negative effect on enzyme function, resulting in defective proliferation, survival of B-2 cells, causing a block in B cell development, and impair humoral function in response to immunization., Topoisomerases are required to release topological stress on DNA during replication and transcription. Here, Broderick et al. report genetic variants in TOP2B that cause a syndromic B cell immunodeficiency associated with reduced TOP2B function, defects in B cell development and B cell activation.

OBJECTIVE To analyze the reported association of IL1RN polymorphisms with response to interleukin-1 (IL-1) blockade in a German cohort of patients with systemic juvenile idiopathic arthritis (JIA), and to assess the impact of other factors on treatment response. METHODS Sixty-one patients with systemic JIA who had received IL-1 blockade were identified within the German Autoinflammatory Disease registry DNA biobank. Response to IL-1 blockade was assessed according to 1) the clinical response (initially at least a transient response or good response compared to a poor response), 2) switch (or no switch) to anti-IL-6 receptor therapy following IL-1 blockade, 3) achievement of clinically inactive disease within 6 months of IL-1 blockade, 4) improvement in disease activity measured using the modified Juvenile Arthritis Disease Activity Score, and 5) achievement of a glucocorticoid-free state. In addition, basic demographic data, key features of the disease course, laboratory data, and IL1RN single-nucleotide polymorphisms (SNPs) were assessed. RESULTS Six of 7 IL1RN SNPs reported to be associated with response to anakinra therapy were analyzed. These 6 IL1RN SNPs were inherited as haplotypes. An association of IL1RN haplotypes and SNPs with response to IL-1 blockade could not be confirmed in this cohort of patients with systemic JIA. Patients who received tocilizumab following IL-1 blockade had a longer duration from disease onset to diagnosis than those who did not receive tocilizumab (median 0.27 years versus 0.08 years). CONCLUSION The results of this study could not confirm an impact of IL1RN SNPs on response to IL-1 blockade therapy with either anakinra or canakinumab in a cohort of patients with systemic JIA. However, a longer time frame from disease onset to diagnosis was associated with poorer long-term treatment response, thereby supporting the "window of opportunity" hypothesis that suggests improved long-term treatment response with shorter time from disease onset to diagnosis (and treatment).

Acid Ceramidase Deficiency (Farber disease, FD) is an ultra-rare Lysosomal Storage Disorder that is poorly understood and often misdiagnosed as Juvenile Idiopathic Arthritis (JIA). Hallmarks of FD are accumulation of ceramides, widespread macrophage infiltration, splenomegaly, and lymphocytosis. The cytokines involved in this abnormal hematopoietic state are unknown. There are dozens of ceramide species and derivatives, but the specific ones that accumulate in FD have not been investigated. We used a multiplex assay to analyze cytokines and mass spectrometry to analyze ceramides in plasma from patients and mice with FD, controls, Farber patients treated by hematopoietic stem cell transplantation (HSCT), JIA patients, and patients with Gaucher disease. KC, MIP-1 alpha, and MCP-1 were sequentially upregulated in plasma from FD mice. MCP-1, IL-10, IL-6, IL-12, and VEGF levels were elevated in plasma from Farber patients but not in control or JIA patients. C16-Ceramide (C16-Cer) and dhC16-Cer were upregulated in plasma from FD mice. a-OH-C18-Cer, dhC12-Cer, dhC24:1-Cer, and C22:1-Cer-1P accumulated in plasma from patients with FD. Most cytokines and only a-OH-C18-Cer returned to baseline levels in HSCT-treated Farber patients. Sphingosines were not altered. Chitotriosidase activity was also relatively low. A unique cytokine and ceramide profile was seen in the plasma of Farber patients that was not observed in plasma from HSCT-treated Farber patients, JIA patients, or Gaucher patients. The cytokine profile can potentially be used to prevent misdiagnosis of Farber as JIA and to monitor the response to treatment. Further understanding of why these signaling molecules and lipids are elevated can lead to better understanding of the etiology and pathophysiology of FD and inform development of future treatments. (C) 2016 Elsevier B.V. All rights reserved.

Morbus Farber ist eine Erkrankung des Sphingolipid-Metabolismus, der seine Ursache in einem Mangel des lysosomalen Enzyms saure Ceramidase hat, woraus eine Unfahigkeit der Zellen entsteht, Ceramide zu zerlegen. Die Erkrankung tritt als Folge der Vererbung von Mutationen auf beiden Allelen des ASAH1-Gens auf, und zeigt sich hauptsachlich mit einem fur lysosomale Speichererkrankungen untypischen, entzundlichen Phanotyp. Betroffen sind Gelenke und Bindegewebe. Eine typische Fazies, Dysostose oder wesentliche Organomegalie fehlen. Dies begrundet sich in der Tatsache, dass Ceramid ein pro-inflammatorisches und pro-apoptotisches Sphingolipid ist. Diese Eigenschaften sind offensichtlich hauptsachlich verantwortlich fur das klinische Erscheinungsbild der Erkrankung, d. h.: Gelenkbeteiligung in Form von Kontrakturen und/oder Arthritis, subkutane Noduli und eine laryngeale Mitbeteiligung in Form einer heiseren oder schwachen Stimme. In den letzten Jahren hat sich jedoch gezeigt, dass Manifestation, Phanotyp und Verlauf des M. Farber eine starke Variabilitat aufweisen: von Tod innerhalb weniger Monate nach der Geburt bis zu einem abgeschwachten Verlauf mit Diagnosestellung im jungen Erwachsenenalter. Es ist bemerkenswert, dass manche Patienten mit Morbus Farber auf eine Behandlung mit anti-entzundlichen Medikamenten – insbesondere mit Biologika – gegen TNF-alpha oder Interleukin-6-Rezeptoren, mit einer Schmerzreduktion und einer Verbesserung der Schwere der Arthritis reagiert haben. Es ist daher angebracht, einen Test auf Morbus Farber bei Patienten in Betracht zu ziehen, deren Arthritis nicht adaquat auf eine Behandlung anspricht.

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.

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.

Juvenile idiopathic arthritis is the most frequent chronic rheumatic disease in childhood. Synthetic disease modifying drugs (DMARDs) have been used in its treatment since the 1980s and have led to substantial improvement of quality of life and disease outcome. Recent pharmacological research has focused on newer medications, especially biologic agents.Synthetic DMARDS, especially methotrexate, rightfully remain the first-line treatment of most categories of juvenile arthritis, as attested by several international guidelines. A substantial body of evidence supports these medications, and recent research tries to clarify their optimal use in the clinical setting, both as monotherapy and in combination with biologics. In addition, new forms of synthetic DMARDs are in the research pipeline, or are already used for rheumatoid arthritis.Methotrexate remains the preferred first-line medication for polyarticular arthritis, with leflunomide as a viable alternative in case of intolerance or toxicity, despite lack of approval in Europe and the US. Sulfasalazine and hydroxychloroquine are used only rarely in clinical practice, considered in combination with methotrexate if biologics are not available. New synthetic DMARDS are in the research pipeline for JIA, in the form of small molecules.

Background Systemic juvenile idiopathic arthritis (sJIA) is a complex disease with an autoinflammatory component of unknown etiology related to the innate immune system. A major role in the pathogenesis has been ascribed to proinflammatory cytokines like interleukin-6 (IL-6), and effective drugs inhibiting their signaling are being developed. This study evaluates sJIA patients treated with the IL-6 inhibitor tocilizumab (TCZ) concerning clinical response rate, disease course and adverse effects in a real-life clinical setting. Methods In 2009 a clinical and research consortium was established, including an online registry for autoinflammatory diseases (AID) (https://aid-register.de). Data for this retrospective TCZ study were documented by 13 centers. Results From 7/2009 to 4/2014, 200 patients with sJIA were recorded in the AID-registry. Out of these, 46 (19 m, 27 f, age 1–18 years) received therapy with TCZ. Long term treatment (median 23 months) has been documented in 24/46 patients who were evaluated according to Wallace criteria (active disease 6/24, inactive disease 5/24, remission 13/24 cases). Under observation co-medication were used in 40/46 cases. Adverse events were reported in 11/46 patients. The clinical response rate (no clinical manifestation, no increased inflammation parameters) within the first 12 weeks of treatment was calculated to be 35%. Conclusion Out of 200 sJIA children reported in the German AID-registry, 46 were treated with TCZ, showing a clinical response rate of 35% during the first 12 weeks, and inactive disease and/or remission under medication in 75% after one year. Adverse events were seen in 24% and severe adverse events in 4%. Trial registration The AID-Registry is funded by the BMBF (01GM08104, 01GM1112D, 01GM1512D).

Objective.To describe characteristics of patients with juvenile idiopathic arthritis (JIA) presenting with isolated arthritis of the temporomandibular joints (TMJ).Methods.Patients with JIA with isolated TMJ arthritis from 4 large tertiary pediatric rheumatology centers were included. Demographic and clinical data were analyzed using descriptive statistics.Results.Fifty-five patients were identified (65% bilateral presentation). Six patients developed arthritis in other joints (median time 6 mos); 4 patients developed uveitis, all prior to arthritis. At last followup, 9% were still taking antirheumatic medications.Conclusion.JIA TMJ arthritis can occur in isolation, and is probably underdiagnosed. Care providers including dentists and orthodontists should be aware of this presentation.

Background: Inflammatory bowel disease can develop with some rheumatic diseases in childhood, including juvenile idiopathic arthritis (JIA). Systemic onset JIA has not been connected to inflammatory bowel disease (IBD), but might be connected especially in the context of new treatments. Methods: [for full text, please go to the a.m. URL], 44. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 30. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 26. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

Cryopyrin-associated periodic syndrome (CAPS) is a rare, heterogeneous disease entity associated with NLRP3 gene mutations and increased interleukin-1 (IL-1) secretion. Early diagnosis and rapid initiation of IL-1 inhibition prevent organ damage. The aim of the study was to develop and validate diagnostic criteria for CAPS. An innovative process was followed including interdisciplinary team building, item generation: review of CAPS registries, systematic literature review, expert surveys, consensus conferences for item refinement, item reduction and weighting using 1000Minds decision software. Resulting CAPS criteria were tested in large cohorts of CAPS cases and controls using correspondence analysis. Diagnostic models were explored using sensitivity analyses. The international team included 16 experts. Systematic literature and registry review identified 33 CAPS-typical items; the consensus conferences reduced these to 14. 1000Minds exercises ranked variables based on importance for the diagnosis. Correspondence analysis determined variables consistently associated with the diagnosis of CAPS using 284 cases and 837 controls. Seven variables were significantly associated with CAPS (pNLRP3 mutation. The novel approach integrated traditional methods of evidence synthesis with expert consensus, web-based decision tools and innovative statistical methods and may serve as model for other rare diseases. These criteria will enable a rapid diagnosis for children and adults with CAPS.

Background Methotrexate (MTX) intolerance is a frequent problem of long-term treatment in juvenile idiopathic arthritis (JIA). Mutations in the methylentetrahydrofolate reductase (MTHFR) gene may increase toxicity of MTX, potentially constituting an initial stimulus for this conditioned response. The objective of this study was to investigate the relationship of common MTHFR gene mutations and occurrence of MTX intolerance in pediatric patients with JIA treated with MTX. Methods Consecutive JIA patients on at least 3 months of MTX treatment were included in this study. Intolerance to MTX was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire, and MTX intolerance was defined as MISS values of ≥ 6. Presence of the two most common mutations in the MTHFR gene (C677T and A1298C) was tested using a PCR assay. Results were analyzed using descriptive and non-parametric statistics. Results 196 patients were included (73 % female). Of those, 93 (46 %) showed MTX intolerance. 168 patients were genotyped for C677T and A1298C. MTX intolerance was not found to be significantly more frequent among patients with hetero- and homozygous or homozygous mutations C677T or A1298C compared to wild type or heterozygous mutations. Analysis of the correlation between numbers of mutations in these two loci to the MISS score did not yield a statistically significant correlation. Conclusion Mutations in the MTHFR gene were not found to be significantly more frequent in JIA patients intolerant to MTX. Toxicity associated with the MTHFR gene seems to result from mechanisms different to those involved in clinical MTX intolerance. Electronic supplementary material The online version of this article (doi:10.1186/s12969-016-0071-y) contains supplementary material, which is available to authorized users.

ZusammenfassungIm Zeitraum von 1981–2001 wurden an der Universitätskinderklinik Leipzig 177 Patienten mit invasiven Meningokokken-Infektionen behandelt. Die Anzahl der stationären Aufnahmen von Kindern mit diesem schweren Krankheitsbild nahm in diesem Zeitraum stark ab. Die meisten invasiven Meningokokken-Infektionen traten im 1. und 4. Quartal auf. Es erkrankten überwiegend Säuglinge und Kleinkinder. In dieser Altersgrupppe fand sich eine leichte Knabenwendigkeit. Die Letalität lag relativ konstant bei knapp 10%, am häufigsten bedingt durch ein Waterhouse-Friderichsen-Syndrom. Die Liegedauer der Patienten in der Klinik nahm von 1981–2001 kontinuierlich ab. Bis 1990 wurde der Großteil der Patienten in der Familie bzw. in einer Kinderkrippe betreut, nach 1990 nahm der Anteil der Kinder, die den Kindergarten bzw. die Schule besuchten, zu.

Background Several medications for treatment of Juvenile Idiopathic Arthritis (JIA) are considered to be carcinogenic. Therefore, the aim was to assess whether there is an association between therapeutic interventions and malignancies in JIA patients. Findings A nested case–control study was carried out within a retrospective cohort study of 3698 JIA patients diagnosed between 1952 and 2010. All 48 JIA patients with a diagnosis of a malignant tumour and up to four matched controls for each received a questionnaire about their use of medication. Subsequently treatment was compared between cases and controls and analyses performed for 37 cases and 125 controls (response 88.5 %). Treatment with DMARD (84 %) was most frequently used, followed by glucocorticoids (66 %) and immunosuppressives (65 %). Twenty percent reported to have ever been taking biologics. Medication use did not differ significantly between cases and controls. Conclusions Our results did not show an association between medications used and malignancies in JIA patients. Electronic supplementary material The online version of this article (doi:10.1186/s12969-016-0066-8) contains supplementary material, which is available to authorized users.

Chronic anterior uveitis is a serious complication of juvenile idiopathic arthritis (JIA); disease flares are highly associated with loss of vision. Leflunomide (LEF) is used successfully for JIA joint disease but its effectiveness in uveitis has not been determined. The aim of this study was to determine whether LEF improves flare rates of uveitis in JIA patients compared to preceding methotrexate (MTX) therapy.A single-centre retrospective study of consecutive children with JIA and chronic anterior uveitis was performed. All children initially received MTX and were then switched to LEF. Demographic, clinical, and laboratory data, dose and duration of MTX and LEF therapy, concomitant medications and rate of anterior uveitis flares, as determined by an expert ophthalmologist, were obtained. Flare rates were compared using a generalized linear mixed model with a negative binomial distribution.A total of 15 children were included (80% females, all antinuclear antibody positive). The median duration of MTX therapy was 51 (range 26-167) months; LEF was given for a median of 12 (range 4-47) months. Anti-tumour necrosis factor (anti-TNF-α) co-medication was given to four children while on MTX. By contrast, LEF was combined with anti-TNF-α treatment in six children. On MTX, JIA patients showed a uveitis flare rate of 0.0247 flares/month, while LEF treatment was associated with a significantly higher flare rate of 0.0607 flares/month (p = 0.008).Children with JIA had significantly more uveitis flares on LEF compared to MTX despite receiving anti-TNF-α co-medication more frequently. Therefore, LEF may need to be considered less effective in controlling chronic anterior uveitis.

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.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).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).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.

X-linked lymphoproliferative disease is a rare T and NK cell immune deficiency which most frequently presents as fulminant infectious mononucleosis following infection with the Epstein-Barr virus (EBV). We report the case of a 4-year-old boy from a Spanish family presenting with severe infectious mononucleosis. In the course of the disease he developed hepatic failure, pancytopenia and neurologic impairment, leading to death after less than 2 months. The results of bone marrow biopsy and autopsy indicated a histological diagnosis of both high-grade B-cell lymphoma and virus-associated haemophagocytic syndrome, thereby confirming the simultaneous presence of two different manifestations of X-linked lymphoproliferative disease (XLP) in this patient. The family history revealed four close male relatives dying under similar circumstances, one of whom died following a vaccination against measles. Molecular genetic studies identified a novel mutation in the SH2D1A gene in several members of the family, establishing the diagnosis of XLP. Fatal EBV infection in male infants is highly indicative of XLP. Virus-associated haemophagocytic syndrome and B-cell lymphoma can occur concomitantly and may be difficult to distinguish due to their similar histological pictures.

ZusammenfassungIm Sommer 2004 hat die Ständige Impfkommission (STIKO) am Robert-Koch-Institut eine Empfehlung für die Standardimpfung gegen Varizellen ausgesprochen. Diese Entscheidung hat die Impfdebatte in Deutschland erneut angeheizt, insbesondere aufgrund der nur geringen Bereitschaft der Krankenkassen, die Kosten für die Impfung uneingeschränkt zu übernehmen. Der impfende Kinderarzt steht nun vor dem Problem, den Eltern eine Impfung gegen eine als „harmlos” angesehene Kinderkrankheit nahe zu bringen. Die folgende übersicht soll grundlegende Informationen über das Krankheitsbild und seine Komplikationen sowie über den Impfstoff und seine Anwendung auch in komplexeren Fällen vermitteln.

ZusammenfassungRotaviren sind die häufigste Ursache für Durchfallerkrankungen im Kleinkindesalter. Während in unseren Regionen die Behandlung sich vergleichsweise einfach darstellt, sind Rotavirus-Enteritiden in den Ländern der dritten Welt ein wesentlich ernsteres Problem: Eines von 293 Kindern weltweit stirbt vor dem 5. Lebensjahr an den Folgen einer Rotaviruserkrankung. Jedes Jahr verursacht dieses Virus über 110 Millionen Erkrankungsfälle. Diese enormen Zahlen haben zu einer verstärkten Suche nach einem entsprechenden Impfstoff geführt. Nachdem in den USA Ende der letzten Dekade ein Impfstoff wegen schwerer Nebenwirkungen nach seiner Einführung rasch vom Markt genommen wurde, werden jetzt bald zwei verträgliche Impfstoffe zur Verfügung stehen. Damit besteht die Hoffnung, nicht nur ein schlagkräftiges Mittel gegen die Kindersterblichkeit in den Entwicklungsländern gefunden zu haben, sondern auch bei uns die wirtschaftlichen und sozialen Folgen der jährlichen Rotavirus-Epidemien deutlich reduzieren zu können.

Die akute infektiose Mononukleose ist die typische klinische Manifestation der Primarinfektion mit dem Epstein-Barr-Virus (EBV) bei immunkompetenten alteren Kindern und Adoleszenten. Bei kleineren Kindern kann die Symptomatik milder ausfallen oder ganz fehlen. Komplikationen konnen alle Organsysteme betreffen. Die Prognose ist in den meisten Fallen sehr gut. Bei stark eingeschrankter zellularer Immunitat (z.B. immunsuppressive Therapie, Immundefekte) konnen sowohl nach einer EBV-Primarinfektion als auch im Rahmen einer Reaktivierung B-Zell-lymphoproliferative Krankheitsbilder und maligne Lymphome auftreten. Weiterhin konnen folgende atypische Krankheitsbilder im Rahmen von EBV-Infektionen vorkommen: Die fulminante, meist fatal verlaufende akute infektiose Mononukleose tritt 1. in sporadischer Form (ca. 1 auf 3000 aller Falle einer akuten infektiosen Mononukleose), 2. bei ca. 60% aller Jungen mit X-chromosomaler lymphoproliferativer Erkrankung (XLP) und 3. in seltenen Fallen auch im Rahmen eines foudroyanten EBV+-T-Zell-lymphoproliferativen Krankheitsbildes auf. Eine suffiziente Therapie gibt es noch nicht. Bei Knaben mit XLP kann eine fruhzeitige allogene Stammzelltransplantation zur kompletten Immunrekonstitution und somit Schutz vor o.g. Komplikation fuhren. Die chronisch-aktive EBV (CAEBV)-Infektion, die uberwiegend im asiatischen Raum beobachtet wird, ist durch eine rezidivierende Mononukleosesymptomatik uber viele Monate bzw. Jahre, durch das zusatzliche Auftreten von ungewohnlichen Komplikationen wie z.B. Koronaraneurysmen, Uberempfindlichkeit gegenuber Moskitostichen und einer Hydroa vacciniforme sowie durch ein stark erhohtes Lymphomrisiko charakterisiert. Die Prognose ist meist schlecht. Eine etablierte Therapie existiert nicht. Eine allogene Stammzelltransplantation fuhrte in Einzelfallen zu einer klinischen Remission. Das EBV-assoziierte Hamophagozytosesyndrom kommt als eigenstandiges Krankhheitsbild (Epstein-Barr-Virus-assoziierte hamophagozytische Lymphohistiozytose [EBV-HLH]) und als Komplikation bei der fulminanten akuten Mononukleose sowie der CAEBV-Infektion vor. Der fruhzeitige Einsatz von Etoposid, Ciclosporin A und Kortikosteroiden kann die ansonsten meist schlechte Prognose verbessern. Die Pathogenese der atypischen EBV-Infektionen ist noch weitgehend unbekannt. Eine weitere molekulare und immunologische Abklarung und Charakterisierung der einzelnen Krankheitsbilder wird moglicherweise helfen, spezifischere und effizientere Therapiestrategien zu entwickeln.

Pain and impaired function in the shoulder can result from a variety of conditions. Dysplasias of the shoulder girdle are usually asymptomatic; previous literature reports on shoulder malformation have focused on glenoid dysplasia or complete agenesis of the clavicle. We report the case of an 11 year old patient with severe shoulder pain after strenuous physical exercise. Physical inspection showed a prominent clavicle and anteriorly displaced humerus. X-ray demonstrated an abnormally shortened clavicle and a hypoplastic acromion; MRI imaging revealed an elongated deltoid muscle leading over the humeral head. The patient recovered with analgesics and careful mobilization. This is the first reported case of a dysplasia of both the acromion and the clavicle. This developmental abnormality can lead to significant pain, but apparently responds well to conservative treatment. It is possible that this condition is underdiagnosed or represents significantly delayed development.

ZusammenfassungEs wird von einen 17-jährigen Patienten mit chronischer Hepatitis C berichtet, der erfolgreich “off-label“ mit pegyliertem Interferon alfa-2a in Kombination mit Ribavirin behandelt wurde. Anhand der guten Resultate ist diese Kombinationstherapie mittlerweile empfohlener Standard bei Erwachsenen mit chronischer Hepatitis C. Es ist davon auszugehen, dass dieses Therapieschema in den nächsten Jahren auch für das Kindes- und Jugendalter als “Leitlinie“ übernommen wird. In Vergleichsstudien muss noch geklärt werden, ob pegyliertes Interferon alfa-2a im Vergleich zu pegyliertem Interferon alfa-2b therapeutische Vorteile bietet.

ZusammenfassungOsteopoikilose ist eine autosomal-dominant vererbte Skelettdysplasie, bei der sich radiologisch symmetrisch angeordnete fleckige Hyperostosen zeigen. Die Diagnose wird in aller Regel als Zufallsbefund gestellt, da die meisten Fälle symptomlos verlaufen.Wir berichten von einem 17 Jahre alten Jugendlichen, der sich wegen zunehmenden Gelenkschmerzen in beiden Knien und im rechten Handgelenk vorstellte. Die Symptomatik trat v. a. bei Belastung, bei schnellen Bewegungen und in Extremstellung auf. Es fand sich eine aktive Beugeund Streckhemmung beidseits. Schwellungen und Rötungen sowie andere Hauterscheinungen wurden verneint. Laborchemisch fand sich kein Anhalt für das Vorliegen einer rheumatischen/entzündlichen Erkrankung.Im Röntgenbild der rechten Hand und des rechten Knies zeigten sich multiple feinfleckige Verdichtungszonen. Molekulargenetisch wurde eine Mutation im LEMD3-Gen nachgewiesen und damit die Diagnose Osteopoikilose gesichert. Der Patient wurde mit nichtsteroidalen Antiphlogistika behandelt. Bei Nachkontrolle nach 6 Monaten berichtete der Patient über weiter bestehende mäßige Schmerzen und gelegentliche Gelenksteife.Die Osteopoikilose ist eine seltene, aber wichtige Differenzialdiagnose bei chronischen Gelenkschmerzen.

Studies of paediatric patients with membranous lupus nephritis (MLN) have yielded variable results, mostly due to the inclusion of mixed, i.e. proliferative nephritis. The aim of this study was to describe clinical and laboratory findings at the diagnosis of paediatric non-proliferative MLN, report the outcome and identify predictors of remission.A single-center cohort study of consecutive children diagnosed with non-proliferative MLN was performed. Clinical and laboratory measures and treatment regimens were obtained in prospective standardized assessments. Renal outcome was measured by renal parameters and steroid requirement. Predictors for remission and time to remission were determined.A total of 30 children were identified with a median follow-up time 4.1 years. Of 21 patients followed for more than 2 years, 19 (90 %) achieved clinical remission, and 16 (76 %) achieved a state of maintained clinical remission on low-dose prednisone. Three patients developed proliferative nephritis on subsequent renal biopsy. Lower albumin at the time of biopsy was correlated with a lower rate of remission and longer time to remission.Among our paediatric patient cohort the outcome of non-proliferative MLN in systemic lupus erythematosus was good. The majority of patients did not require aggressive immunosuppressive treatment to reach a stable disease state on low-dose steroid treatment.

Chronic anterior uveitis is a common complication of juvenile idiopathic arthritis (JIA). Leflunomide is a frequently used alternative to methotrexate in the treatment of joint manifestations of JIA. However, very little is known on the effect of leflunomide treatment on concurrent chronic uveitis in JIA.

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.