Publications by authors named "Johannes-Peter Haas"

54 Publications

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

Clin Exp Rheumatol 2020 Oct 29. Epub 2020 Oct 29.

German Rheumatism Research Center, Leibniz Institute, Berlin, Germany.

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.
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October 2020

[Medical pain care for children and adolescents with chronic pain in Germany : An inventory].

Schmerz 2020 Oct 28. Epub 2020 Oct 28.

Klinik für Kinder- und Jugendmedizin, St. Vincenz-Krankenhaus, Husener Str. 81, 33098, Paderborn, Deutschland.

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.
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http://dx.doi.org/10.1007/s00482-020-00510-9DOI Listing
October 2020

Salivary gland ultrasound in the diagnostic workup of juvenile Sjögren's syndrome and mixed connective tissue disease.

Pediatr Rheumatol Online J 2020 Jun 9;18(1):44. Epub 2020 Jun 9.

German Center for Pediatric and Adolescent Rheumatology (GCPAR), Gehfeldstr. 24, D-82467, Garmisch-Partenkirchen, Germany.

Background: Juvenile Sjögren's Syndrome (jSS) is a rare phenomenon that may appear as primary jSS or associated with mixed connective tissue disease (MCTD) and other autoimmune diseases as secondary jSS. With currently no standard diagnostic procedures available, jSS in MCTD seems to be underdiagnosed. We intended to describe and identify similar distinct salivary gland ultrasound (SGUS) findings in a cohort of primary and secondary jSS patients, focusing on sicca like symptoms and glandular pain/swelling in the patients'history.

Methods: We present a single-center study with chart data collection. B-mode examinations of salivary glands were obtained with a linear high-frequency transducer and evaluated using the scoring-system of Hocevar. Inclusion criteria were: (i) primary or secondary jSS and/or (ii) diagnosis of MCTD and additionally (iii) any presence of sicca like symptoms or glandular pain/swelling.

Results: Twenty five patients with primary (pjSS) and secondary jSS (sjSS) were included in the study (n = 25, 21 female, 4 male), with a median age of 15.3 years at the time of first visit and a mean disease duration of 4.9 years. Pathologic SGUS findings were observed in 24 of 25 patients, with inhomogeneous parenchymal appearances with hypoechoic lesions present in 96% of patients. At least one submandibular gland was affected in 88.5% of the whole group, and all patients in the MCTD-group. Twenty of twenty five patients were scanned and scored on a second visit. Pre-malignancies or mucosa-associated lymphoid tissue (MALT) were detected in biopsies of three patients (Hocevar scoring of 40, 33, and 28).

Conclusion: SGUS in patients with pjSS and sjSS is a helpful first-line tool to detect and score salivary gland involvement, in particular when keratoconjunctivitis sicca, xerostomia, or glandular swelling occurs. Juvenile MCTD patients have a significant risk of developing secondary jSS. We propose SGUS as a method in the diagnostic workup and screening for inflammatory changes. Further studies have to determine the predictive value of SGUS for follow up.
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http://dx.doi.org/10.1186/s12969-020-00437-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285617PMC
June 2020

Increased Prevalence of Q703K Variant Among Patients With Autoinflammatory Diseases: An International Multicentric Study.

Front Immunol 2020 14;11:877. Epub 2020 May 14.

Pediatric Rheumatology Unit of Western Switzerland, Pediatric Department, Lausanne University Hospital (CHUV), Lausanne, Switzerland.

The inflammasome has been recognized as one of the key components of innate immunity. Gain-of-function mutations in the exon 3 of gene have been implicated in inflammatory diseases suggesting the presence of functionally important sites in this region. Q703K (c.2107C>A, p.Gln703Lys, also known in the literature as Q705K) is a common variant of , that has been considered to be both clinically unremarkable or disease-causing with a reduced penetrance. We aimed to investigate the potential genetic impact of the variant Q703K in patients with recurrent fever presenting with two autoinflammatory diseases: PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) and CAPS (cryopyrin-associated periodic syndrome), as well as with undefined autoinflammatory disease (uAID). This is an international multicentric observational retrospective study characterizing the clinical phenotype of patients presenting with recurrent fever suspected to be of auto-inflammatory origin and where the Q703K variant was found. Monocytes of parents of 6 Q703K+ PFAPA patients were studied and levels of pro-inflammatory cytokines produced by monocytes of Q703K+ and Q703K- parents have been compared by ELISA. We report 42 patients with the Q703K genetic variant: 21 were PFAPA patients, 6 had a CAPS phenotype, and 15 had an uAID. The phenotypes of PFAPA, CAPS and uAID were quite similar between Q703K positive and negative patients with the exception of increased prevalence of pharyngitis in the Q703K positive CAPS population compared to the negative one. The production of IL-1β was not significantly different between Q703K+ and Q703K- monocytes from asymptomatic parents. The evidence we report in our study shows an increased prevalence of Q703K in patients with autoinflammatory diseases, suggesting an association between the Q703K variant and the risk of PFAPA, CAPS and uAID syndromes. However, we did not show a functional effect of this mutation on the inflammasome basal activity.
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http://dx.doi.org/10.3389/fimmu.2020.00877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241420PMC
May 2020

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.

Arthritis Res Ther 2020 04 15;22(1):81. Epub 2020 Apr 15.

German Rheumatism Research Center, a Leibniz Institute, Berlin, 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.
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http://dx.doi.org/10.1186/s13075-020-02166-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161187PMC
April 2020

Impact of IL1RN Variants on Response to Interleukin-1 Blocking Therapy in Systemic Juvenile Idiopathic Arthritis.

Arthritis Rheumatol 2020 03 28;72(3):499-505. Epub 2020 Jan 28.

University Hospital Munster, Munster, Germany.

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).
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http://dx.doi.org/10.1002/art.41130DOI Listing
March 2020

Pharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15,000 patients from Pharmachild and national registries.

Arthritis Res Ther 2018 12 27;20(1):285. Epub 2018 Dec 27.

IRCCS Istituto Giannina Gaslini, Clinica Pediatrica e Reumatologia, PRINTO, Via Gaslini, 5, 16147, Genoa, Italy.

Background: The availability of methotrexate and the introduction of multiple biological agents have revolutionized the treatment of juvenile idiopathic arthritis (JIA). Several international and national drug registries have been implemented to accurately monitor the long-term safety/efficacy of these agents. This report aims to present the combined data coming from Pharmachild/PRINTO registry and the national registries from Germany (BiKeR) and Sweden.

Methods: Descriptive statistics was used for demographic, clinical data, drug exposure, adverse events (AEs) and events of special interest (ESIs). For the Swedish register, AE data were not available.

Results: Data from a total of 15,284 patients were reported: 8274 (54%) from the Pharmachild registry and 3990 (26%) and 3020 (20%) from the German and the Swedish registries, respectively. Pharmachild children showed a younger age (median of 5.4 versus 7.6 years) at JIA onset and shorter disease duration at last available visit (5.3 versus 6.1-6.8) when compared with the other registries. The most frequent JIA category was the rheumatoid factor-negative polyarthritis (range of 24.6-29.9%). Methotrexate (61-84%) and etanercept (24%-61.8%) were the most frequently used synthetic and biologic disease-modifying anti-rheumatic drugs (DMARDs), respectively. There was a wide variability in glucocorticoid use (16.7-42.1%). Serious AEs were present in 572 (6.9%) patients in Pharmachild versus 297 (7.4%) in BiKeR. Infection and infestations were the most frequent AEs (29.4-30.1%) followed by gastrointestinal disorders (11.5-19.6%). The most frequent ESIs were infections (75.3-89%).

Conclusions: This article is the first attempt to present a very large sample of data on JIA patients from different national and international registries and represents the first proposal for data merging as the most powerful tool for future analysis of safety and effectiveness of immunosuppressive therapies in JIA.

Registry Registration: The Pharmachild registry is registered at ClinicalTrials.gov ( NCT01399281 ) and at the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) ( http://www.encepp.eu/encepp/viewResource.htm?id=19362 ). The BiKeR registry is registered at ENCePP ( http://www.encepp.eu/encepp/viewResource.htm?id=20591 ).
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http://dx.doi.org/10.1186/s13075-018-1780-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307151PMC
December 2018

Vitamin D deficiency is associated with higher disease activity and the risk for uveitis in juvenile idiopathic arthritis - data from a German inception cohort.

Arthritis Res Ther 2018 12 13;20(1):276. Epub 2018 Dec 13.

German Rheumatism Research Center, a Leibniz Institute, Charitéplatz 1, 10117, Berlin, Germany.

Objective: The objective was to evaluate the 25(OH) vitamin D (25(OH)D) status of patients with juvenile idiopathic arthritis (JIA) and determine whether the 25(OH)D level is associated with disease activity and the course of JIA.

Methods: Patients ≤ 16 years of age with recently diagnosed JIA (< 12 months) were enrolled in the inception cohort of patients with newly diagnosed JIA (ICON), an ongoing prospective observational, controlled multicenter study started in 2010. Clinical and laboratory parameters were ascertained quarterly during the first year and half-yearly thereafter. Of the 954 enrolled patients, 360 patients with two blood samples taken during the first 2 years after inclusion and with follow up of 3 years were selected. The serum 25(OH)D levels were determined and compared with those of subjects from the general population after matching for age, sex, migration status and the month of blood-drawing.

Results: Nearly half of the patients had a deficient 25(OH)D level (< 20 ng/ml) in the first serum sample and a quarter had a deficient level in both samples. Disease activity and the risk of developing JIA-associated uveitis were inversely correlated with the 25(OH)D level (β = - 0.20, 95% CI - 0.37; 0.03, hazard ratio 0.95, 95% CI 0.91; 0.99, respectively).

Conclusion: In this study, 25(OH)D deficiency was common and associated with higher disease activity and risk of developing JIA-associated uveitis. Further studies are needed to substantiate these results and determine whether correcting 25(OH)D deficiency is beneficial in JIA.
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http://dx.doi.org/10.1186/s13075-018-1765-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293517PMC
December 2018

Combined three-dimensional gait and plantar pressure analyses detecting significant functional deficits in children with juvenile idiopathic arthritis.

Gait Posture 2018 10 9;66:247-254. Epub 2018 Sep 9.

Department of Biomechanics in Sports, Faculty of Sports and Health Sciences, Technical University of Munich, Georg-Brauchle-Ring 60/62, 80992 Munich, Germany. Electronic address:

Background: Children suffering from juvenile idiopathic arthritis (JIA), a heterogeneous group of chronic inflammatory joint diseases, adapt to individual gait patterns to avoid loading of inflamed, swollen and painful joints. As the interpretability of previous studies is limited, this study aims to assess the functional capacity, loads and plantar pressure distribution in the gait of a homogeneous JIA group.

Research Question: Does a symmetrical lower limb joint involvement influence the gait dynamics in JIA patients, and how are the results of three-dimensional gait analysis (3DGA) and pedobarography related?

Methods: Fifty JIA patients with symmetrical hip, knee and ankle joint arthritis and 27 healthy controls performed 3DGA and pedobarography at self-selected walking speeds. Kinematics and kinetics of lower limb joints were retrospectively compared in range of motion and in time-normalized waveforms. Plantar load was evaluated by measuring peak pressure, pressure-time integral and maximum force of the whole foot and ten selected foot regions. 1D-SPM analysis, parametric and non-parametric statistical significance tests and correlation coefficients were used for statistical analysis.

Results: JIA patients had a significantly slower walking speed with an anteriorly tilted pelvis and a reduced extension motion of all joints of the lower limb. The horizontal ground reaction forces and generated hip and ankle power during propulsion phase were small. Patients experienced reduced loading at toe regions, which correlated with limited ankle plantarflexion motion in the push-off phase. The total peak pressure was significantly increased and loads at lateral midfoot and metatarsal regions were higher in patients.

Significance: Symmetrical lower limb arthritis is linked to crouch-like gait and restricted gait dynamics with increased total peak pressure. The results confirm earlier results of 3DGA and provide new insights regarding waveform analysis and plantar loading in JIA patients. The used methods help to design individualized functional treatment of JIA patients.
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http://dx.doi.org/10.1016/j.gaitpost.2018.08.041DOI Listing
October 2018

Time of Disease-Modifying Antirheumatic Drug Start in Juvenile Idiopathic Arthritis and the Likelihood of a Drug-Free Remission in Young Adulthood.

Arthritis Care Res (Hoboken) 2019 04;71(4):471-481

German Rheumatism Research Center and Charité-University Medicine Berlin, Berlin, Germany.

Objective: To study juvenile idiopathic arthritis (JIA) long-term outcomes in relation to the time of initiation of biologic disease-modifying antirheumatic drug (bDMARD).

Methods: Outcomes of JIA patients prospectively followed by the Biologika in der Kinderrheumatologie (BiKeR) and Juvenile Arthritis Methotrexate/Biologics Long-Term Observation (JuMBO) registers were analyzed with regard to drug-free remission and inactive disease, functional status and quality of life, and surgery. To analyze the influence of early bDMARD therapy on outcomes, patients were assigned to 3 groups based on the time from symptom onset to bDMARD start (G1: ≤2 years, G2: >2 to ≤5 years, and G3: >5 years). Propensity score-adjusted outcome differences were analyzed by multinomial logistic regression analyses among the groups.

Results: A total of 701 JIA patients were observed for mean ± SD 9.1 ± 3.7 years. At the last follow-up (disease duration mean ± SD 14.3 ± 6.1 years), 11.7% of patients were in drug-free remission, and 40.0% had inactive disease. More than half of the patients reported no functional limitation, while 5% had undergone arthroplasty, and 3% had eye surgery. At the 10-year time point, patients in G1 (n = 108) were significantly more likely to be in drug-free remission than those patients who began treatment later (G2, n = 199; G3, n = 259), with 18.5%, 10.1%, and 4.9%, respectively. Patients in G1 had significantly lower disease activity (clinical Juvenile Arthritis Disease Activity Score in 10 joints = 4.9), a better overall well-being (18.2% patient global assessment score = 0), and higher functional status (59.2% Health Assessment Questionnaire score = 0), compared to patients in G3 (7.1, 8.4%, and 43.7%, respectively). G1 patients required arthroplasty significantly less frequently than G3 patients and had significantly lower disease activity over time than patients in both G2 and G3.

Conclusion: Early DMARD treatment is associated with better disease control and outcomes, which supports the concept of a "window of opportunity" for JIA.
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http://dx.doi.org/10.1002/acr.23709DOI Listing
April 2019

Development of practice and consensus-based strategies including a treat-to-target approach for the management of moderate and severe juvenile dermatomyositis in Germany and Austria.

Pediatr Rheumatol Online J 2018 Jun 25;16(1):40. Epub 2018 Jun 25.

German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen Department of Dermatology, Oberammergau Center for Rheumatic Diseases, Oberammergau, Germany.

Background: Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy in childhood and a major cause of morbidity among children with pediatric rheumatic diseases. The management of JDM is very heterogeneous. The JDM working group of the Society for Pediatric Rheumatology (GKJR) aims to define consensus- and practice-based strategies in order to harmonize diagnosis, treatment and monitoring of JDM.

Methods: The JDM working group was established in 2015 consisting of 23 pediatric rheumatologists, pediatric neurologists and dermatologists with expertise in the management of JDM. Current practice patterns of management in JDM had previously been identified via an online survey among pediatric rheumatologists and neurologists. Using a consensus process consisting of online surveys and a face-to-face consensus conference statements were defined regarding the diagnosis, treatment and monitoring of JDM. During the conference consensus was achieved via nominal group technique. Voting took place using an electronic audience response system, and at least 80% consensus was required for individual statements.

Results: Overall 10 individual statements were developed, finally reaching a consensus of 92 to 100% regarding (1) establishing a diagnosis, (2) case definitions for the application of the strategies (moderate and severe JDM), (3) initial diagnostic testing, (4) monitoring and documentation, (5) treatment targets within the context of a treat-to-target strategy, (6) supportive therapies, (7) explicit definition of a treat-to-target strategy, (8) various glucocorticoid regimens, including intermittent intravenous methylprednisolone pulse and high-dose oral glucocorticoid therapies with tapering, (9) initial glucocorticoid-sparing therapy and (10) management of refractory disease.

Conclusion: Using a consensus process among JDM experts, statements regarding the management of JDM were defined. These statements and the strategies aid in the management of patients with moderate and severe JDM.
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http://dx.doi.org/10.1186/s12969-018-0257-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019723PMC
June 2018

Current management of juvenile dermatomyositis in Germany and Austria: an online survey of pediatric rheumatologists and pediatric neurologists.

Pediatr Rheumatol Online J 2018 Jun 20;16(1):38. Epub 2018 Jun 20.

German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany.

Background: Juvenile Dermatomyositis (JDM) is a rare pediatric autoimmune disease with broad variations of the individual course. Data on the optimal management are mostly lacking. Currently treatment decisions are often based on experts' opinions. In order to develop consensus-based treatment strategies for JDM in Germany a survey was pursued to analyze the current clinical practice.

Methods: An online survey addressing all members of the Society for Pediatric Rheumatology (GKJR) in Germany and Austria and pediatric neurologists with expertise in JDM was performed in February/March of 2016. The questionnaire consisted of 5 case scenarios including diagnostic criteria, treatment of moderate, severe and refractory JDM, using either multiple choice or a 5-point Likert scale. Basic descriptive statistics were used to analyze the findings.

Results: The survey was completed by 60 pediatric rheumatologists and 7 pediatric neurologists experienced in the management of JDM. Typical findings allowing a diagnosis were considered to be: typical skin changes, proximal muscle weakness, MRI findings, elevated muscle enzymes, nailfold capillary changes, presence of calcinosis and muscle biopsy. Regarding induction treatment of moderate/severe JDM: 59%/74% opted for intermittent intravenous methylprednisolone (IVMP) pulse therapy, and 21%/40% for conventional high-dose oral glucocorticoids. Methotrexate (MTX) was the preferred disease-modifying conventional anti-rheumatic drug (cDMARD) for moderate and severe JDM. Regarding the management of refractory moderate or severe JDM, intravenous immune globulins, mycophenolate mofetil and rituximab were preferred treatment options.

Conclusion: There is consensus about the diagnosis of JDM strongly supported by classic clinical and MRI findings. There is great variety in the treatment of JDM in Germany regarding both induction and maintenance therapy. The development of consensus-based treatment strategies for JDM based on harmonization of current clinical practice is essential in order to allow comparative effectiveness research in the future.
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http://dx.doi.org/10.1186/s12969-018-0256-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011340PMC
June 2018

Transcription factor motif enrichment in whole transcriptome analysis identifies STAT4 and BCL6 as the most prominent binding motif in systemic juvenile idiopathic arthritis.

Arthritis Res Ther 2018 05 30;20(1):98. Epub 2018 May 30.

Department of Pediatrics, Universitätsklinikum Aachen, Aachen, Germany.

Background: The term systemic juvenile idiopathic arthritis (sJIA) describes an autoinflammatory condition characterized by arthritis and severe systemic inflammation, which in later stages can transform into interleukin (IL)-17-driven autoimmune arthritis. IL-1 antagonists have been used with good efficacy in the early stages of sJIA.

Methods: A whole transcriptome analysis of peripheral blood RNA samples was performed in six patients with sJIA and active systemic disease, before initiating treatment with the IL-1β receptor antagonist anakinra, and after induction of inactive disease, compared with a single-sample control cohort of 21 patients in several clinical stages of sJIA activity. Whole transcriptomes were compared longitudinally and interindividually including gene ontology and motif enrichment analysis of differentially expressed genes.

Results: There were 741 transcripts were identified using a threshold with a p value <0.01 and a fold change > 2. HLADRB1 and CD74 were identified as the most strongly upregulated genes in inactive compared to active disease; CD177 expression was significantly enhanced in active disease compared to inactive disease. Motif enrichment analysis revealed STAT4, BCL6, and STAT3 as the most prominent transcription factors that were present during active disease. In addition, strong upregulation of the major histocompatability complex II (MHCII) ligand CD74 was found in both active and inactive sJIA compared to healthy controls.

Conclusion: Using transcription factor motif enrichment, this study identifies novel putative pathways in sJIA (STAT4, BCL6) implicating B cell activation at an earlier stage than predicted in refractory disease. The implication of BCL-6 dependent pathways argues for occurrence of autoimmunity early within the process of sJIA chronification. Transcriptional regulation of HLA-DRB1, a recently described independent genetic risk factor, in combination with its cooperating partner CD74 in patients where sJIA is confirmed, supports pathogenic involvement in alterations in antigen presentation during sJIA.
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http://dx.doi.org/10.1186/s13075-018-1603-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977738PMC
May 2018

The majority of patients with newly diagnosed juvenile idiopathic arthritis achieve a health-related quality of life that is similar to that of healthy peers: results of the German multicenter inception cohort (ICON).

Arthritis Res Ther 2018 05 30;20(1):106. Epub 2018 May 30.

Deutsches Rheuma-Forschungszentrum Berlin, Epidemiology Unit, Charitéplatz 1, 10117, Berlin, Germany.

Background: Achieving the best possible health-related quality of life (HRQoL) for a patient is an important treatment goal in juvenile idiopathic arthritis (JIA). We investigated the 36-month trajectories of HRQoL in children with JIA compared with healthy peers and identified the predictors of an unfavorable HRQoL.

Methods: Patients with a recent JIA diagnosis were enrolled in the German inception cohort study ICON. As a peer group, friends of patients of the same age and sex were asked to cooperate. Children were prospectively followed and regularly questioned about their HRQoL using the Pediatric Quality of Life Inventory 4.0 (PedsQL). Disease activity was assessed by the clinical Juvenile Arthritis Disease Activity Score (cJADAS-10), and the burden of the child's chronic illness on their family was assessed by the Family Burden Questionnaire (FaBel). Linear mixed models were used to compare the HRQoL of the patients and their peers. Associations between the health status of a patient at enrollment and an unfavorable HRQoL (PedsQL total < 79.3) at their 3-year follow-up (FU) were analyzed by logistic regression.

Results: Data from 953 patients (median symptom duration 6 months, mean age 7.9 years) and 491 healthy peers (aged 8.4 years) were analyzed. During 3 years of FU, the disease activity and HRQoL of the patients improved significantly (cJADAS-10 from 9.8 (6.2) to 2.7 (3.6) and PedsQL total score from 71.7 (18.2) to 87.3 (13.9)). While the HRQoL of the patients varied among the several JIA categories at the time of enrollment, no significant differences were found at the 3-year FU. After 36 months, the HRQoL of the patients had largely converged with that of their healthy peers. JIA patients had a psychosocial health status comparable with their healthy peers, whereas a small significant mean difference remained in physical health (5.8, 95% confidence interval (CI) 4.1-7.6). Up to the 36-month FU, three-quarters of JIA patients attained a favorable HRQoL (PedsQL ≥ 79.3) which was achieved by 90% of the peers. A higher family burden, higher pain level, and lower well-being at enrollment were associated with an unfavorable HRQoL.

Conclusions: Under current therapeutic conditions, an HRQoL corresponding with that of healthy children is a realistic treatment goal in JIA.
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http://dx.doi.org/10.1186/s13075-018-1588-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977761PMC
May 2018

The German version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

Rheumatol Int 2018 Apr 7;38(Suppl 1):211-218. Epub 2018 Apr 7.

Clinica Pediatrica e Reumatologia, Paediatric Rheumatology International Trials Organisation (PRINTO), Istituto Giannina Gaslini, Via Gaslini 5, 16147, Genoa, Italy.

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.
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http://dx.doi.org/10.1007/s00296-018-3953-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893737PMC
April 2018

IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis.

Arthritis Rheumatol 2018 08 28;70(8):1319-1330. Epub 2018 Jun 28.

National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.

Objective: To determine whether systemic juvenile idiopathic arthritis (JIA) susceptibility loci that were identified by candidate gene studies demonstrate association with systemic JIA in the largest study population assembled to date.

Methods: Single-nucleotide polymorphisms (SNPs) from 11 previously reported systemic JIA risk loci were examined for association in 9 populations, including 770 patients with systemic JIA and 6,947 controls. The effect of systemic JIA-associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from the lymphoblastoid cell lines (LCLs) of 373 European subjects from the 1000 Genomes Project. Responses of systemic JIA-associated SNPs to anakinra treatment were evaluated in 38 US patients for whom treatment response data were available.

Results: We found no association between the previously reported 26 SNPs and systemic JIA. Expanded analysis of the regions containing the 26 SNPs revealed only 1 significant association: the promoter region of IL1RN (P < 1 × 10 ). Systemic JIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between systemic JIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 [95% confidence interval 3.2-255.8]).

Conclusion: In our study, IL1RN was the only candidate locus associated with systemic JIA. The implicated SNPs are among the strongest known determinants of IL1RN and interleukin-1 receptor antagonist levels, linking low expression with increased systemic JIA risk. Homozygous high expression alleles predicted nonresponsiveness to anakinra therapy, making them ideal candidate biomarkers to guide systemic JIA treatment. This study is an important first step toward the personalized treatment of systemic JIA.
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http://dx.doi.org/10.1002/art.40498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105455PMC
August 2018

Varicella-zoster-virus vaccination in immunosuppressed children with rheumatic diseases using a pre-vaccination check list.

Pediatr Rheumatol Online J 2018 Mar 2;16(1):15. Epub 2018 Mar 2.

German Center for Pediatric and Adolescent Rheumatology, Gehfeldstr. 24, 82467, Garmisch-Partenkirchen, Germany.

Background: The goal of this study was to apply the varicella zoster virus (VZV) vaccine to patients with pediatric rheumatic diseases (PRD) at risk for severe chickenpox, without interrupting their current immunosuppression, including biological agents, using an immunological-based pre-vaccination checklist to assure safety. A pre-vaccination checklist was implemented to ensure adequate immune competence prior to immunization.

Methods: This prospective study included seronegative patients (VZV-IgG ≤200 mIU/ml) and patients who had previously received only a single dose of VZV vaccine. All vaccinees demonstrated clinically inactive PRD. Patients were categorized according to their actual treatment in low-intensity IS (LIIS) and high-intensity IS (HIIS) including biological therapy. The pre-vaccination checklist defined thresholds for the following basic laboratory tests: white blood cell count ≥3000/mm, lymphocytes ≥1200/mm, serum IgG ≥500 mg/dl, IgM ≥20 mg/dl, tetanus toxoid antibody ≥0.1 IU/ml. In case of HIIS additional specifications included a CD4+ lymphocyte count ≥200/mm and a positive T-cell function (via analyzable positive control of a standard tuberculosis interferon-gamma-release-assay (TB-IGRA) indicating mitogen-induced T cell proliferation). Patients who met the criteria of the pre-vaccination checklist received the first and/or second VZV vaccination. Immunologic response and side effects were monitored.

Results: Twenty-three patients were recruited of whom nine had already received one VZV immunization before initiating IS. All patients met the pre-vaccination checklist criteria despite ongoing IS. There was no overall difference in VZV-IgG levels when comparing the LIIS (n=9) and HIIS (n=14) groups. In total, 21 patients (91%) showed a positive vaccination response, after the first immunization the median VZV-IgG across all patients was 224 (59-1219) mIU/ml (median (range)), after booster immunization it increased to 882 (30-4685) mIU/ml. Two patients in the HIIS group failed to raise positive VZV-IgG, despite booster immunization. All nine patients receiving only the second immunization on IS reached high titers of VZV-IgG >500 mIU/ml (1117 (513-4685) mIU/ml). There were no cases of rash or other vaccine-induced varicella disease symptoms and no evidence of PRD flare.

Conclusions: VZV vaccination is safe and largely immunogenic in children with ongoing IS fulfilling an immunological based pre-vaccination checklist. This new approach is based on immunologic function rather than on type of medications.

Trial Registration Number: ISRCRTN trial registration number 21654693 , date of registration February 12, 2018, retrospectively registered.
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http://dx.doi.org/10.1186/s12969-018-0231-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833060PMC
March 2018

Successful treatment of methotrexate intolerance in juvenile idiopathic arthritis using eye movement desensitization and reprocessing - treatment protocol and preliminary results.

Pediatr Rheumatol Online J 2018 Feb 13;16(1):11. Epub 2018 Feb 13.

German Center for Pediatric and Adolescent Rheumatology (DZKJR), Gehfeldstrasse 24, 82467, Garmisch-Partenkirchen, Germany.

Background: Methotrexate (MTX), commonly used in juvenile idiopathic arthritis (JIA), frequently has to be discontinued due to intolerance with anticipatory and associative gastrointestinal adverse effects. Eye Movement Desensitization and Reprocessing (EMDR) is a psychological method where dysfunctional experiences and memories are reprocessed by recall combined with bilateral eye movements. The objective of this study was to assess efficacy of EMDR for treatment of MTX intolerance in JIA patients.

Methods: We performed an open prospective study on consecutive JIA patients with MTX intolerance. Intolerance was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire prior to treatment, directly after treatment and after four months. Health-related quality of life was determined using the PedsQL prior to and four months after treatment. Patients were treated according to an institutional EMDR protocol with 8 sessions over two weeks. Changes in MISS and PedsQL were analyzed using non-parametric statistics.

Results: Eighteen patients with MTX intolerance (median MISS at inclusion 16.5, IQR = 11.75-20.25) were included. Directly after treatment, MTX intolerance symptoms were significantly improved (median MISS 1 (IQR = 0-2). After four months, median MISS score was at 6.5 (IQR = 2.75-12.25, p = 0.001), with 9/18 patients showing MISS scores ≥6. Median PedsQL after 4 months improved significantly from 77.6% to 85.3% (p = 0.008).

Conclusion: MTX intolerance in children with JIA was effectively treated using an EMDR protocol, with lasting effect over a period of 4 months. EMDR treatment can potentially increase quality of life of affected patients and enable continued MTX treatment.
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http://dx.doi.org/10.1186/s12969-018-0228-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809965PMC
February 2018

Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis.

Arthritis Rheumatol 2018 06 21;70(6):957-962. Epub 2018 Apr 21.

Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia.

Objective: Juvenile idiopathic arthritis (JIA) comprises 7 heterogeneous categories of chronic childhood arthritides. Approximately 5% of children with JIA have rheumatoid factor (RF)-positive arthritis, which phenotypically resembles adult rheumatoid arthritis (RA). Our objective was to compare and contrast the genetics of RF-positive polyarticular JIA with those of RA and selected other JIA categories, to more fully understand the pathophysiologic relationships of inflammatory arthropathies.

Methods: Patients with RF-positive polyarticular JIA (n = 340) and controls (n = 14,412) were genotyped using the Immunochip array. Single-nucleotide polymorphisms were tested for association using a logistic regression model adjusting for admixture proportions. We calculated weighted genetic risk scores (wGRS) of reported RA and JIA risk loci, and we compared the ability of these wGRS to predict RF-positive polyarticular JIA.

Results: As expected, the HLA region was strongly associated with RF-positive polyarticular JIA (P = 5.51 × 10 ). Nineteen of 44 RA risk loci and 6 of 27 oligoarticular/RF-negative polyarticular JIA risk loci were associated with RF-positive polyarticular JIA (P < 0.05). The RA wGRS predicted RF-positive polyarticular JIA (area under the curve [AUC] 0.71) better than did the oligoarticular/RF-negative polyarticular JIA wGRS (AUC 0.59). The genetic profile of patients with RF-positive polyarticular JIA was more similar to that of RA patients with age at onset 16-29 years than to that of RA patients with age at onset ≥70 years.

Conclusion: RF-positive polyarticular JIA is genetically more similar to adult RA than to the most common JIA categories and thus appears to be a childhood-onset presentation of autoantibody-positive RA. These findings suggest common disease mechanisms, which could lead to novel therapeutic targets and shared treatment strategies.
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http://dx.doi.org/10.1002/art.40443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984672PMC
June 2018

Successful use of secukinumab in a 4-year-old patient with deficiency of interleukin-36 antagonist.

Rheumatology (Oxford) 2018 May;57(5):936-938

German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany.

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http://dx.doi.org/10.1093/rheumatology/kex510DOI Listing
May 2018

Practice and consensus-based strategies in diagnosing and managing systemic juvenile idiopathic arthritis in Germany.

Pediatr Rheumatol Online J 2018 Jan 22;16(1). Epub 2018 Jan 22.

Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Albert-Schweitzer-Campus 1, Building W30, 48149, Münster, Germany.

Background: Systemic juvenile idiopathic arthritis (SJIA) is an autoinflammatory disease associated with chronic arthritis. Early diagnosis and effective therapy of SJIA is desirable, so that complications are avoided. The PRO-KIND initiative of the German Society for Pediatric Rheumatology (GKJR) aims to define consensus-based strategies to harmonize diagnostic and therapeutic approaches in Germany.

Methods: We analyzed data on patients diagnosed with SJIA from 3 national registries in Germany. Subsequently, via online surveys and teleconferences among pediatric rheumatologists with a special expertise in the treatment of SJIA, we identified current diagnostic and treatment approaches in Germany. Those were harmonized via the formulation of statements and, supported by findings from a literature search. Finally, an in-person consensus conference using nominal group technique was held to further modify and consent the statements.

Results: Up to 50% of patients diagnosed with SJIA in Germany do not fulfill the International League of Associations for Rheumatology (ILAR) classification criteria, mostly due to the absence of chronic arthritis. Our findings suggest that chronic arthritis is not obligatory for the diagnosis and treatment of SJIA, allowing a diagnosis of probable SJIA. Malignant, infectious and hereditary autoinflammatory diseases should be considered before rendering a diagnosis of probable SJIA. There is substantial variability in the initial treatment of SJIA. Based on registry data, most patients initially receive systemic glucocorticoids, however, increasingly substituted or accompanied by biological agents, i.e. interleukin (IL)-1 and IL-6 blockade (up to 27.2% of patients). We identified preferred initial therapies for probable and definitive SJIA, including step-up patterns and treatment targets for the short-term (resolution of fever, decrease in C-reactive protein by 50% within 7 days), the mid-term (improvement in physician global and active joint count by at least 50% or a JADAS-10 score of maximally 5.4 within 4 weeks) and the long-term (glucocorticoid-free clinically inactive disease within 6 to 12 months), and an explicit treat-to-target strategy.

Conclusions: We developed consensus-based strategies regarding the diagnosis and treatment of probable or definitive SJIA in Germany.
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http://dx.doi.org/10.1186/s12969-018-0224-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778670PMC
January 2018

Education and employment in patients with juvenile idiopathic arthritis - a standardized comparison to the German general population.

Pediatr Rheumatol Online J 2017 May 22;15(1):45. Epub 2017 May 22.

Unit of Occupational and Environmental Epidemiology and NetTeaching, Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital of Munich (LMU), Ziemssenstrasse 1, D-80336, Munich, Germany.

Background: Although several studies show that JIA-patients have significantly lower employment rates than the general population, the research on educational and occupational attainments in patients with juvenile idiopathic arthritis (JIA) remain conflicting most likely due to small sample sizes. Therefore, aim of this study is to compare the educational achievements and employment status of 3698 JIA-patients with the German general population (GGP).

Methods: "SEPIA" was a large cross-sectional study on the current status of a historic cohort of JIA-patients treated in a single center between 1952 and 2010. For the analyses of education and employment a sub-cohort was extracted, including only adult cases with a confirmed diagnosis of JIA (N = 2696). Participants were asked to fill out a standardized written questionnaire on education and employment. Outcome measures (education/unemployment) were directly standardized to the GGP using data obtained from the National Educational Panel Study 2013 (N = 11,728) and the German Unemployment Statistics 2012 of the Federal Statistical Office (N = 42,791,000).

Results: After age- and sex-standardization, 3% (95% Confidence Interval 1.9 to 4.1%) more of the JIA-patients (26%) than of the GGP (23%) had only reached primary education. In contrast, parents of JIA-patients had similar levels of education as parents in the GGP. With a standardized difference of 0.2% (95% CI: 0.16 to 0.19%), the unemployment rate in JIA-patients was slightly, but not significantly higher than in the GGP. Stratifying for disease duration and the current treatment status, differences were confirmed for persons diagnosed before 2001, whilst for patients diagnosed after 2000, differences were found only in JIA-patients with ongoing disease. Medium and high educational achievements did not differ statistically significant between JIA patients and the GPP.

Conclusion: Educational achievements in German JIA-patients are significantly lower than in the GGP. Furthermore we were able to identify a slightly higher level of unemployment, especially in those with still under treatment and longer disease duration. Better treatment options as well as further development of social support programs might help to overcome this lifelong secondary effect of JIA.
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http://dx.doi.org/10.1186/s12969-017-0172-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440947PMC
May 2017

Inflammatory bowel disease following anti-interleukin-1-treatment in systemic juvenile idiopathic arthritis.

Pediatr Rheumatol Online J 2017 Mar 14;15(1):16. Epub 2017 Mar 14.

German Center for Pediatric and Adolescent Rheumatology (GCPAR), Gehfeldstrasse 24, 82467, Garmisch-Partenkirchen, Germany.

Background: Inflammatory bowel disease can develop in the context of some rheumatic diseases in childhood, including juvenile idiopathic arthritis (JIA). Inflammatory bowel disease (IBD) is frequently associated with other immune-mediated diseases; however, systemic onset JIA (sJIA) has not previously been connected to IBD. Treatment of sJIA has significantly changed in recent years, possibly causing changes in inflammatory patterns. Therefore, data from the German Center for Pediatric and Adolescent Rheumtology from 2010 until 2015 were analyzed by retrospective chart review.

Findings: Eighty-two patients with confirmed diagosis of sJIA were found. Of these, three were identified with a diagnosis of IBD confirmed by colonoscopy (two cases of Crohn's disease, one case of ulcerative colitis) 0.8 - 4.3 years after diagnosis. All three were treated with IL-1 antagonists (anakinra in two cases, canakinumab in one case) and were well controlled for sJIA symptoms at time of diagnosis of IBD CONCLUSIONS: IBD seems to be a rare, but possible complication of sJIA. Treatment with IL-1 antagonists might be a relevant factor for a switch in the clinical phenotype of the underlying inflammatory process.
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http://dx.doi.org/10.1186/s12969-017-0147-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348783PMC
March 2017

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

Rheumatology (Oxford) 2017 06;56(6):901-906

German Center for Pediatric Rheumatology, Garmisch-Partenkirchen, Germany.

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.
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http://dx.doi.org/10.1093/rheumatology/kew507DOI Listing
June 2017

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

Clin Exp Rheumatol 2017 Jan-Feb;35(1):161-168. Epub 2017 Jan 5.

German Center for Paediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany.

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.
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June 2017

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

Ann Rheum Dis 2017 May 7;76(5):906-913. Epub 2016 Dec 7.

Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, Manchester, UK.

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.
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http://dx.doi.org/10.1136/annrheumdis-2016-210324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530341PMC
May 2017

Comparison of treatment response, remission rate and drug adherence in polyarticular juvenile idiopathic arthritis patients treated with etanercept, adalimumab or tocilizumab.

Arthritis Res Ther 2016 11 24;18(1):272. Epub 2016 Nov 24.

Department of Pediatrics, Section of Rheumatology, Olgahospital, Klinikum, Stuttgart, Germany.

Background: Treatment response, remission rates and compliance in patients with polyarticular juvenile idiopathic arthritis (polyJIA) treated with adalimumab, etanercept, or tocilizumab were analyzed in clinical practice.

Methods: Data collected in the German BIKER registry were analyzed in patients with polyJIA who started treatment with approved biologics, adalimumab, etanercept or tocilizumab, from 2011 to 2015. Baseline patient characteristics, treatment response, safety and drug survival were compared.

Results: Two hundred thirty-six patient started adalimumab, 419 etanercept and 74 tocilizumab, with differences in baseline patient characteristics. Baseline Juvenile Disease Activity Score (JADAS)10 (mean ± SD) in the adalimumab/etanercept/tocilizumab cohorts was 12.1+/-7.6, 13.8 ± 7.1 and 15.1 ± 7.4, respectively (adalimumab vs etanercept, p = 0.01), and Childhood Health Assessment Questionnaire (CHAQ)-disability index scores was 0.43 ± 0.58, 0.59 ± 0.6 and 0.63 ± 0.55, respectively (adalimumab vs etanercept, p < 0.001). Uveitis history was more frequent in the adalimumab cohort (OR 5.73; p < 0.001). Balanced patients' samples were obtained by a generalized propensity score to adjust for baseline differences. Pediatric ACR30/50/70/90 criterion improvement after 3 months treatment was achieved by 68%/60%/42%/24% in the etanercept cohort, 67%/59%/43%/27% in the adalimumab cohort and 61%/52%/35%/26% in the tocilizumab cohort. At 24 months, JADAS minimal disease activity was achieved in 52.4%/61.3%/52.4% and JADAS remission in 27.9%/34.8%/27.9% patients in the adalimumab/etanercept/tocilizumab cohorts, respectively. Etanercept was used in 95.5% of patients as a first biologic, adalimumab in 50.8% and tocilizumab in 20.2%. There were no important differences in efficacy between first-line and second-line use of biologics. In total 60.4%/49.4%/31.1% patients discontinued adalimumab/etanercept/tocilizumab, respectively (HR for adalimumab 1.67; p < 0.001; HR for tocilizumab 0.35; p = 0.001). Drug survival rates did not differ significantly in patients on biologic monotherapy compared with combination therapy with methotrexate. Over 4 years observation under etanercept/adalimumab/tocilizumab, 996/386/103 adverse events, and 148/119/26 serious adverse events, respectively, were reported.

Conclusions: In clinical practice, etanercept is most frequently used as first-line biologic. Adalimumab/etanercept/tocilizumab showed comparable efficacy toward polyJIA. Overall, tolerance was acceptable. Interestingly, compliance was highest with tocilizumab and lowest with adalimumab. This study provides the first indication for the comparison of different biologic agents in polyarticular JIA based on observational study data with all their weaknesses and demonstrates the need for well-controlled head-to-head studies for confirmation.
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http://dx.doi.org/10.1186/s13075-016-1170-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5122012PMC
November 2016

Treatment with high-dose recombinant human hyaluronidase-facilitated subcutaneous immune globulins in patients with juvenile dermatomyositis who are intolerant to intravenous immune globulins: a report of 5 cases.

Pediatr Rheumatol Online J 2016 Sep 13;14(1):52. Epub 2016 Sep 13.

Klinik für Pädiatrische Rheumatologie und Immunologie, Universitätsklinikum Münster, Münster, Germany.

Background: High-dose intravenous immune globulins (IVIg) are frequently used in refractory juvenile dermatomyositis (JDM) but are often poorly tolerated. High-dose recombinant human hyaluronidase-facilitated subcutaneous immune globulins (fSCIg) allow the administration of much higher doses of immune globulins than conventional subcutaneous immune globulin therapy and may be an alternative to IVIg. The safety and efficacy of fSCIg therapy in JDM is unknown.

Case Presentation: In this retrospective case series, five patients with steroid-refractory severe JDM were treated with high-dose fSCIg due to IVIg adverse effects (severe headaches, nausea, vomiting, difficult venous access). Peak serum IgG levels, muscle enzymes, the childhood myositis assessment scale and adverse effects were retrieved for at least 6 months following intiation of fSCIg. Data were analyzed by descriptive statistics. Patients initially received fSCIg 1 g/kg every 14 days, resulting in median IgG peak levels of 1901 mg/dl (1606-2719 mg/dl), compared to median IgG peak and trough levels while previously receiving IVIg of 2741 mg/dl (2429-2849 mg/dl) and 1351 mg/dl (1156-1710 mg/dl). Additional antirheumatic therapies consisted of low-dose glucocorticoid therapy, methotrexate, mycophenolate mofetil and/or rituximab. Two patients maintained clinically inactive disease and three patients had only a partial treatment response. In the three patients with partial treatment response, fSCIg 1 g/kg was then given on days 1 and 6 of every 28-day cycle resulting in IgG peak levels of between 2300-2846 mg/dl (previously 1606-1901 mg/dl on the biweekly regimen), resulting in clinically inactive disease in two of the three patients. There were no relevant adverse effects that limited continuation of fSCIg treatment.

Conclusions: High-dose fSCIg is well-tolerated in patients with JDM and high peak serum IgG levels can be achieved which may be important for treatment success. High-dose fSCIg may therefore be an alternative to high-dose IVIg and deserves further study.

Trial Registration: This is a case series and data were retrospectively registered.
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http://dx.doi.org/10.1186/s12969-016-0112-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5022227PMC
September 2016

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

Mod Rheumatol 2017 Jan 7;27(1):60-65. Epub 2016 Jul 7.

b German Center for Pediatric and Adolescent Rheumatology , Garmisch-Partenkirchen , Germany , and.

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.
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http://dx.doi.org/10.1080/14397595.2016.1204711DOI Listing
January 2017

Correlation of Secretory Activity of Neutrophils With Genotype in Patients With Familial Mediterranean Fever.

Arthritis Rheumatol 2016 12;68(12):3010-3022

University Children's Hospital, Muenster, Germany.

Objective: Familial Mediterranean fever (FMF) is an autoinflammatory disorder caused by pyrin-encoding MEFV mutations. Patients present with recurrent but self-limiting episodes of acute inflammation and often have persistent subclinical inflammation. The pathophysiology is only partially understood, but neutrophil overactivation is a hallmark of the disease. S100A12 is a neutrophil-derived proinflammatory danger signal that is strongly elevated in active FMF. This study was undertaken to characterize the secretory activity of neutrophils in vitro and investigate the association of S100A12 with disease activity and genotype in patients with FMF.

Methods: Neutrophils from FMF patients carrying the p.M694V mutation (1 compound heterozygous and 5 homozygous) and neutrophils from 4 healthy control subjects were purified and stimulated in vitro. Neutrophil secretion of S100A12, interleukin-18 (IL-18), IL-1β, and caspase 1 was determined. Based on these in vitro analyses, serum concentrations of S100A12, IL-18, and IL-1β were also analyzed in 128 clinically and genetically characterized patients with FMF.

Results: In vitro, unstimulated neutrophils from p.M694V-positive patients spontaneously secreted more S100A12, IL-18, and caspase 1 compared to neutrophils from healthy controls. Serum concentrations of S100A12 correlated with disease activity and genotype, with the levels being highest in homozygous patients and with compound heterozygotes displaying higher levels than heterozygotes. Compared to individuals negative for the p.M694V mutation, heterozygous, compound heterozygous, or homozygous p.M694V-positive patients had higher serum levels of S100A12 and IL-18 during inactive and subclinical disease.

Conclusion: The FMF phenotype is known to be more severe in patients carrying the p.M694V mutation. This report describes 2 molecules secreted by unconventional secretory pathways, S100A12 and IL-18, whose concentrations correlated with clinical disease activity and genotype in patients with FMF. In this clinically and genetically heterogeneous disease, management of these surrogate markers might help to improve patient care and outcomes.
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http://dx.doi.org/10.1002/art.39784DOI Listing
December 2016