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Objective Rheumatic diseases are characterized by different patterns of immune overactivation. This study investigated the correlation of whole blood type 1 interferon (IFN) stimulated gene (ISG), IL18, and CXCL9 expression with clinical disease activity in pediatric rheumatic diseases and assessed the required number of ISGs to be included in a composite type 1 IFN score. Methods Whole blood‐derived RNA and clinical data were collected from 171 mostly pediatric patients with connective tissue diseases (CTDs), systemic autoinflammatory diseases (SAIDs), monogenic interferonopathies (IFNPs) and other inflammatory diseases, and from 38 controls. The expression of six previously established ISGs, IL18, and CXCL9 was assessed by real‐time polymerase chain reaction (471 samples). Individual and composite gene expression was assessed, and correlation and threshold analyses were performed. Results Correlation between ISG expression and clinical disease activity was strongest in CTD, especially in juvenile dermatomyositis (JDM) and IFNP, and modest in patients with SAID. Threshold ISG expression levels for the detection of at least mild clinical disease activity were substantially higher in patients with systemic lupus erythematosus compared with JDM. The correlation of expression levels of limited sets of ISGs and even individual ISGs with clinical disease activity were not inferior to a composite score of six ISGs. Conclusion In a real‐world cohort, individual ISG expression levels robustly reflected clinical disease activity in CTD and IFNP, especially in JDM, which would simplify such analyses in clinical routine and be more cost‐effective. Threshold levels varied across diseases, potentially reflecting different mechanisms of type 1 IFN overactivation.

Abstract Objective Juvenile idiopathic arthritis (JIA) is a heterogeneous group of inflammatory joint disorders with a chronic-remitting disease course. Treat-to-target approaches have been proposed but monitoring disease activity and predicting the response to treatment remains challenging. Methods We analyzed biomarkers and their relationship to outcome within the first year after JIA diagnosis in the German Inception Cohort of Newly diagnosed patients with JIA (ICON-JIA). CRP, CXCL9, CXCL10, CXCL11, erythrocyte sedimentation rate, G-CSF, IL-6, IL-17A, IL-18, MCP-1, MIP-1α, MMP-3, S100A8/A9, S100A12, TNFα, and TWEAK were measured at baseline and 3 months later. Results Two-hundred-sixty-six JIA patients with active disease at baseline were included, with oligoarthritis and rheumatoid factor-negative polyarthritis representing the most frequent categories (72.9%). Most biomarkers were elevated in JIA compared to healthy pediatric controls. Patients with systemic JIA had higher CRP, S100A8/A9 and S100A12 levels compared to other JIA categories. Baseline levels of TWEAK, G-CSF and IL-18 were lower in oligoarthritis patients with disease extension within 1 year. Increased baseline levels of CRP, S100A8/A9, S100A12 and ESR were associated with the subsequent addition of biologic disease-modifying antirheumatic drugs (DMARDs). Higher baseline ESR, G-CSF, IL-6, IL-17A and TNF levels indicated an increased risk for ongoing disease activity after 12 months. Conclusion Our data demonstrate that elevated baseline levels of CRP, S100A8/A9 and S100A12 as well as increased ESR are associated with the necessity to escalate therapy during the first 12 month of follow-up. Furthermore, biomarkers related to Th17 activation may inform on future disease course in previously treatment-naïve JIA patients.

Abstract 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.

Abstract 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.

Abstract 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/mm3, lymphocytes ≥1200/mm3, 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/mm3 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.

Abstract 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.