Human TH17 cells engage gasdermin E pores to release IL-1α on NLRP3 inflammasome activation.

It has been shown that innate immune responses can adopt adaptive properties such as memory. Whether T cells utilize innate immune signaling pathways to diversify their repertoire of effector functions is unknown. Gasdermin E (GSDME) is a membrane pore-forming molecule that has been shown to execute pyroptotic cell death and thus to serve as a potential cancer checkpoint. In the present study, we show that human T cells express GSDME and, surprisingly, that this expression is associated with durable viability and repurposed for the release of the alarmin interleukin (IL)-1α. This property was restricted to a subset of human helper type 17 T cells with specificity for Candida albicans and regulated by a T cell-intrinsic NLRP3 inflammasome, and its engagement of a proteolytic cascade of successive caspase-8, caspase-3 and GSDME cleavage after T cell receptor stimulation and calcium-licensed calpain maturation of the pro-IL-1α form. Our results indicate that GSDME pore formation in T cells is a mechanism of unconventional cytokine release. This finding diversifies our understanding of the functional repertoire and mechanistic equipment of T cells and has implications for antifungal immunity.

Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children.

Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children.

Patients' and parents' satisfaction to improve patient care in JIA: factors determining acceptable symptom state measured with JAMAR.

OBJECTIVES: The aim of this study was to identify factors associated with patients' and parents' reported satisfaction with JIA care, measured with the juvenile arthritis child and parent acceptable symptom state (JA-CASS and JA-PASS, respectively). METHODS: A prospective cohort of 239 JIA patients and 238 parents in a tertiary centre who completed the juvenile arthritis multidimensional assessment report (JAMAR) was analysed cross-sectionally. The primary outcomes were positive JA-CASS and JA-PASS, respectively. Items in the JAMAR, as well as JIA subtype, demographics, and disease activity parameters, were analysed in univariate analysis. A multivariable logistic regression analysis was used to build models explaining the variance of the primary outcome as a dependent variable. RESULTS: According to the JAMAR, 141 (59.0%) of 239 patients and 149 (62.6%) of 238 parents were satisfied with their or their child's current condition. For patients, the determinants in the final model were a shorter duration of morning stiffness (P = 0.001), a lower age at disease onset (P = 0.044), a longer disease duration (P = 0.009) and a higher rating of the patient's well-being measured on a visual analogue scale (VAS) (P = 0.004). For parents, the determinants were the current state of disease activity (current state of persistent activity P = 0.002, relapse P < 0.005), problems at school (P = 0.002) and the items regarding quality of life (QoL) (P = 0.005). CONCLUSION: Our data highlight the importance of patients' and parents' opinions in the evaluation of disease activity, and support their integration into the shared decision-making in daily clinical practice to improve the quality of medical care.

Anti-CD74 IgA antibodies show diagnostic potential for axial spondyloarthritis but are not associated with microscopic gut inflammation.

OBJECTIVES: Gut inflammation commonly occurs in axial SpA (axSpA), and is linked to disease activity and outcome. Given the role of IgA in mucosal immunity, we explored the association between anti-CD74 IgA antibodies, gut inflammation and axSpA. METHODS: Anti-CD74 IgA was measured by ELISA in serum samples of axSpA patients, fulfilling the 2009 Assessment of SpondyloArthritis international Society classification criteria. A group of fibromyalgia (FM) and RA patients served as non-inflammatory and inflammatory controls. Newly diagnosed axSpA patients underwent ileocolonoscopy; mucosal biopsies were histopathologically assessed as normal, acute or chronically inflamed. Optimal anti-CD74 IgA cut-off values were determined with a receiver operating characteristics curve. RESULTS: axSpA patients (n = 281) showed higher anti-CD74 IgA levels [mean (s.d.) 18.8 (12.4) U/ml] compared with 100 FM patients [10.9 (5.0) U/ml, P < 0.001] and 34 RA patients [13.7 (9.6) U/ml, P = 0.02]. The area under the receiver operating characteristics curve for diagnosis (axSpA vs FM) was 0.70, providing a sensitivity of 60% and specificity of 87% (cut-off 15 U/ml). Antibody concentrations were not significantly different between axSpA patients with (n = 40) and without (n = 69) gut inflammation (P = 0.83), yielding an area under the receiver operating characteristics curve of 0.51. Anti-CD74 IgA levels were not associated with degree of bone marrow oedema on MRI of the sacroiliac joints, CRP or any other disease-specific feature such as the use of NSAIDs or biological treatment. CONCLUSION: Serum anti-CD74 IgA is a potentially useful diagnostic biomarker for axSpA. However, antibody levels do not correlate with any phenotypical feature, including microscopic gut inflammation, suggesting this to be a disease-specific rather than an inflammatory marker.

Pharmacological treatment patterns in patients with juvenile idiopathic arthritis in the Netherlands: a real-world data analysis.

OBJECTIVE: To investigate medication prescription patterns among children with JIA, including duration, sequence and reasons for medication discontinuation. METHODS: This study is a single-centre, retrospective analysis of prospective data from the electronic medical records of JIA patients receiving systemic therapy aged 0-18 years between 1 April 2011 and 31 March 2019. Patient characteristics (age, gender, JIA subtype) and medication prescriptions were extracted and analysed using descriptive statistics, Sankey diagrams and Kaplan-Meier survival methods. RESULTS: Over a median of 4.2 years follow-up, the 20 different medicines analysed were prescribed as monotherapy (n = 15) or combination therapy (n = 48 unique combinations) among 236 patients. In non-systemic JIA, synthetic DMARDs were prescribed to almost all patients (99.5%), and always included MTX. In contrast, 43.9% of non-systemic JIA patients received a biologic DMARD (mostly adalimumab or etanercept), ranging from 30.9% for oligoarticular persistent ANA-positive JIA, to 90.9% for polyarticular RF-positive JIA. Among systemic JIA, 91.7% received a biologic DMARD (always including anakinra). When analysing medication prescriptions according to their class, 32.6% involved combination therapy. In 56.8% of patients, subsequent treatment lines were initiated after unsuccessful first-line treatment, resulting in 68 unique sequences. Remission was the most common reason for DMARD discontinuation (44.7%), followed by adverse events (28.9%) and ineffectiveness (22.1%). CONCLUSION: This paper reveals the complexity of pharmacological treatment in JIA, as indicated by: the variety of mono- and combination therapies prescribed, substantial variation in medication prescriptions between subtypes, most patients receiving two or more treatment lines, and the large number of unique treatment sequences.

Epigenetic changes in inflammatory arthritis monocytes contribute to disease and can be targeted by JAK inhibition.

OBJECTIVES: How the local inflammatory environment regulates epigenetic changes in the context of inflammatory arthritis remains unclear. Here we assessed the transcriptional and active enhancer profile of monocytes derived from the inflamed joints of JIA patients, a model well-suited for studying inflammatory arthritis. METHODS: RNA sequencing and H3K27me3 chromatin immunoprecipitation sequencing (ChIP-seq) were used to analyse the transcriptional and epigenetic profile, respectively, of JIA synovial fluid-derived monocytes. RESULTS: Synovial-derived monocytes display an activated phenotype, which is regulated on the epigenetic level. IFN signalling-associated genes are increased and epigenetically altered in synovial monocytes, indicating a driving role for IFN in establishing the local inflammatory phenotype. Treatment of synovial monocytes with the Janus-associated kinase (JAK) inhibitor ruxolitinib, which inhibits IFN signalling, transformed the activated enhancer landscape and reduced disease-associated gene expression, thereby inhibiting the inflammatory phenotype. CONCLUSION: This study provides novel insights into epigenetic regulation of inflammatory arthritis patient-derived monocytes and highlights the therapeutic potential of epigenetic modulation for the treatment of inflammatory rheumatic diseases.

Quantifying hospital-associated costs, and accompanying travel costs and productivity losses, before and after withdrawing tumour necrosis factor-alfa inhibitors in juvenile idiopathic arthritis.

OBJECTIVE: To quantify differences in hospital-associated costs, and accompanying travel costs and productivity losses, before and after withdrawing TNFi in JIA patients. METHODS: Retrospective analysis of prospectively collected data from electronic medical records of paediatric JIA patients treated with TNFi, which were either immediately discontinued, spaced (increased treatment interval) or tapered (reduced subsequent doses). Costs of hospital-associated resource use (consultations, medication, radiology procedures, laboratory testing, procedures under general anaesthesia, hospitalisation) and associated travel costs and productivity losses were quantified during clinically inactive disease until TNFi withdrawal (pre-withdrawal period) and compared with costs during the first and second year after withdrawal initiation (first and second year post-withdrawal). RESULTS: Fifty-six patients were included of whom 26 immediately discontinued TNFi, 30 spaced and zero tapered. Mean annual costs were €9,165/patient on active treatment (pre-withdrawal) and decreased significantly to €5,063/patient (-44.8%) and €6,569/patient (-28.3%) in the first and second year post-withdrawal, respectively (p< 0.05). Of these total annual costs, travel costs plus productivity losses were €834/patient, €1,180/patient, and €1,320/patient, in the three periods respectively. Medication comprised 80.7%, 61.5% and 72.4% of total annual costs in the pre-withdrawal, first, and second year post-withdrawal period, respectively. CONCLUSION: In the first two years after initiating withdrawal, the total annual costs are decreased compared with the pre-withdrawal period. However, cost reductions were lower in the second year compared with the first year post-withdrawal, primarily due to restarting or intensifying biologics. To support biologic withdraw decisions, future research should assess the full long-term societal cost impacts, and include all biologics.

Management of adult-onset Still's disease: evidence- and consensus-based recommendations by experts.

BACKGROUND: Adult-onset Still's disease (AOSD) is a rare condition characterized by fevers, rash, and arthralgia/arthritis. Most doctors treating AOSD in the Netherlands treat <5 patients per year. Currently, there is no internationally accepted treatment guideline for AOSD. OBJECTIVES: To conduct a Delphi panel aimed at reaching consensus about diagnostic and treatment strategies for patients with AOSD and to use the outcomes as a basis for a treatment algorithm. METHODS: The Delphi panel brought together 18 AOSD experts: rheumatologists, internists and paediatricians. The Delphi process consisted of 3 rounds. In the first two rounds, online list of questions and statements were completed. In the third round, final statements were discussed during a virtual meeting and a final vote took place. Consensus threshold was set at 80%. Two targeted literature searches were performed identifying the level of evidence of the consensus-based statements. RESULTS: Consensus was reached on 29 statements, including statements related to diagnosis and diagnostic tests, definition of response and remission, the therapy, the use of methotrexate, and tapering of treatment. The panel consented on reduction of the use of glucocorticoids to avoid side-effect, and preferred the use of biologics over conventional treatment. The role of interleukin-1 and interleukin-6 blocking agents was considered important in the treatment of AOSD. CONCLUSIONS: In this Delphi panel, a high level of consensus was achieved on recommendations for diagnosis and therapy of AOSD that can serve as a basis for a treatment guideline.

Siglec-1 expression on monocytes is associated with the interferon signature in juvenile dermatomyositis and can predict treatment response.

OBJECTIVE: JDM is a rare chronic immune-mediated inflammatory disease with a predominant role for type I IFN responses. We aimed to determine the potential of Siglec-1 expression on monocytes as a novel IFN-inducible biomarker for disease activity monitoring and prediction of treatment response in patients with JDM. METHODS: Siglec-1 was measured by flow cytometry on circulating monocytes of 21 newly diagnosed JDM patients before start of treatment and, for 10 of these, also during follow-up. The expression levels of five type I IFN-stimulated genes, MX1, IFI44, IFI44L, LY6E and IFIT3, were measured by RT-qPCR to determine the IFN signature and calculate an IFN score. IFN-inducible plasma proteins CXCL10 and galectin-9 were measured by multiplex immunoassay. RESULTS: Siglec-1 and IFN score were increased in JDM patients compared with controls and correlated with clinical disease activity. Stratification of patients by Siglec-1 expression at diagnosis identified those with high Siglec-1 expression as having a higher risk of requiring treatment intensification within the first 3 months after diagnosis (55% vs 0% of patients, P = 0.01). Siglec-1 expression strongly correlated with plasma levels of previously validated biomarkers CXCL10 (rs = 0.81, P < 0.0001) and galectin-9 (rs = 0.83, P < 0.0001), and was superior to the IFN score in predicting treatment response (area under the curve 0.87 vs 0.53, P = 0.01). CONCLUSION: Siglec-1 on monocytes is a novel IFN-inducible biomarker in JDM that correlates with clinical disease activity and identifies patients at risk for a suboptimal treatment response. Further studies are required to validate these findings and their clinical potential.

Consensus-based recommendations for the management of juvenile systemic sclerosis.

Juvenile systemic sclerosis (JSSc) is a rare disease of childhood and currently no international consensus exists with regard to its assessment and treatment. This SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) initiative, based on expert opinion informed by the best available evidence, provides recommendations for the assessment and treatment of patients with JSSc with a view to improving their outcome. Experts focused attention not only on the skin assessment but also on the early signs of internal organ involvement whose proper treatment can significantly affect the long-term outcome. A score for disease severity is proposed in order to perform a structured assessment of outcome over time but a validation in a wider patient population is recommended. Finally, a stepwise treatment approach is proposed in order to unify the standard of care throughout Europe with the aim to reduce morbidity and mortality in this disease.

Consensus-based recommendations for the management of juvenile localised scleroderma.

In 2012, a European initiative called Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile localised scleroderma (JLS) is a rare disease within the group of paediatric rheumatic diseases (PRD) and can lead to significant morbidity. Evidence-based guidelines are sparse and management is mostly based on physicians' experience. This study aims to provide recommendations for assessment and treatment of JLS. Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was formed, mainly from Europe, and consisted of 15 experienced paediatric rheumatologists and two young fellows. Recommendations derived from a validated systematic literature review were evaluated by an online survey and subsequently discussed at two consensus meetings using a nominal group technique. Recommendations were accepted if ≥80% agreement was reached. In total, 1 overarching principle, 10 recommendations on assessment and 6 recommendations on therapy were accepted with ≥80% agreement among experts. Topics covered include assessment of skin and extracutaneous involvement and suggested treatment pathways. The SHARE initiative aims to identify best practices for treatment of patients suffering from PRDs. Within this remit, recommendations for the assessment and treatment of JLS have been formulated by an evidence-informed consensus process to produce a standard of care for patients with JLS throughout Europe.

Molecular signature characterisation of different inflammatory phenotypes of systemic juvenile idiopathic arthritis.

OBJECTIVES: The International League of Associations for Rheumatology classification criteria define systemic juvenile idiopathic arthritis (SJIA) by the presence of fever, rash and chronic arthritis. Recent initiatives to revise current criteria recognise that a lack of arthritis complicates making the diagnosis early, while later a subgroup of patients develops aggressive joint disease. The proposed biphasic model of SJIA also implies a 'window of opportunity' to abrogate the development of chronic arthritis. We aimed to identify novel SJIA biomarkers during different disease phases. METHODS: Children with active SJIA were subgrouped clinically as systemic autoinflammatory disease with fever (SJIA syst ) or polyarticular disease (SJIA poly ). A discovery cohort of n=10 patients per SJIA group, plus n=10 with infection, was subjected to unbiased label-free liquid chromatography mass spectrometry (LC-MS/MS) and immunoassay screens. In a separate verification cohort (SJIA syst , n=45; SJIA poly , n=29; infection, n=32), candidate biomarkers were measured by multiple reaction monitoring MS (MRM-MS) and targeted immunoassays. RESULTS: Signatures differentiating the two phenotypes of SJIA could be identified. LC-MS/MS in the discovery cohort differentiated SJIA syst from SJIA poly well, but less effectively from infection. Targeted MRM verified the discovery data and, combined with targeted immunoassays, correctly identified 91% (SJIA syst vs SJIA poly ) and 77% (SJIA syst vs infection) of all cases. CONCLUSIONS: Molecular signatures differentiating two phenotypes of SJIA were identified suggesting shifts in underlying immunological processes in this biphasic disease. Biomarker signatures separating SJIA in its initial autoinflammatory phase from the main differential diagnosis (ie, infection) could aid early-stage diagnostic decisions, while markers of a phenotype switch could inform treat-to-target strategies.

Anakinra in children and adults with Still's disease.

Systemic juvenile idiopathic arthritis and adult-onset Still's disease are rare autoinflammatory disorders with common features, supporting the recognition of these being one disease-Still's disease-with different ages of onset. Anakinra was recently approved by the European Medicines Agency for Still's disease. In this review we discuss the reasoning for considering Still's disease as one disease and present anakinra efficacy and safety based on the available literature. The analysis of 27 studies showed that response to anakinra in Still's disease was remarkable, with clinically inactive disease or the equivalent reported for 23-100% of patients. Glucocorticoid reduction and/or stoppage was reported universally across the studies. In studies on paediatric patients where anakinra was used early or as first-line treatment, clinically inactive disease and successful anakinra tapering/stopping occurred in >50% of patients. Overall, current data support targeted therapy with anakinra in Still's disease since it improves clinical outcome, especially if initiated early in the disease course.

Recommendations for collaborative paediatric research including biobanking in Europe: a Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative.

Innovative research in childhood rheumatic diseases mandates international collaborations. However, researchers struggle with significant regulatory heterogeneity; an enabling European Union (EU)-wide framework is missing. The aims of the study were to systematically review the evidence for best practice and to establish recommendations for collaborative research. The Paediatric Rheumatology European Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) project enabled a scoping review and expert discussion, which then informed the systematic literature review. Published evidence was synthesised; recommendations were drafted. An iterative review process and consultations with Ethics Committees and European experts for ethical and legal aspects of paediatric research refined the recommendations. SHARE experts and patient representatives vetted the proposed recommendations at a consensus meeting using Nominal Group Technique. Agreement of 80% was mandatory for inclusion. The systematic literature review returned 1319 records. A total of 223 full-text publications plus 22 international normative documents were reviewed; 85 publications and 16 normative documents were included. A total of 21 recommendations were established including general principles (1-3), ethics (4-7), paediatric principles (8 and 9), consent to paediatric research (10-14), paediatric databank and biobank (15 and 16), sharing of data and samples (17-19), and commercialisation and third parties (20 and 21). The refined recommendations resulted in an agreement of >80% for all recommendations. The SHARE initiative established the first recommendations for Paediatric Rheumatology collaborative research across borders in Europe. These provide strong support for an urgently needed European framework and evidence-based guidance for its implementation. Such changes will promote research in children with rheumatic diseases.

Treating juvenile idiopathic arthritis to target: recommendations of an international task force.

Recent therapeutic advances in juvenile idiopathic arthritis (JIA) have made remission an achievable goal for most patients. Reaching this target leads to improved outcomes. The objective was to develop recommendations for treating JIA to target. A Steering Committee formulated a set of recommendations based on evidence derived from a systematic literature review. These were subsequently discussed, amended and voted on by an international Task Force of 30 paediatric rheumatologists in a consensus-based, Delphi-like procedure. Although the literature review did not reveal trials that compared a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated development of recommendations. The group agreed on six overarching principles and eight recommendations. The main treatment target, which should be based on a shared decision with parents/patients, was defined as remission, with the alternative target of low disease activity. The frequency and timeline of follow-up evaluations to ensure achievement and maintenance of the target depend on JIA category and level of disease activity. Additional recommendations emphasise the importance of ensuring adequate growth and development and avoiding long-term systemic glucocorticoid administration to maintain the target. All items were agreed on by more than 80% of the members of the Task Force. A research agenda was formulated. The Task Force developed recommendations for treating JIA to target, being aware that the evidence is not strong and needs to be expanded by future research. These recommendations can inform various stakeholders about strategies to reach optimal outcomes for JIA.

Prediction of inactive disease in juvenile idiopathic arthritis: a multicentre observational cohort study.

Objectives: To predict the occurrence of inactive disease in JIA in the first 2 years of disease. Methods: An inception cohort of 152 treatment-naïve JIA patients with disease duration <6 months was analysed. Potential predictors were baseline clinical variables, joint US, gut microbiota composition and a panel of inflammation-related compounds in blood plasma. Various algorithms were employed to predict inactive disease according to Wallace criteria at 6-month intervals in the first 2 years. Performance of the models was evaluated using the split-cohort technique. The cohort was analysed in its entirety, and separate models were developed for oligoarticular patients, polyarticular RF negative patients and ANA positive patients. Results: All models analysing the cohort as a whole showed poor performance in test data [area under the curve (AUC): <0.65]. The subgroup models performed better. Inactive disease was predicted by lower baseline juvenile arthritis DAS (JADAS)-71 and lower relative abundance of the operational taxonomic unit Mogibacteriaceae for oligoarticular patients (AUC in test data: 0.69); shorter duration of morning stiffness, higher haemoglobin and lower CXCL-9 levels at baseline for polyarticular RF negative patients (AUC in test data: 0.69); and shorter duration of morning stiffness and higher baseline haemoglobin for ANA positive patients (AUC in test data: 0.72). Conclusion: Inactive disease could not be predicted with satisfactory accuracy in the whole cohort, likely due to disease heterogeneity. Interesting predictors were found in more homogeneous subgroups. These need to be validated in future studies.

European evidence-based recommendations for diagnosis and treatment of paediatric antiphospholipid syndrome: the SHARE initiative.

Antiphospholipid syndrome (APS) is rare in children, and evidence-based guidelines are sparse. Consequently, management is mostly based on observational studies and physician's experience, and treatment regimens differ widely. The Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative was launched to develop diagnostic and management regimens for children and young adults with rheumatic diseases. Here, we developed evidence-based recommendations for diagnosis and treatment of paediatric APS. Evidence-based recommendations were developed using the European League Against Rheumatism standard operating procedure. Following a detailed systematic review of the literature, a committee of paediatric rheumatologists and representation of paediatric haematology with expertise in paediatric APS developed recommendations. The literature review yielded 1473 articles, of which 15 were valid and relevant. In total, four recommendations for diagnosis and eight for treatment of paediatric APS (including paediatric Catastrophic Antiphospholipid Syndrome) were accepted. Additionally, two recommendations for children born to mothers with APS were accepted. It was agreed that new classification criteria for paediatric APS are necessary, and APS in association with childhood-onset systemic lupus erythematosus should be identified by performing antiphospholipid antibody screening. Treatment recommendations included prevention of thrombotic events, and treatment recommendations for venous and/or arterial thrombotic events. Notably, due to the paucity of studies on paediatric APS, level of evidence and strength of the recommendations is relatively low. The SHARE initiative provides international, evidence-based recommendations for diagnosis and treatment for paediatric APS, facilitating improvement and uniformity of care.

Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in juvenile idiopathic arthritis patients.

OBJECTIVE: To determine association of erythrocyte methotrexate polyglutamates (MTX-PG) with disease activity and adverse effects in a prospective juvenile idiopathic arthritis (JIA) cohort. METHODS: One hundred and thirteen JIA patients were followed from MTX start until 12 months. Erythrocyte MTX-PGs with 1-5 glutamate residues were measured at 3 months with tandem mass spectrometry. The outcomes were Juvenile Arthritis Disease Activity Score (JADAS)-27 and adverse effects. To determine associations of MTX-PGs with JADAS-27 at 3 months and during 1 year of MTX treatment, linear regression and linear mixed-model analyses were used. To determine associations of MTX-PGs with adverse effects during 1 year of MTX treatment, logistic regression was used. Analyses were corrected for JADAS-27 at baseline and co-medication. RESULTS: Median JADAS-27 decreased from 12.7 (IQR: 7.8-18.2) at baseline to 2.9 (IQR: 0.1-6.5) at 12 months. Higher concentrations of MTX-PG3 (ß: -0.006, p=0.005), MTX-PG4 (ß: -0.015, p=0.004), MTX-PG5 (ß: -0.051, p=0.011) and MTX-PG3-5 (ß: -0.004, p=0.003) were associated with lower disease activity at 3 months. Higher concentrations of MTX-PG3 (ß: -0.005, p=0.028), MTX-PG4 (ß: -0.014, p=0.014), MTX-PG5 (ß: -0.049, p=0.023) and MTX-PG3-5 (ß: -0.004, p=0.018) were associated with lower disease activity over 1 year. None of the MTX-PGs was associated with adverse effects. CONCLUSIONS: In the first prospective study in JIA, long-chain MTX-PGs were associated with lower JADAS-27 at 3 months and during 1 year of MTX treatment. Erythrocyte MTX-PG could be a plausible candidate for therapeutic drug monitoring of MTX in JIA.

Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a disease of early onset which can lead to significant morbidity. In 2012, Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched with the aim of optimising and disseminating diagnostic and management regimens for children and young adults with rheumatic diseases. The objective was to establish recommendations for FMF focusing on provision of diagnostic tools for inexperienced clinicians particularly regarding interpretation of MEFV mutations. Evidence-based recommendations were developed using the European League against Rheumatism standard operating procedure. An expert committee of paediatric rheumatologists defined search terms for the systematic literature review. Two independent experts scored articles for validity and level of evidence. Recommendations derived from the literature were evaluated by an online survey and statements with less than 80% agreement were reformulated. Subsequently, all recommendations were discussed at a consensus meeting using the nominal group technique and were accepted if more than 80% agreement was reached. The literature search yielded 3386 articles, of which 25 were considered relevant and scored for validity and level of evidence. In total, 17 articles were scored valid and used to formulate the recommendations. Eight recommendations were accepted with 100% agreement after the consensus meeting. Topics covered were clinical versus genetic diagnosis of FMF, genotype-phenotype correlation, genotype-age at onset correlation, silent carriers and risk of amyloid A (AA) amyloidosis, and role of the specialist in FMF diagnosis. The SHARE initiative provides recommendations for diagnosing FMF aimed at facilitating improved and uniform care throughout Europe.