Objective. To design and validate a new questionnaire for identifying patients with methotrexate (MTX) intolerance, and to determine the prevalence of MTX intolerance in patients with juvenile idiopathic arthritis (JIA) using this questionnaire.Methods. The MTX Intolerance Severity Score (MISS) questionnaire was constructed, consisting of 5 domains: stomach ache, nausea, vomiting, sore mouth, and behavioral symptoms. The domains each consisted of 3 questions pertaining to the presence of a symptom upon, prior to (anticipatory), and when thinking of (associative) MTX intake. The MISS questionnaire was validated in 86 patients by determining its discriminative power between patients with and those without MTX intolerance, identified as such by a gold standard (physician's opinion). Using the MISS questionnaire, the prevalence of MTX intolerance was determined in 297 JIA patients.Results. The MISS questionnaire discriminated well between MTX-intolerant and MTX-tolerant patients. A cutoff score of 6 yielded the best sensitivity (88%) and specificity (80%). MTX intolerance was found in 150 (50.5%) of 297 patients. Of 220 patients receiving oral MTX, 98 (44.5%) experienced MTX intolerance, whereas 67.5% of 77 patients receiving parenteral MTX experienced intolerance to the drug (P ‫؍‬ 0.001).Conclusion. Our findings indicate that the MISS questionnaire is a highly sensitive and specific tool for the diagnosis of MTX intolerance, and that there is a high prevalence of MTX intolerance among JIA patients. The prevalence of intolerance in patients receiving parenteral MTX exceeds that in patients receiving oral MTX. The frequent occurrence of anticipatory and associative symptoms suggests that classic conditioning plays an important role in MTX intolerance.

Objective Systemic juvenile idiopathic arthritis (JIA) is a multifactorial autoinflammatory disease with a historically poor prognosis. With current treatment regimens, approximately half of patients still experience active disease after 1 year of therapy. This study was undertaken to evaluate a treat‐to‐target approach using recombinant interleukin‐1 receptor antagonist (rIL‐1Ra; anakinra) as first‐line monotherapy to achieve early inactive disease and prevent damage. Methods In this single‐center, prospective study, patients with new‐onset systemic JIA with an unsatisfactory response to nonsteroidal antiinflammatory drugs received rIL‐1Ra monotherapy according to a treat‐to‐target strategy. Patients with an incomplete response to 2 mg/kg rIL‐1Ra subsequently received 4 mg/kg rIL‐1Ra or additional prednisolone, or switched to alternative therapy. For patients in whom inactive disease was achieved, rIL‐1Ra was tapered after 3 months and subsequently stopped. Results Forty‐two patients, including 12 who had no arthritis at disease onset, were followed up for a median of 5.8 years. The median time to achieve inactive disease was 33 days. At 1 year, 76% had inactive disease, and 52% had inactive disease while not receiving medication. High neutrophil counts at baseline and a complete response after 1 month of rIL‐1Ra were highly associated with inactive disease at 1 year. After 5 years of follow‐up, 96% of the patients included had inactive disease, and 75% had inactive disease while not receiving medication. Articular or extraarticular damage was reported in <5%, and only 33% of the patients received glucocorticoids. Treatment with rIL‐1Ra was equally effective in systemic JIA patients without arthritis at disease onset. Conclusion Treatment to target, starting with first‐line, short‐course monotherapy with rIL‐1Ra, is a highly efficacious strategy to induce and sustain inactive disease and to prevent disease‐ and glucocorticoid‐related damage in systemic JIA.

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Objective To assess the composition of gut microbiota in Italian and Dutch patients with juvenile idiopathic arthritis ( JIA ) at baseline, with inactive disease, and with persistent activity compared to healthy controls. Methods In a multicenter, prospective, observational cohort study, fecal samples were collected at baseline from 78 Italian and 21 Dutch treatment‐naive JIA patients with <6 months of disease duration and compared to 107 geographically matched samples from healthy children. Forty‐four follow‐up samples from patients with inactive disease and 25 follow‐up samples from patients with persistent activity were analyzed. Gut microbiota composition was determined by 16S ribosomal RNA –based metagenomics. Alpha‐ and β‐diversity were computed, and log ratios of relative abundance were compared between patients and healthy controls using random forest models and logistic regression. Results Baseline samples from Italian patients showed reduced richness compared to healthy controls ( P < 0.001). Random forest models distinguished between Italian patient baseline samples and healthy controls and suggested differences between Dutch patient samples and healthy controls (areas under the curve >0.99 and 0.71, respectively). The operational taxonomic units ( OTU s) of Erysipelotrichaceae (increased in patients) , Allobaculum (decreased in patients), and Faecalibacterium prausnitzii (increased in patients) showed different relative abundance in Italian patient baseline samples compared to controls after controlling for multiple comparisons. Some OTU s differed between Dutch patient samples and healthy controls, but no evidence remained after controlling for multiple comparisons. No differences were found in paired analysis between Italian patient baseline and inactive disease samples. Conclusion Our findings show evidence for dysbiosis in JIA patients. Only patient/control status, age, and geographic origin appear to be drivers of the microbiota profiles, regardless of disease activity stage, inflammation, and markers of autoimmunity.

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Juvenile idiopathic arthritis (JIA) is the leading cause of childhood disability from a musculoskeletal disorder. It generally affects large joints such as the knee and the ankle, often causing structural damage. Different factors contribute to the damage onset, including altered joint loading and other mechanical factors, associated with pain and inflammation. The prediction of patients’ joint loading can hence be a valuable tool in understanding the disease mechanisms involved in structural damage progression. A number of lower-limb musculoskeletal models have been proposed to analyse the hip and knee joints, but juvenile models of the foot are still lacking. This paper presents a modelling pipeline that allows the creation of juvenile patient-specific models starting from lower limb kinematics and foot and ankle MRI data. This pipeline has been applied to data from three children with JIA and the importance of patient-specific parameters and modelling assumptions has been tested in a sensitivity analysis focused on the variation of the joint reaction forces. This analysis highlighted the criticality of patient-specific definition of the ankle joint axes and location of the Achilles tendon insertions. Patient-specific detection of the Tibialis Anterior, Tibialis Posterior, and Peroneus Longus origins and insertions were also shown to be important.Electronic supplementary materialThe online version of this article (doi:10.1007/s10439-015-1451-z) contains supplementary material, which is available to authorized users.

BackgroundMethotrexate (MTX) is an effective and safe drug in the treatment of juvenile idiopathic arthritis (JIA). Despite its safety, MTX-related gastrointestinal adverse effects before and after MTX administration, termed MTX intolerance, occur frequently, leading to non-compliance and potentially premature MTX termination. The aim of this study was to construct a risk model to predict MTX intolerance.MethodsIn a prospective JIA cohort, clinical variables and single nucleotide polymorphisms were determined at MTX start. The Methotrexate Intolerance Severity Score was employed to measure MTX intolerance in the first year of treatment. MTX intolerance was most prevalent at 6 or 12 months after MTX start, which was defined as the outcome for the prediction model. The model was developed in 152 patients using multivariable logistic regression analysis and subsequently internally validated using bootstrapping.ResultsThe prediction model included the following predictors: JIA category, antinuclear antibody, parent/patient assessment of pain, Juvenile Arthritis Disease Activity Score-27, thrombocytes, alanine aminotransferase and creatinine. The model classified 77.5% of patients correctly, and 66.7% of patients after internal validation by bootstrapping. The lowest predicted risk of MTX intolerance was 18.9% and the highest predicted risk was 85.9%. The prediction model was transformed into a risk score (range 0–17). At a cut-off of ≥6, sensitivity was 82.0%, specificity 56.1%, positive predictive value was 58.7% and negative predictive value 80.4%.ConclusionsThis clinical prediction model showed moderate predictive power to detect MTX intolerance. To develop into a clinically usable tool, it should be validated in an independent cohort and updated with new predictors. Such an easy-to-use tool could then assist clinicians in identifying patients at risk to develop MTX intolerance, and in turn to monitor them closely and intervene timely in order to prevent the development of MTX intolerance.Trial registrationISRCTN register, www.isrctn.com, ISRCTN13524271

ObjectivesTo assess if the Juvenile Arthritis Disease Activity Score (JADAS71) could be used to correctly identify patients with juvenile idiopathic arthritis (JIA) in need of antitumour necrosis factor therapy (anti-TNF) therapy 3 and 6 months after start of methotrexate (MTX).MethodsMonocentric retrospective cohort study from 2011 to 2015 analysing all patients with oligoarticular JIA (OJIA) (n=39) and polyarticular course JIA (PJIA) (n=74) first starting MTX. Three and 6 months after MTX start, clinical and laboratory features and the 2011 American College of Rheumatology (ACR) JIA treatment recommendations (ACR clinical practice guideline (ACR-CPG)) were compared between groups starting and not starting anti-TNF therapy. The sensitivity and specificity of the ACR-CPG, JADAS71 and the clinical JADAS to identify non-responders after 12 months were calculated.ResultsPhysicians escalated patients with significantly higher physician global assessment, clinical JADAS (cJADAS) and patient Visual Analogue Scale (VAS). The decision not to escalate was correct in 70%–75% as shown by MTX response. The implementation of the ACR-CPG would increase the current anti-TNF use from 12% to 65%. The use of (c)JADAS in identifying patients in need of anti-TNF therapy outperformed the ACR-CPG with a much higher sensitivity, specificity and accuracy. The cJADAS threshold for treatment escalation at month 3 and 6 was >5 and >3 for OJIA and >7 and >4 for PJIA, respectively. The performance of the cJADAS decreased when the patient VAS contribution to the total score was restricted and overall did not improve by adding the erythrocyte sedimentation rate.ConclusionsThe cJADAS identifies patients in need of anti-TNF and is a user-friendly tool ready to be used for treat to target in JIA. The patient VAS is a critical item in the cJADAS for the decision to escalate to anti-TNF.