OBJECTIVES:To explore the association between serum S100A8/9 (calprotectin), clinical and ultrasound (US) assessment in juvenile idiopathic arthritis (JIA) patients.METHODS:A total of 30 well-characterised consecutive patients (18 female) with non-systemic JIA and 20 age-matched healthy controls were included. Serum and plasma samples obtained the same day of the clinical and sonographical assessment were tested for calprotectin levels by ELISA. Clinical status was defined using Wallace criteria. Ultrasonographic B-mode and power Doppler (PD) assessment of 44 joints for each subject was performed.RESULTS:Clinically active disease was present in 14 patients, while 16 patients were active according to US evaluation. We found no differences in the serum/plasma calprotectin levels in clinically active disease group [29.6 (5.4-198.1) ng/ml; 12.6 (2.8-65.8) ng/ml] as compared with inactive disease group [24.8 (14.1-204.3); 12.7 (3.4-65.1)] (p=0.73; p=0.29). There was also no difference between US active disease [29.8 (5.4-204.3); 12.9 (2.8-65.8)] and US inactive disease [24.8 (12.1-197.1); 11.7 (3.4-44.2)] with regard to the serum/plasma calprotectin levels (p=0.83; p=1.0). Serum/plasma calprotectin levels correlated moderately with C-reactive protein (CRP) (Spearman r=0.44, p=0.01; Spearman r=0.56, p=0.0021).CONCLUSIONS:To our knowledge, this is the first study to simultaneously examine the correlation between serum/plasma calprotectin levels, clinical and US assessment in JIA. Calprotectin was not associated with the disease status in JIA patients with low number of active joints and its levels were moderately correlated with CRP. Our preliminary study needs to be extended with a larger number of patients.

Objective. To assess the relationship between infection risk and abatacept (ABA) exposure levels in patients with polyarticular-course juvenile idiopathic arthritis (pJIA) following treatment with subcutaneous (SC) and intravenous (IV) ABA. Methods. Data from 2 published studies (ClinicalTrials.gov: NCT01844518, NCT00095173) of ABA treatment in pediatric patients were analyzed. One study treated patients aged 2–17 years with SC ABA and the other treated patients aged 6–17 years with IV ABA. Association between serum ABA exposure measures and infection was evaluated using Kaplan-Meier plots of probability of first infection vs time on treatment by ABA exposure quartiles and log-rank tests. Number of infections by ABA exposure quartiles was investigated. Results. Overall, 343 patients were included in this analysis: 219 patients received SC ABA and 124 patients received IV ABA. Overall, 237/343 (69.1%) patients had ≥ 1 infection over 24 months. No significant difference in time to first infection across 4 quartiles of ABA exposure levels was observed in the pooled (P = 0.45), SC (2–5 yrs: P = 0.93; 6–17 yrs: P = 0.48), or IV (P = 0.50) analyses. Concomitant use of methotrexate and glucocorticoids (at baseline and throughout) with ABA did not increase infection risk across the ABA exposure quartiles. There was no evidence of association between number of infections and ABA exposure quartiles. No opportunistic infections related to ABA were reported. Conclusion. In patients aged 2–17 years with pJIA, no evidence of association between higher levels of exposure to IV ABA or SC ABA and incidence of infection was observed.

Following publication of the original article [1], we have been notified that the author Joan Calzada should not have been included to the team of authors. The authors' team, thus, should be as follows:

Juvenile Idiopathic Arthritis (JIA) is one of the most common chronic diseases in children. Recently, the management of JIA has substantially changed, thanks to the availability of new treatment options, represented by biological drugs or biologics. These drugs modulate the specific mechanisms of the immune systems, such as TNF-α, IL-1 and IL-6 signaling, or lymphocyte activation and/or functioning. In this review, we provide a comprehensive discussion on the current recommendations and clinical evidence regarding the use of the available biologics in the treatment of JIA; moreover, the main pharmacokinetic and pharmacodynamic aspects of any specific biologic drug have been summarized.

BackgroundSjögren syndrome (SS) is a chronic autoimmune disorder characterized by inflammation of the lacrimal and salivary glands leading to oral and ocular dryness. Childhood SS is rare and poorly defined and underdiagnosed owing to the lack of child-specific diagnostic or classification criteria [1].ObjectivesThe purpose of this study is to describe five cases with pediatric SS in order to better clarify the characteristics of the disease in the childhood.MethodsWe retrospectively reviewed medical records of patients with pediatric SS referring to our center (ASST-PINI-CTO, University of Milan) from November 2008 to December 2018. No adequate childhood SS-specific criteria exist. Therefore we select our pts according to a combination of clinical, serological, histopatological findings. For the assessment of systemic disease activity we applied ESSDAI (EULAR Sjögren’s syndrome disease activity index). We calculated ESSDAI at diagnosis, at the peak disease activity and at the last follow up visit.ResultsWe collected data on 5 pts (4 females). The mean of age at onset is 8.4 yrs (range 4.8-11.2). The mean of age at diagnosis is 10.8 (range 6.5-13.3). The follow up period varied from 1.2 to 9.3 yrs (mean 6.3). The most common manifestations were parotid/salivary glands swelling (5/5 pts) and articular involvement (5/5 pts) with arthritis in 2 pts and arthralgia in the others. Nobody of our pts presented dryness of eyes. Xerostomia was found in 2/5 pts. Fever and fatigue occurred in 2/5 and 3/5 pts respectively. We also recorded 2 cases of abdominal pain, 1 case of glomerular proteinuria, 2 cases of purpura and 1 case of erythema nodosum. ANA, anti-SSA, anti-SSB, RF, elevation of ERS and hypergammaglobulinemia (1.6 – 8.04 g/dl) were present in all cases. Minor salivary gland biopsy was performed in 4 pts resulting in histological evidence of focal lymphocytic sialadenitis (one of them showed chronic sialadenitis with a focus score <1/4mm2). Ultrasound studies of salivary glands were positive in 5/5 cases. Mean ESSDAI scores at diagnosis, peak activity and the last follow up visit were 8 (range 5-11), 13.2 (9-20), 4.8 (0-9). The most frequently involved domains at the peak activity were biological (5/5), parotid/salivary glands swelling (5/5) and articular (5/5). No major complications have been observed. With regard to treatment, all patient received corticosteroids and DMARDs (5/5 hydroxychloroquine, 3/5 methotrexate, 1/5 azathioprine, 1/5 leflunomide); one patient needed plasmapheresis and immunosuppressive therapy with cyclophosphamide. Biological therapy was administered to 2 patients: 1 received belimumab and then rituximab, while the other patient received rituximab.ConclusionXerostomia and keratoconjunctivitis sicca are not a common features in children, on the other hand juvenile SS has higher incidence of recurrent parotid swellings than adults [2, 3]. All pts had laboratory abnormalities. The long-term prognosis of pediatric SS is unknown, in our series only 2 patients were inactive (ESSDAI score <5, according to the definition by EULAR) at last evaluation, 3 were moderately active with a minimal clinically important improvement (MCII) observed in all of them [4].References[1] Lieberman SM. Curr Opin Rheumatol, 2013. [2] Kobayashi I et al, Modern Rheumatology, 2018. [3] Cimaz Ret al, Eur J Pediatr, 2003 [4] Seror Ret al, RMD Open, 2015.Disclosure of InterestsNone declared

Abstract Background JIA-associated uveitis (JIAU) is a serious, sight-threatening disease with significant long-term complications and risk of blindness, even with improved contemporary treatments. The MIWGUC was set up in order to propose specific JIAU activity and response items and to validate their applicability for clinical outcome studies. Methods The group consists of 8 paediatric rheumatologists and 7 ophthalmologists. A consensus meeting took place on November 2015 in Barcelona (Spain) with the objective of validating the previously proposed measures. The validation process was based on the results of a prospective open, international, multi-centre, cohort study designed to validate the outcome measures proposed by the initial MIWGUC group meeting in 2012. The meeting used the same Delphi and nominal group technique as previously described in the first paper from the MIWGUC group (Arthritis Care Res 64:1365–72, 2012). Patients were included with a diagnosis of JIA, aged less than 18 years, and with active uveitis or an uveitis flare which required treatment with a disease-modifying anti-rheumatic drug. The proposed outcome measures for uveitis were collected by an ophthalmologist and for arthritis by a paediatric rheumatologist. Patient reported outcome measures were also measured. Results A total of 82 patients were enrolled into the validation cohort. Fifty four percent (n = 44) had persistent oligoarthritis followed by rheumatoid factor negative polyarthritis (n = 15, 18%). The mean uveitis disease duration was 3.3 years (SD 3.0). Bilateral eye involvement was reported in 65 (79.3%) patients. The main findings are that the most significant changes, from baseline to 6 months, are found in the AC activity measures of cells and flare. These measures correlate with the presence of pre-existing structural complications and this has implications for the reporting of trials using a single measure as a primary outcome. We also found that visual analogue scales of disease activity showed significant change when reported by the ophthalmologist, rheumatologist and families. The measures formed three relatively distinct groups. The first group of measures comprised uveitis activity, ocular damage and the ophthalmologists’ VAS. The second comprised patient reported outcomes including disruption to school attendance. The third group consisted of the rheumatologists’ VAS and the joint score. Conclusions We propose distinctive and clinically significant measures of disease activity, severity and damage for JIAU. This effort is the initial step for developing a comprehensive outcome measures for JIAU, which incorporates the perspectives of rheumatologists, ophthalmologists, patients and families.

Juvenile Idiopathic Arthritis (JIA) is one of the most common chronic diseases in children. Recently, the management of JIA has substantially changed, thanks to the availability of new treatment options, represented by biological drugs or biologics. These drugs modulate specific mechanisms of the immune systems, such as TNF-alpha, IL-1 and IL-6 signaling, or lymphocyte activation and/or functioning. In this review, we provide a comprehensive discussion on the current recommendations and clinical evidences regarding the use of the available biologics in the treatment of JIA; moreover, the main pharmacokinetic and pharmacodynamic aspects of any specific biologic drug have been summarized.

Objectives To define the correlation between joint ultrasonography and clinical examination in patients with juvenile idiopathic arthritis (JIA) and to assess whether synovitis detected by ultrasonography in clinically inactive patients predicts arthritis flares. Methods 88 consecutive patients with JIA-46 (52%) with persistent oligoarthritis, 15 (17%) with extended oligoarthritis, 15 (17%) with rheumatoid factor-negative polyarthritis and 12 (14%) with other forms of JIA, all clinically inactive for a minimum of 3 months-underwent ultrasound (US) assessment of 44 joints. Joints were scanned at study entry for synovial hyperplasia, joint effusion and power Doppler (PD) signal. Patients were followed clinically for 4 years. Results US was abnormal in 20/88 (22.7%) patients and in 38/3872 (0.98%) joints. Extended oligoarthritis and rheumatoid factor-negative polyarthritis were more frequent in US-positive than in US-negative patients (35.0% vs 11.8% and 30.0% vs 13.2%, respectively; P=0.005). During 4 years of follow-up, 41/88 (46.6%) patients displayed a flare; 26/68 (38.2%) were US-negative and 15/20 (75%) were US-positive at baseline. Abnormality on US examination, after correction for therapy modification, significantly increased the risk of flare (OR=3.8, 95% CI 1.2 to 11.5). The combination of grey scale and PD abnormalities displayed a much higher predictive value of relapse (65%, 13/20) than grey scale alone (33%, 6/18). Conclusions US abnormalities are a strong predictor of relapse at individual patient level. Irrespective of treatment, the risk of flare in US-positive versus US-negative patients was almost four times higher. In case of US abnormalities, patients should be carefully followed regardless of both the International League of Associations for Rheumatology and Wallace categories.

The aim of this study is to retrospectively analyze 10-year drug survival of first-line TNF inhibitor (TNFi) in rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA) patients, comparing withdrawal rates and discontinuation pattern between adult- and juvenile-onset populations. RA, AS, PsA, and JIA patients treated with infliximab, etanercept, or adalimumab as first TNFi between 1999 and 2015 were extracted from a local registry. Drug survival up to 10-year follow-up was evaluated by the Kaplan-Meier method and compared according to age (adult vs juvenile onset), TNFi agent, and discontinuation reason by a stratified log-rank test. Three hundred sixty JIA (205 etanercept, 66 adalimumab, and 89 infliximab) and 951 (607 RA, 188 AS, and 156 PsA) adult patients (464 infliximab, 262 adalimumab, and 225 etanercept) were included. After exclusion of systemic-onset JIA (18.5%), overall 10-year retention rate was 31.8%, with no difference between adult- and juvenile-onset patients (32.1 and 30.2%, respectively; HR 0.938 [95% CI 0.782–1.125]). Etanercept showed the highest drug survival in adult-onset population (p < 0.0001 vs both monoclonal antibodies) and infliximab the lowest in juvenile-onset population (p = 0.005 vs adalimumab and p < 0.0001 vs etanercept). Inefficacy was the most frequent reason for TNFi withdrawal in adult population (29.75%) with a significantly higher risk of discontinuation than in juvenile-onset subgroup (HR 1.390 [95% CI 1.060–1.824]). Serious infections and malignancies caused TNFi withdrawal only in adult whereas gastrointestinal, neuropsychiatric, and ocular complications quite only in juvenile patients. Despite a similar 10-year drug survival, adult- and juvenile-onset subpopulations showed a significantly different pattern of TNFi reasons for discontinuation.

Poddighe, Dimitri MD*; Romano, Micol MD†; Gattinara, Maurizio MD†; Gerloni, Valeria MD† Author Information

Canakinumab is a human anti-interleukin-1β (IL-1β) monoclonal antibody neutralizing IL-1β-mediated pathways. We sought to characterize the molecular response to canakinumab and evaluate potential markers of response using samples from two pivotal trials in systemic juvenile idiopathic arthritis (SJIA).

Background MRP8/14 (also known as calprotectin) has been widely studied as potential predictor of disease activity and response to treatment in inflammatory diseases. In Juvenile Idiopathic Arthritis (JIA), MRP8/14 levels are highly predictive of disease flares in systemic JIA. In a more heterogeneous group of JIA patients (pts), MRP8/14 levels have been shown to predict response to MTX. High levels of baseline MRP8/14 are associated with good response to anti-TNF treatment, whereas elevated MRP8/14 levels at time of discontinuation are associated with higher chance to flare. In clinical practice, ultrasound could be usefull to define the state of disease activity. Indeed, PD-US assessment of synovial vascularization has been shown to be more sensitive than serum markers of inflammation in the identification of active disease in JIA. Objectives To explore the association between calprotectin, clinical and US assessment in JIA pts. Methods A total of 30 consecutive pts (aged under 18 years) with oligo or poly JIA were assessed by US, clinical examination and MRP8/14 serum levels. Serum MRP8/14 was measured by ELISA in all pts and in 20 age matched healthy controls. Ultrasonographic B-mode and power Doppler assessment of 44 joints each pts were performed. Patients were evaluated using Wallace criteria. Results 30 consecutive non systemic JIA pts (F 18) were evaluated: 13 persistent and 8 extended oligoarticular, 6 polyarticular (1 RF positive), 2 ERA, 1 psoriatic JIA. Median age at disease onset was 10.6 yrs (mean 10.8, range 2–16). Mean disease duration was 5.4 yrs (range 0.1–15.9). Mean active joints was 2 (range 0–26). 14 pts were active according to Wallace criteria and 16 pts were active according to US evaluation. Ultrasonographic B-mode and power Doppler assessment was significantly correlated with clinical examination (Mcnemar test p=0.683, Cohen9s K 0.602). The majority of our enrolled pts were in phase of oligoarticular involvement with minimal disease activity (median active joints=0). No statistically significant difference in serum MRP8/14 was found between all JIA pts and healthy controls (p=0.33). No statistically significant difference in serum MRP8/14 was found between active (according to clinical examination) JIA pts and healthy controls (p=0.69) and between inactive JIA pts and healthy control (p=0.23). Concentrations of MRP8/14 in active and inactive pts according to Wallace were not significantly different (p=0.75). No statistically significant difference in serum MRP8/14 was found between active and inactive pts according to US assessment (0.85). Only 6 pts (4 out of 6 with polyarticular course) showed calprotectin levels higher than normal. We found a correlation between calprotectin and CRP (Spearman r 0.4380, p=0.01) and between calprotectin and ESR (Spearman r 0.3800, p=0.05). Conclusions To our knowledge this is the first study to examine the correlation between MRP8/14 levels, clinical and US assessment in JIA. Serum levels of MRP8/14 (a biomarker of activation of the innate immune system) are not significatively different in oligoarticular JIA from healthy controls. Calprotectin high levels, could be related with a poliarticular disease either in clinical activity or in subclinical remission. However our study need to be extended to a larger number of pts followed prospectively. Disclosure of Interest None declared

BACKGROUND:Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy. METHODS:We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m2; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70. FINDINGS:Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32%) patients assigned to intra-articular corticosteroids alone and 39 (37%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0·48). Adverse events were recorded for 20 (17%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event. INTERPRETATION:Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis. FUNDING:Italian Agency of Drug Evaluation.

Background: Data from routine clinical practice are needed to further define the efficacy and safety of biologic medications in children with juvenile idiopathic arthritis (JIA). The aim of this analysis was to investigate the disease status, reasons for discontinuation and adverse events in Italian JIA patients treated with etanercept (ETN).Methods: In 2013, all centers of the Italian Pediatric Rheumatology Study Group were asked to make a census of patients given ETN after January 2000. Patients were classified in three groups: group 1 = patients still taking ETN; group 2 = patients discontinued from ETN for any reasons; group 3 = patients lost to follow-up while receiving ETN. All three groups received a retrospective assessment; patients in group 1 also underwent a cross-sectional assessment.Results: 1038 patients were enrolled by 23 centers: 422 (40.7%) were in group 1, 462 (44.5%) in group 2, and 154 (14.8%) in group 3. Median duration of ETN therapy was 2.5 years. At cross-sectional assessment, 41.8% to 48.6% of patients in group 1 met formal criteria for inactive disease, whereas 52.4% of patients in group 2 and 55.8% of patients in group 3 were judged in clinical remission by their caring physician at last visit. A relatively greater proportion of patients with systemic arthritis were discontinued or lost to follow-up. Parent evaluations at cross-sectional visit in group 1 showed that 52.4% of patients had normal physical function, very few had impairment in quality of life, 51.2% had no pain, 76% had no morning stiffness, and 82.7% of parents were satisfied with their child's illness outcome. Clinically significant adverse events were reported for 27.8% of patients and ETN was discontinued for side effects in 9.5%. The most common adverse events were new onset or recurrent uveitis (10.2%), infections (6.6%), injection site reactions (4.4%), and neuropsychiatric (3.1%), gastrointestinal (2.4%), and hematological disorders (2.1%). Ten patients developed an inflammatory bowel disease and 2 had a malignancy. One patient died of a fulminant streptococcal sepsis.Conclusions: Around half of the patients achieved complete disease quiescence under treatment with ETN. The medication was overall well tolerated, as only one quarter of patients experienced clinically significant adverse events and less than 10% had treatment discontinued for toxicity.