J.M. van den Berg

Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide

Artemis deficiency is known to result in classical T−B− severe combined immunodeficiency (SCID) in case of Artemis null mutations, or Omenns syndrome in case of hypomorphic mutations in the Artemis gene. We describe two unrelated patients with a relatively mild clinical T−B− SCID phenotype, caused by different homozygous Artemis splice-site mutations. The splice-site mutations concern either dysfunction of a 5′ splice-site or an intronic point mutation creating a novel 3′ splice-site, resulting in mutated Artemis protein with residual activity or low levels of wild type (WT) Artemis transcripts. During the first 10 years of life, the patients suffered from recurrent infections necessitating antibiotic prophylaxis and intravenous immunoglobulins. Both mutations resulted in increased ionizing radiation sensitivity and insufficient variable, diversity and joining (V(D)J) recombination, causing B-lymphopenia and exhaustion of the naive T-cell compartment. The patient with the novel 3′ splice-site had progressive granulomatous skin lesions, which disappeared after stem cell transplantation (SCT). We showed that an alternative approach to SCT can, in principle, be used in this case; an antisense oligonucleotide (AON) covering the intronic mutation restored WT Artemis transcript levels and non-homologous end-joining pathway activity in the patient fibroblasts.

Anticarbamylated protein (anti-CarP) antibodies are present in sera of juvenile idiopathic arthritis (JIA) patients

In juvenile idiopathic arthritis (JIA) patients there is a lack of markers that predict severe disease. Although anticitrullinated protein antibodies (ACPA) have contributed substantially to the understanding of rheumatoid arthritis (RA),1 their detection in JIA has not been equally useful as incidence rates in JIA patients are low2 and merely confined to the polyarticular immunoglobulin (Ig)M-rheumatoid factor (RF)-positive category resembling RA. Recently, anticarbamylated protein (anti-CarP) antibodies were detected in 45% of RA patients and importantly also in 16%–20% ACPA-negative patients.3–5 Within the ACPA-negative patients, anti-CarP antibodies were associated with more severe radiographic progression.3 Since most JIA patients are ACPA-negative we investigated whether anti-CarP antibodies are present in the sera of JIA patients and how they are related to ACPA and IgM-RF.nnJIA patients from three Dutch sources were included: the BeSt for Kids trial (NTR 1574, a treatment strategy study) (n=33), a previously described cohort6 (n=48) and the Arthritis and Biologicals in Children (ABC) register7 (n=153). Healthy controls (n=107) (mean age/range 11/(2–20)) are stem-cell graft …

PReS-FINAL-2160: Intestinal microbiome in polyarticular juvenile idiopathic arthritis: a pilot study

The intestinal microbiome may play a role in the pathogenesis of Juvenile Idiopathic Arthritis (JIA). In IBD patients an overall decrease in microbial diversity of the intestinal microbiota has been observed. Studies comparing intestinal microbiome in children with JIA and healthy controls have not been conducted to date.

PReS-FINAL-2146: Trends in prescription of biologics and outcomes of juvenile idiopathic arthritis; results of the Dutch national arthritis and biologicals in children register.

Treatment of juvenile idiopathic arthritis (JIA) has changed dramatically since the introduction of biologics in 1999. Because of more insight in the cytokines involved in JIA the number of available biologic agents increased. Together with the introduction of these new drugs, new insights in the optimal treatment of JIA indicate that earlier and more aggressive therapy is associated with better outcomes. Whether these developments with regard to biologic treatment have resulted in better patients outcomes in daily practice is not yet reported.

An Unusual Cause of a Recurrent Liver Abscess in a Young Boy

DIS 5.4.0 DTD YGAST60700 proof 2 January 2017 8:41 pm ce Gastr 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 Question: A boy, 6 months of age and previously healthy, was evaluated for unexplained fever of 2 weeks’ duration. He was ill appearing and had a high white blood cell count (19.5 10/L) and C-reactive protein (CRP) of 265 mg/L. The diagnosis of a liver abscess sup84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 posedly by a bacterial pathogen was made based on abdominal ultrasound (US) examination, which showed an abscess in the left lobe (segments 2 and 3). The abscess was drained and amoxicillin/clavulanic acid, which had been initiated before drainage, was continued for 5 weeks. Cultures of the drained purulent fluid and blood remained negative. The boy recovered fully and the fever disappeared. US examination 4 weeks after drainage showed a small cavity with clear fluid at the site of the initial abscess. Four weeks after the end of the antibiotic course, he presented again with fever and discomfort. Laboratory tests showed leukocytosis and elevated CRP; US examination showed recurrence of the liver abscess. The abscess was drained again and amoxicillin/clavulanic acid for 5 weeks was started. Four weeks into the second antibiotic course, he presented with feeding difficulties and bouts of painful crying. He had no fever and CRP was only mildly elevated (13 mg/L). On US examination, the liver abscess had decreased in size compared with 4 weeks earlier. However, an additional cystic structure between the stomach and liver, adjacent to the liver abscess, was noted. The cyst was hypoechoic and had a multiple layered wall (Figure A, arrow). Magnetic resonance imaging showed the liver abscess (Figure B, black arrow) and adjacent a tubular cyst between the liver and the antrum of the stomach (Figure B, white arrow), which was 1.3 cm in diameter and filled with clear fluid. What is the diagnosis of the cyst? What is the most likely cause of the recurrent liver abscess? Look on page 000 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. 101 102 103 104 105 106 107 Conflicts of interest The authors disclose no conflicts.

OP0297 Trends in Prescription of Biologics and Outcomes of Juvenile Idiopathic Arthritis; Results of the Dutch National Arthritis and Biologicals in Children Register

Background Treatment of juvenile idiopathic arthritis (JIA) has changed dramatically since the introduction of biologics in 1999. Because of more insight in the immunological and biological pathways involved in the development of JIA the number of available biologic agents increased. Together with the introduction of these new drugs, also new insights in the optimal treatment of JIA indicate that earlier and more aggressive therapy is associated with better outcomes. Whether these new insights with regard to biologic treatment have been adopted in daily practice and resulted in better patients’ outcomes is not yet reported. Objectives o evaluate trends in prescription of biologics and influence on outcomes of Dutch JIA patients that started their first biologic between 1999 and 2010. Methods The Arthritis and Biologicals in Children register (a multicenter prospective observational study) aims to include all JIA patients in the Netherlands who use or used biologic agents since 1999. Patients were divided in time periods according to the year of introduction of first biologic agent. Trends in characteristics of patients before introduction of first biologic and effectiveness of the first biologic were analyzed over a 12 year period. Results 343 non-systemic and 86 systemic JIA patients started at least 1 biologic agent between 1999 and 2010. Etanercept remained biologic of first choice for non-systemic JIA and anakinra has become first choice for systemic JIA. The use of systemic prednisone and synthetic disease-modifying anti-rheumatic drugs (besides methotrexate) prior to biologics decreased. During these 12 years of observation, biologics were prescribed after shorter disease durations; the proportion of patients with less than 1.5 years of disease duration before start of the first biologic agent increased from zero in the years 1999-2001 to 31% in 2008-2010. Disease activity and acquired sequelae at baseline decreased with regard to number of joints with arthritis (median of 18 active joints in 1999-2001 to 5 in 2008-2010), number of joints with limited motion (median of 12 limited joints in 1999-2001 decreased to 3 in 2008-2010) and functional disability scores (median CHAQ score of 1.8 in 1999-2001 decreased to 1.1 in 2008-2010). For systemic JIA, prescription patterns changed towards introduction in patients with higher ESR values. These changes for both systemic and non-systemic JIA resulted in more patients with inactive disease and less joints with limited motion after 3 and 15 months of treatment. Conclusions Biologics are prescribed increasingly, are introduced earlier during the disease course and in JIA patients with lower disease activity. These changes are subsequently accompanied by better short-term disease outcomes. Etanercept remains biologic of first choice for non-systemic JIA and anakinra has become first choice for systemic JIA. Disclosure of Interest M. Otten Grant/research support from: Abbott, Novartis, Roche, Pfizer, Consultant for: Roche, J. Anink: None Declared, F. Prince Grant/research support from: Abbott, Bristol-Myers Squibb, Novartis, Tevapharma, and Pfizer, Consultant for: Roche, M. Twilt: None Declared, S. Vastert: None Declared, R. ten Cate Grant/research support from: Pfizer, Consultant for: Pfizer, E. Hoppenreijs: None Declared, W. Armbrust: None Declared, S. Gorter: None Declared, P. van Pelt: None Declared, S. Kamphuis Grant/research support from: Pfizer, K. Dolman: None Declared, J. Swart: None Declared, J. van den Berg: None Declared, Y. Koopman-Keemink: None Declared, M. van Rossum: None Declared, N. Wulffraat Grant/research support from: Pfizer, Novartis and Roche, L. van Suijlekom-Smit Grant/research support from: Dutch Board of Health Insurances, Dutch Arthritis Association, Pfizer, Abbott, Consultant for: Roche, Novartis

SAT0452 Distribution Pattern of MRI Abnormalities Within the Knee and Wrist of Juvenile Idiopathic Arthritis Patients; MRI made Easy

Background MRI plays an increasingly important role in the assessment and monitoring of disease activity in juvenile idiopathic arthritis (JIA). Awareness of the incidence and distribution pattern of MRI abnormalities in JIA is a valuable tool in the daily practice of the reading radiologist and the treating clinician. Preferred locations for pathology within target joints are facilitated by knowledge on common distribution patterns of MRI abnormalities, enabling rapid differentiation between JIA abnormalities and normal variants. Objectives To determine (1) incidence and (2) distribution pattern of soft-tissue- and osseous abnormalities upon MRI of the two of the most affected joints in JIA (i.e. the knee and wrist) Methods MRI datasets of 166 active JIA patients (123 with knee and 43 with wrist involvement) were analyzed. Two readers evaluated presence of 4 literature-based items per joint. Common items included synovial hypertrophy (SH), bone marrow changes (BMC), and bone erosions (BE). Joint-specific features were additionally evaluated: cartilage lesions (CL) for the knee and tenosynovits (TS) for the wrist. Scoring locations in these two joints were also literature-based. Incidence of each scored item was defined separately. Involvement per location, analyzed as percentage of the total amount of affected locations, was determined. Results SH showed the highest incidence in both the knee and wrist (56.9-65.1% of the patients). Besides BMC (34.1%), the incidence of osteochondral features was low in the knee (CL 6.5%; BE 4.9%). In contrast, the incidence of these features in the wrist were relatively high (BMC 37.2% and BE 30.2%) and TS was present in 46.5% of the patients with wrist involvement. In order to make MRI easy, ‘top-3-location’ per feature was constituted. Below, the ‘number 1’ or most frequently affected location per feature is mentioned. In the knee these locations consisted of cruciate ligaments (25.1% in SH), medial patella (28.1% in BMC, 33.3% in CL) and lateral femur trochlea (50% in BE). In the wrist, the radiocarpal joint (32.8% in SH), extensor-tendon-group (83.3% in TS), lunate (15.2% in BMC) and capitate/triquetrum (21.4% in BE) were mostly affected. Being the most important feature in JIA, SH in the knee showed preferred presence in the central locations, which accounted for >85% of the total affected locations. Less obvious demarcation for SH was found in the wrist. Both in the knee and wrist the three least affected locations of SH were never found to be involved without the presence of at least one of the three other most frequently affected locations. Conclusions This study provides an overview of incidence and distribution of a well-defined spectrum of MRI abnormalities within the knee or wrist of clinically active JIA patients. SH has highest incidence in both joints. In daily practice, a top-3-location per feature suggestive for pathology is helpful in navigation through the MRI of the knee or wrist in JIA patients. Disclosure of Interest None Declared

Etanercept in juvenile idiopathic arthritis: Who will benefit?

Results 262 previously biologic-naive JIA-patients initiated etanercept; 71% female, 18% systemic-onset subtype. Median age at onset 6.9 (IQR 3.6-11.1) years, median followup 35.6 (IQR 17.4-53.6) months. In the long-term, the overall majority responded to etanercept and up to 40% reached inactive disease. Excellent response after 15 months (85 patients, 32%) was associated with low baseline disability (OR 0.49/point increase, 95%CI 0.33-0.74), fewer DMARDs used before etanercept (OR 0.64/ DMARD used, 95%CI 0.43-0.95) and younger age at onset (OR 0.92/year, 95%CI 0.84-0.99); poor response (88 patients, 34%) was associated with female gender (OR 2.12, 95%CI 1.11-4.08) and systemic-onset subtype (OR 3.24, 95%CI 1.39-7.56). However, 24% of systemiconset patients reached excellent response. Reasons for discontinuation: ineffectiveness in 78, adverse events (AEs) in 25, remission in 39 patients. Etanercept was well tolerated. Patients who developed AEs could not be identified at baseline.