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BackgroundFluorescence optical imaging (FOI) has been used for assessment of inflammation (i.e. synovitis) in the hands and has in several cross sectional studies been compared with ultrasonography (US) and magnetic resonance imaging (MRI), using different, but not validated scoring systems.ObjectivesThe primary objective was to examine the association between FOI and US for assessment of synovitis in the rheumatoid arthritis (RA) hands, in a longitudinal study, using a new validated and clinically feasible FOI scoring system.Methods46 RA patients, eligible for induction or intensification of conventional synthetic or biological disease modifying anti-rheumatic drugs and with ≥1 clinically swollen joint in the hand, were included. FOI image-sets of both wrists and hands were obtained at baseline and 6 months‘ follow-up using a Xiralite system unit (nanoPET Pharma GmbH, Berlin, Germany). The patients received a bolus of i.v. indocyanine green (ICG) pulsion 10 s after starting the examination, which obtained 1 image/second for 6 min.All FOI images were scored by two readers for synovitis at the wrist, 1st-5th metacarpophalangeal, 1st interphalangeal and 2nd-4th proximal interphalangeal joint levels in both hands, using the novel semiquantitative scoring system. Each joint was scored 0–3 (range 0–66) for synovitis. The readers were blinded to patient data, but not chronology and had previously showed a high intra- and inter-reader agreement (intra-class correlation coefficient (ICC):0.70–0.92).For ultrasound assessment, a GE Logiq E9 US unit with a high frequency linear 6–15 ML probe and with Doppler settings according to published recommendations was used. Synovitis was scored from 0–3 for grey scale (GS) and Doppler (DP) using the OMERACT US synovitis scoring system by two trained assessors who had previously demonstrated high intra- and inter-reader agreement (wKappa;0.88–0.95).DAS28-CRP and swollen joint count (SJC) in the hand were assessed at both time points.Descriptive statistics and the Wilcoxon signed-rank test were used to assess change in score over time. Agreement for status and change scores were assessed using single measure ICCs and spearman’s correlation (SP). Responsiveness was assessed using standardised response mean (SRM).ResultsMedian (IQR) total score at baseline was FOI 11.0 (6;19), GS 14.5 (8;22.), DP 8 (3;14), DAS28 5 (4.4;5.4) and SJC 6 (3;8) and improved with −7.8 (-13;−3.5) −9 (−15;−3.5),–5.5 (-11;−0.5), −2(−2.9;- 0.8) and −4(−7;−2) at 6 months‘ follow up, respectively (p<0.01). Figure 1 presents the change score and a trend line based on 4 patients’ average score.ICC and SP between FOI and US (GS and DP) total scores were low for both readers at baseline (range 0.3–0–4) (p<0.05), and low to moderate (range 0.31–0.54) (p<0.01) for change scores. The mean SRM for total change scores between baseline and 6 months’ follow-up were good for all parameters (FOI:0.9, GS:1.0, DP:0.8, DAS28:0.9 and SJC:1.0). The average time required to score one patient was 140 s.Abstract AB1202 – Figure 1Scatterplot for FOI and US changes sum score and 4 patient avenges trendlinesConclusionsThis study shows a significant correlation and corresponding trendlines between FOI and US for change over time, and good responsiveness using the new FOI scoring system. FOI may therefore be used as an alternative to known imaging modalities for monitoring RA patients in clinical trials, and potentially in the daily clinical practice.Disclosure of InterestNone declared

BackgroundIn Rheumatoid Arthritis (RA), patient-reported tender joints (PrTJ) correlate better with clinical examination than patient-reported swollen joints (PrSJ).1 Clinical examination has inferior sensitivity to detect synovitis compared to ultrasonography (US).2 However, data is sparse about these findings at the time of patient-reported flare (PRFl).ObjectivesTo investigate agreement between PrSJ, PrTJ, clinically detected swollen and tender joints (cSJ and cTJ,) and inflammation by Colour Doppler (CD) US in RA patients at the time of PRFl.Methods80 consecutive rheumatoid-factor and/or anti-cyclic citrullinated peptide antibody positive RA patients with DAS28-CRP<3.2 and no swollen joints at baseline were during a one-year follow-up period requested to contact the hospital in case of a hand flare according to patients’ perspective. At the flare visit, patients indicated PrSJ and PrTJ, and underwent examination for cSJ and cTJ, and US of bilateral wrists (wrist joints and six extensor tendon compartments), 1–5 metacarpophalangeal joints (MCP) and 1–5 proximal interphalangeal joints (PIP). CD synovitis and tenosynovitis were graded 0–3 according to EULAR/OMERACT scoring system3 and joints and tendon sheaths with CD ≥1 were considered positive. Percentage agreement and Cohen’s kappa were calculated between PrSJ, PrTJ, cSJ, cTJ and CD in joints and tendon sheaths.ResultsThirty-six percent (29/80) of the RA patients reported a hand flare (69% female, mean age 65 years, median DAS28-CRP 1.8, at baseline). At flare, mean (±SD) number of PrSJ, cSJ, PrTJ, cTJ and CD positive joints were 2.7 (2.86), 1.5 (1.02), 4 (3.04), 4 (3.46) and 1.8 (1.31), respectively. For swelling, there was slightly superior agreement with CD for cSJ than for PrSJ, except for wrist tenosynovitis where patients agreed more frequently with CD than clinical examination did (table 1). Highest percentage agreement was seen for PIP, followed by MCP. Agreement, as assessed by kappa, was poor to fair, ranging from −0.009 to 0.33. Swelling in MCP and PIP joints, by patients and clinicians, and swelling in the wrist by clinician showed better agreement with CD than tenderness did.Abstract SAT0630 – Table 1Concordance between patient-reported and clinically examined swollen and tender joints versus CD at the time of patient-reported flareConclusionsThirty-six percent of the RA patients reported flares in the hand during one year follow-up. Numbers of joints affected by swelling, tenderness or positive CD sign were low. Limited concordance between US, patient-reports and clinical examination suggests that these domains reflect different and potentially complementary aspects of inflammation in patient-reported flare.References[1] Cheung PP, et al. Arthritis Care Res2010;62:1112.[2] Naredo E, et al. Ann Rheum Dis2005;64:375.[3] Terslev L, et al. RMD Open2017;3: e00042.AcknowledgementsThe study was supported by a grant from the Danish Rheumatism Association, the University of Southern Denmark, the Region of Southern Denmark and Knud and Edith Eriksens’ Commemorative Fund.Disclosure of InterestNone declared

Background A fast, physician-independent, sensitive, reproducible tool for assessment of disease activity would be useful in rheumatoid arthritis (RA) clinical practice. Objectives This study aimed to compare a new technique, optical spectral transmission imaging (OST), and clinical examination with colour Doppler (CD) ultrasound as gold standard reference. Primary outcomes were sensitivity and specificity of OST for joint inflammation at joint level, and correlations of the summation of joint scores at patient level. Methods This cross-sectional study included 62 RA patients, 50 with ≥1 clinically swollen joint in the hands or wrists and 12 patients without tender or swollen joints. Joint examination, patient global VAS, HAQ and CRP were registered. OST was obtained by Hemics Full Hand Proto at two wavelengths (660nm and 810nm) before, during and after the inflation of a pressure cuff to 50 mm Hg for 60 seconds (total duration of examination 1.5 minutes). OST scores for each joint were based on a previously developed algorithm aimed to mimic a combination of Doppler and grey-scale synovitis, using a predefined cutoff of 0.521 for inflammatory activity. A GE Logiq® E9 US machine with a 5-16ML linear array transducer and Doppler setting optimized for slow flow was used for grading CD activity (0-3) in wrist joints, metacarpophalangeal joints (MCPs) and proximal interphalangeal joints (PIPs). CD activity ≥1 was used as gold standard for inflammation. CD, OST and clinical data were obtained separately and blinded to other data. Results CD activity ≥1 was observed in 167 (12%) of 1364 joints. An OST score larger than the predefined cut-off of 0.521 was found in 343 (25%) joints. AUC of the ROC curve of OST score vs. the gold standard reference was 0.690, p<0.001. For all joints, using cut-offs of 0.145 (wrists)/0.103 (MCPs)/0.697 (PIPs) as optimized for a sensitivity of 75% for the individual joint areas, specificity was 42%. Using cut-offs of 0.525/0.951/1.293 as optimized for a specificity of 90% for the individual joint areas, sensitivity was 23%. Table 1. Sensitivity, specificity and kappa values of OST score and clinical examination compared to CD activity ≥1 as gold standard OST score >0.521 Swollen Tender Sens. Spec. Kappa Sens. Spec. Kappa Sens. Spec. Kappa All joints 54% 79% 0.23 41% 93% 0.35 34% 91% 0.25 Only PIPs 29% 89% 0.09 48% 95% 0.29 33% 94% 0.17 Only MCPs 44% 75% 0.15 36% 93% 0.32 25% 91% 0.17 Only Wrists 91% 24% 0.12 49% 77% 0.27 56% 71% 0.26 At the patient level, the OST score correlated with CD (rho=0.28, p=0.03), patient global VAS (rho=0.31, p=0.02), DAS28 (rho=0.29, p=0.02) and HAQ (rho=0.26, p=0.04). Using new cutoffs as described above, we found even tighter correlations at the patient level with CD (rho=0.31, p=0.01), SJC (rho=0.28, p=0.03), patient global VAS (rho=0.41, p=0.001), CRP (rho=0.29, p=0.03), DAS28 (rho=0.40, p=0.001) and HAQ (rho=0.48, p<0.001). Conclusions Significant correlations with clinical and CD measures of joint inflammation documented the construct validity of OST assessment of joint inflammation. However, with CD as gold standard reference, OST did not demonstrate improved sensitivity and specificity compared to clinical joint examination. Further analyses of the data, including ultrasound grey-scale synovitis, are pending. After further development, OST may be a feasible technique for quick, physician-independent, non-invasive assessment of joint inflammation in RA. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4364

Objective: To examine hospital readmissions for premature infants during the first year of life. Study Design: The California maternal and newborn/infant hospital discharge records were examined for subsequent readmission during the first year of life for all newborns from 1992 to 2000. Discharge diagnoses, hospital days, demographic data and hospital charges for infants born preterm (<36 weeks gestation) were identified and evaluated. Result: About 15% of preterm infants required at least one rehospitalization within the first year of life (average cost per readmission $8468, average annual cost in excess of $41 million). Infants with gestational age <25 weeks had the highest rate of readmission (31%) and longest average length of stay (12 hospital days). The largest cohort, infants born at 35 weeks gestation, had the highest total cost of readmission ($92.9 million). The most common cause of rehospitalization was acute respiratory disease. There was no decrease in the number or cost of readmissions of premature infants for respiratory syncytial virus infections following the introduction of palivizumab in 1998. Conclusion: After initial discharge, premature infants continue to have significant in-patient health-care needs and costs.

Mutations in CHD7 are the major cause of CHARGE syndrome, an autosomal dominant disorder with an estimated prevalence of 1/15,000. We have little understanding of the disruptions in the developmental programme that underpin brain defects associated with this syndrome. Using mouse models, we show that Chd7 haploinsufficiency results in reduced Fgf8 expression in the isthmus organiser (IsO), an embryonic signalling centre that directs early cerebellar development. Consistent with this observation, Chd7 and Fgf8 loss-of-function alleles interact during cerebellar development. CHD7 associates with Otx2 and Gbx2 regulatory elements and altered expression of these homeobox genes implicates CHD7 in the maintenance of cerebellar identity during embryogenesis. Finally, we report cerebellar vermis hypoplasia in 35% of CHARGE syndrome patients with a proven CHD7 mutation. These observations provide key insights into the molecular aetiology of cerebellar defects in CHARGE syndrome and link reduced FGF signalling to cerebellar vermis hypoplasia in a human syndrome. CHARGE syndrome is a rare genetic condition that causes various developmental abnormalities, including heart defects, deafness and neurological defects. In most cases, it is caused by mutations in a human gene called CHD7. CHD7 is known to control the expression of other genes during embryonic development, but the molecular mechanisms by which mutations in CHD7 lead to the neural defects found in CHARGE syndrome are unclear. During embryonic development, the neural tube—the precursor to the nervous system—is divided into segments, which give rise to different neural structures. The r1 segment, for example, forms the cerebellum, and the secretion of a protein called FGF8 (short for fibroblast growth factor 8) by a nearby structure called the isthmus organiser has an important role in this process. Since a reduction in FGF8 causes defects similar to those found in CHARGE syndrome, Yu et al. decided to investigate if the FGF signalling pathway was involved in this syndrome. Mice should have two working copies of the Chd7 gene, and mice that lack one of these suffer from symptoms similar to those of humans with CHARGE syndrome. Yu et al. examined the embryos of these mice and found that the isthmus organiser produced less FGF8. Embryos with no working copies of the gene completely lost the r1 segment. The loss of this segment appeared to be caused by changes in the expression of homeobox genes (the genes that determine the identity of brain segments). Embryos that did not have any working copies of the Chd7 gene died early in development, which made further studies impossible. However, embryos that had one working copy of the Chd7 gene survived, and Yu et al. took advantage of this to study the effects of reduced FGF8 expression on these mice. These experiments showed that mice with just one working copy of the Fgf8 gene and one working copy of the Chd7 gene had a small cerebellar vermis. This part of the cerebellum is known to be very sensitive to changes in FGF8 signalling. Yu et al. then used an MRI scanner to look at the cerebellar vermis in patients with CHARGE syndrome, and found that more than half of the patients had abnormal cerebella. In addition to confirming that studies on mouse embryos can provide insights into human disease, the work of Yu et al. add defects in the cerebellar vermis to the list of developmental abnormalities associated with CHARGE syndrome. The next step will be to test if any mutations in the human FGF8 gene can contribute to cerebellar defects in CHARGE syndrome, and to investigate if any other developmental defects in CHARGE syndrome are associated with abnormal FGF8 levels.

Background:Improvement in ultrasound technology in the last decade results in high resolution images. Therefore, previously undetected ultrasound lesions in joints of asymptomatic healthy individuals have now become apparent.At present, the cut-off between normal vs abnormal sonographic findings in small joints is unclear. Therefore, the threshold of normality in ultrasound that discriminates normal physiological vs minimal pathological changes at each joint level in different age groups needs to be defined.Objectives:The objective of this study was to define the threshold of normality in ultrasound according to joint type and age groups. In order to achieve this, we systematically graded ultrasound lesions (synovial hypertrophy, Doppler activity and synovial effusion) in the metacarpophalangeal (MCP), proximal interphalangeal (PIP), wrist and metatarsophalangeal (MTP) joints of healthy individuals aged 18 – 80 years old.Methods:This was an observational cross-sectional multi-centre study under the ‘Minimal Disease’ subgroup of the OMERACT Ultrasound Working Group. Healthy individuals aged 18- 80 years old were included. Exclusion criteria were current/previous history of inflammatory arthritis, joint trauma of hands/wrist in previous month; hand/wrist pain with VAS ≥10/100; hand osteoarthritis according to American College of Rheumatology criteria; history of infection in the last month; and recent/current use of medications that could affect ultrasound assessment.Clinical data including age, sex, body mass index and ethnicity were recorded. Bilateral MCP, PIP, wrist and MTP joints were clinically examined by an independent assessor in each centre, and subjects were excluded if synovitis or swelling was detected. Ultrasound assessment of bilateral MCP 1- 5, PIP 1 – 5, wrist radio-carpal, inter-carpal and ulnar-carpal and MTP 1 – 5 was conducted according to EULAR standardised procedures. Presence of synovial hypertrophy, synovial effusion and Doppler activity of each joint were recorded using the EULAR-OMERACT semi-quantitative grading system; grade 0-3.All images were acquired, recorded and graded by the same sonographer during the scanning assessment and sent to the central hub. Quality and grading of recorded images were confirmed by a review of all images for the first participant recruited in each centre by an experienced blinded independent assessor (IS) in the hub centre. Any disagreement was then fed back to the centre and consensus was achieved to ensure reliability in subsequent scans.Results:849 participants were recruited between Feb 2017 and July 2019 from 21 centres across 13 countries. 802 participants were included in final analysis (Figure 1). Median age was 42 years (IQR 30-56), and majority were female (72%) and white (81%). Other ethnic groups were Asian Japanese, Middle Eastern, Black, other Asian and mixed ethnicity.28,735 joints were scanned; of these 3728 (13%) had at least one abnormal ultrasound finding. Highest proportion of ultrasound abnormal findings was observed in MTP 1 (45%) followed by MTP 2 (39%). Lowest proportion of changes was observed in wrist ulnar-carpal and MTP 5 (2%).Next, we identified the threshold of abnormality for each joint type by age groups. The threshold of abnormality chosen was 5% in line with conventional biomedical cut-off levels. (i.e. 95% of the normal population would fall within this threshold). Presence of Doppler activity in MCP, PIP, wrist and MTP joints should be regarded as abnormal in any age range. Presence of synovial hypertrophy in PIP 1 – 5 should be regarded as abnormal in any age range. Presence of synovial hypertrophy in MCP 5 and MTP 5 at any age is abnormal (Table 1).Conclusion:This is the first study that describes ultrasound changes observed in the MCP, PIP, wrist and MTP joints of normal population across a wide age range and nationalities. This gives an indication on what could constitute background changes or ‘minimal disease changes’ and what should be regarded as normal. This has major implication in the interpretation of ultrasound findings in rheumatology.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Ilfita Sahbudin: None declared, Jeanette Trickey: None declared, Hélène GOUZE: None declared, Maria Simona Stoenoiu: None declared, Georgios Filippou: None declared, Garifallia Sakellariou: None declared, Mihaela Maruseac: None declared, Ruth Wittoek: None declared, Phillippe Carron: None declared, Ilaria Tinazzi: None declared, Annamaria Iagnocco: None declared, Teodora Serban: None declared, Irene Azzolin: None declared, Lene Terslev Speakers fee from Janssen, Novartis and GE., Mads Ammitzbøll-Danielsen: None declared, Mads Nyhuus Bendix Rasch: None declared, Ellen-Margrethe Hauge: None declared, Hilde Berner Hammer Honoraria for lectures from AbbVie, Novartis, Lilly and UCB., Marcin Milchert: None declared, Jacek Fliciński: None declared, Peter Mandl: None declared, Carina Borst: None declared, Daniela Fodor: None declared, Florentin Ananu Vreju: None declared, Rositsa Karalilova: None declared, Esperanza Naredo: None declared, Cesar Sifuentes-Cantú: None declared, Giuliana M.C. La Paglia: None declared, Carlos Pineda: None declared, Marwin Gutierrez: None declared, Gustavo Leon: None declared, Cristina Reátegui-Sokolova: None declared, Mohammed A Mortada: None declared, Takeshi Suzuki: None declared, Kei Ikeda: None declared, Coziana Ciurtin: None declared, Marion Kortekaas: None declared, Sarah Ohrndorf Speakers’ honoraria or travel expense reimbursements by: AbbVie, Amgen, BMS, Galapagos, Janssen, Mylan, Novartis, UCB, Helen Keen: None declared, George Bruyn: None declared, Andrew Filer: None declared, Maria Antonietta D’Agostino: None declared