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BackgroundEnthesitis-related Arthritis (ERA) is a category of juvenile idiopathic arthritis (JIA) characterised by heterogeneous and insidious manifestations comprising axial and/or peripheral arthritis, and enthesitis.1 Secukinumab (SEC) demonstrated efficacy and safety in both ERA and juvenile psoriatic arthritis (JPsA) in the JUNIPERA trial.2ObjectivesTo evaluate the rate of flare risk reduction and efficacy of SEC on axial and peripheral manifestations in patients (pts) with active ERA.MethodsERA pts (2 to 3 Evaluation of axial and peripheral manifestations at the end of TP1 and TP2 in pts who experienced these symptoms at BL included modified Schober test (lumbar flexion), inflammatory back pain, FABER (Flexion, ABduction, External Rotation) test, JIA-ACR responses, Juvenile Arthritis Disease Activity Score (JADAS)-27, and resolution of enthesitis and dactylitis for peripheral disease. These outcomes were also used to assess JIA disease course at the end of TP2.ResultsA total of 52/86 (60.5%) pts with ERA were enrolled in the OL period TP1 (mean age, 13.7 years; male, 78.8%). In total, 51/52 (98.1%) pts completed TP1 and 41/44 (93.2%) completed TP2. At BL, mean JADAS-27 was 14.8, mean JSpADA index was 3.9, mean enthesitis and dactylitis counts were 2.7 and 0.4, respectively, mean number of active joints was 6.2 and of mean joints with limited range of motion 4.9. The relative risk reduction of experiencing a disease flare in TP2 was 55% (HR 0.45, 95% CI: 0.16–1.28, p=0.075) in ERA pts (Figure 1). The overall axial and peripheral disease symptoms improved over time and are presented in the Table 1. At the end of TP1, 84.6% (44/52) of pts achieved JIA-ACR 30 and 65.4% (34/52) achieved JIA-ACR 70. Clinically relevant reduction of functional ability as assessed by Childhood Health Assessment Questionnaire (CHAQ) also occurred (see Table 1).Table 1.Resolution of axial and peripheral disease symptoms and JIA ACR responses at the end of TP1 and 2Clinical response, mean (SD) change from BL (unless otherwise stated)TP1-Wk 12End of TP2*SEC (N=52)SEC (N=22)PBO (N=22)JSpADA index−2.4 (1.7)−2.7 (1.7)−2.3 (2.1)JSpADA Schöber, %58.3100.0100.0Inflammatory back pain, %77.8100.050.0FABER test, %52.6100.083.3Clinical sacroiliitis, %53.3100.050.0Enthesitis−2.2 (1.9)−2.5 (2.1)−1.3 (1.8)Dactylitis−0.2 (0.8)−0.2 (1)−0.1 (0.4)JIA ACR30, %84.690.968.2JIA ACR50, %78.881.868.2JIA ACR70, %65.468.254.5JIA ACR90, %32.745.550.0JIA ACR100, %26.936.445.5Inactive disease, %38.550.050.0CHAQ−0.5 (0.5)−0.6 (0.7)−0.4 (0.5)CRP, median (SD) change from BL−1.8 (38.7)−5.8 (38.3)0 (35.9)JADAS-27−9.6 (7.5)−11.0 (8.9)−7.6 (8.9)Resolution of enthesitis#, %72.378.683.3Resolution of dactylitis#, %5066.70*End of TP2 is based on individual pts’ last visit at TP2. #At BL, in TP1, enthesitis (n= 46); dactylitis (n=5). In TP2, no. of pts who had presence at BL and showed complete resolution at the end of TP2: enthesitis, SEC 14, PBO 18; dactylitis, SEC 3, PBO, 0. CRP, C-reactive proteinConclusionIn pts with ERA, SEC demonstrated longer time to disease flare vs PBO and exhibited rapid and sustained improvement of axial and peripheral manifestations up to Wk 104.References[1]Pagnini I, et al. Front Med 2021;8:6673052.[2]Brunner H, et al. Arthritis Rheumatol 2021;73 (suppl 10).[3]Weiss PF, et al. Arthritis Care Res 2014;66:1775-82.Disclosure of InterestsNicolino Ruperto Speakers bureau: Eli Lilly, GlaxoSmith and Kline, Pfizer, SOBI and UCB, Paid instructor for: Eli Lilly and Pfizer, Consultant of: Ablynx, Amgen, Astrazeneca-Medimmune, Aurinia, Bayer, Bristol Myers and Squibb, Cambridge Healthcare Research (CHR), Celegene, Domain therapeutic, Eli Lilly, EMD Serono, GlaxoSmith and Kline, Idorsia, Janssen, Novartis, Pfizer, SOBI and UCB, Grant/research support from: Bristol Myers and Squibb, Eli Lilly, F Hoffmann-La Roche, Novartis, Pfizer and SOBI, Elena Chertok: None declared, Joke Dehoorne Speakers bureau: Abbvie, Roche, Consultant of: Abbvie, Roche, Pfizer, Grant/research support from: Abbvie, Roche, Gerd Horneff Speakers bureau: Novartis, Pfizer, Janssen, Grant/research support from: Pfizer, Novartis, Roche, MSD, Tilmann Kallinich Speakers bureau: Roche, Ingrid Louw Speakers bureau: Pfizer, Abbvie, BMS, Consultant of: Pfizer, Abbvie, Janssen, Amgen and Cipla, Sandrine Compeyrot-Lacassagne: None declared, Bernard Lauwerys Employee of: UCB Pharma, Neil Martin: None declared, Katherine Marzan Grant/research support from: Novartis, Sanofi, William Knibbe Speakers bureau: Novartis, Amgen, UCB, Abbvie, Ruvie Martin Shareholder of: Novartis, Employee of: Novartis, Xuan Zhu Shareholder of: Novartis, Employee of: Novartis, sarah whelan Shareholder of: Novartis, Employee of: Novartis, Luminita Pricop Shareholder of: Novartis, Employee of: Novartis, Alberto Martini Speakers bureau: Aurinia, Bristol Myers and Squibb, Eli Lilly, EMD, Janssen, Pfizer, Roche and Serono, Consultant of: Aurinia, Bristol Myers and Squibb, Eli Lilly and EMD, Daniel J Lovell Consultant of: Astra Zeneca, Boehringer Ingelheim, GSK, Hoffman LaRoche, Novartis, UBC, Grant/research support from: Astra Zeneca, Boehringer Ingelheim, GSK, Hoffman LaRoche, Novartis, UBC, Hermine Brunner Consultant of: Novartis, Grant/research support from: Novartis

BackgroundChildren with chronic non-infectious uveitis (NIU) are at risk for sight-threatening complications. Methotrexate (MTX) is the preferred first-line systemic treatment. Initial therapeutic response takes 3-6 months to achieve NIU control, leading to prolonged glucocorticoid use. Moreover, at least 50-70% of children fail to fully respond and may accrue ocular damage while awaiting MTX response.ObjectivesTo identify features of children with NIU that are associated with MTX failure.MethodsWe included children who started MTX monotherapy for NIU. We collected demographics, NIU features (type, location, & complications), ANA status, and clinical examination. We characterized children as MTX responders or non-responders. MTX responders are those whose NIU was controlled, defined by: 1) inactive graded by SUN criteria, 2) absence of new or worsening complications, and 3) requirement for ≤2 drops of prednisolone acetate and no oral glucocorticoids.ResultsOf 47 NIU children, 68% were MTX non-responders (Table 1), having a longer duration of NIU (Odds Ratio [OR]=1.28, [CI=1.03-1.8], p =0.023) and developing more ocular complications (OR=1.95 [CI=1.23-3.38], p=0.017), (ROC Area Under the Curve = 0.85). MTX non-responders were more likely to have anterior and/or posterior synechiae (p = 0.001), cataracts (p=0.015), and ocular hypertension (p=0.039). Treatment included adalimumab: 27, infliximab: 14, tocilizumab: 5, golimumab: 4, etanercept: 3, and abatacept: 2.Table 1.Comparison of children with NIU based on MTX response.Responders n=15Non-responders n=32Caucasian14 (93)27 (84)Hispanic or Latino0 (0)3 (9)Female12 (80)23 (72)Age of NIU onset, yrs, median (IQR)4.3 (2.9 – 12.3)4.6 (2.8 - 7.0)Duration of NIU, yrs, median, (IQR)4.1 (2.6 – 5.3)8.2 (4.7 - 11.3)JIA-NIU10 (67)25 (78)Idiopathic CAU2 (13)3 (9)Other3 (20)4 (12)Bilateral disease12 (80)23 (72)Anterior12 (86)29 (91)Presenting BCVA (LogMAR) worst eye, median (IQR)0.2 (0.1 – 0.3)0.1 (0.0 - 0.2)Average # of total complications/person, median (IQR)1 (0 – 2)2.5 (1.0 – 5.5)ANA positive10 (67)26 (81)Earliest ESR8 (6– 18)12 (8 - 18)Earliest Vitamin D32 (26 – 35)31 (23 - 35)Time on MTX, months, median (IQR)35 (19 - 64)19 (7 - 74)Time from systemic or NIU onset to MTX, yrs, median (IQR)0.3 (0.1 – 0.5)0.2 (0.0 - 0.8)MTX PO6 (40)19 (59)MTX SC13 (87)31 (97)We performed a sub analysis of children with idiopathic chronic anterior NIU (CAU) and JIA-associated NIU that included children who failed MTX due to intolerance/toxicity (Figure 1). Using Cox proportional hazard regression, 8 idiopathic CAU failed MTX earlier than 38 JIA-associated NIU (HR 2.77, [CI-=1.06-7.27], p=0.039). Results were similar with the inclusion of other types of NIU (p=0.088) (e.g., HLA-B27, non-anterior idiopathic or with systemic disease).Figure 1.Kaplan-Meier curve showing freedom from TNFi (mos) stratified by diagnosisConclusionTwo out of three children with NIU fail initial MTX monotherapy, exposing them to increased accrual of ocular complications prior to biologic starts. The risk for delay in starting tumor necrosis factor α inhibitors (TNFi) seems higher with CAU. Future studies will examine risk factors that predict MTX response in NIU.References[1]McCracken C, Angeles-Han ST, et.al. Timing of infliximab and adalimumab initiation despite methotrexate in children with chronic non-infectious anterior uveitis. Eye (Lond). 2019;33(4):629-39.[2]Henderson LA, Angeles-Han ST, et.al., Medication use in juvenile uveitis patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance Registry. Pediatr Rheumatol Online J. 2016;14(1):9.[3]Cooper A, et.al., Failure of methotrexate monotherapy and subsequent response to tumor necrosis factor inhibitors in pediatric non-infectious uveitis (abstract). Arthritis Rheumatol. 2020:72 (suppl 4).Disclosure of InterestsSheila Angeles-Han: None declared, Amy Cassedy: None declared, Theresa Hennard: None declared, Mekibib Altaye: None declared, Hermine Brunner Consultant of: Dr. Brunner’s affiliation Cincinnati Children’s Hospital Medical Center has received consulting fees or other remuneration from AstraZeneca, Boehringer Ingelheim, GSK, Roche, Novartis, Pfizer Inc, Takeda, and UBC for the work of Dr. Brunner. Dr. Brunner is a DSMB member for Janssen Pharmaceutical’s trial of ustekinumab pediatric Crohn and Ulcerative colitis., Grant/research support from: Dr. Brunner’s affiliation Cincinnati Children’s Hospital Medical Center has received research grants from BMS, Janssen, Novartis, Pfizer Inc, Roche, and UBC., Eniolami Dosunmu: None declared, Alexei Grom: None declared, Michael Henrickson: None declared, Jennifer Huggins: None declared, Sarah Lopper: None declared, Daniel J Lovell Consultant of: AstraZeneca, Boehringer Ingelheim, GSK, Roche, Novartis, Pfizer Inc, Takeda, and UBC, Grant/research support from: BMS, Janssen, Novartis, Pfizer Inc, Roche, and UBC, Robert Sisk Consultant of: AGTC, Gyroscope, and Leica, Tracy Ting: None declared, Adam Kaufman Consultant of: Consultant for Alcon, Bausch & Lomb, and 1800contacts, not related or relevant to study content., Virginia Utz: None declared

BackgroundFor children with polyarticular juvenile idiopathic arthritis (pJIA) and inadequate response or intolerance to initial treatment with MTX, treatment options include abatacept.1 Abatacept, a selective T-cell co-stimulation modulator, has a distinct mechanism of action from other current treatments for rheumatic diseases,2 and factors predicting clinical response can help determine optimal treatment strategy. Two phase 3 studies demonstrated the efficacy and safety of IV and SC abatacept in patients with pJIA and an inadequate response to other DMARDs.2,3ObjectivesTo determine baseline and post-baseline factors that may predict a clinical response in children and adolescents with pJIA treated with abatacept for 2 years.MethodsBaseline demographic and disease characteristics and post-baseline factors (50% and 70% improvement in ACR criteria [ACR50, ACR70] at days 57 and 85) were analyzed using data from 2 phase 3 studies of abatacept in patients with JIA aged 2–17 years (SC administration) and 6–17 years (IV administration). Efficacy endpoints were Juvenile Arthritis Disease Activity Score in 10 joints based on CRP (JADAS10-CRP) inactive disease (ID; score of ≤ 2.7),4 and remission, defined as 6 consecutive months of post-baseline JADAS10-CRP ID. Data were analyzed over the entire 2-year study period. The earliest time point at which patients achieved these outcomes was reported. The aforementioned study factors were subjected to a time-to-event analysis, including Cox proportional hazards univariate regression analysis and Cox proportional hazards multivariate regression analysis using stepwise regression; results of the multivariate analysis are reported. Kaplan–Meier analysis was used to estimate time to achieve clinical response. Receiver operating characteristic curves were used to determine threshold values for continuous variables.ResultsOverall, 347 patients were included in the analysis (SC, n = 219; IV, n = 128; 73.8% female; mean [SD] age, 11.3 [4.0] years). Following abatacept treatment, both time to JADAS10-CRP ID and time to JADAS10-CRP remission were predicted (nominal P ≤ 0.05) by age (≤ 11 years: hazard ratio [HR], 1.52 [95% CI, 1.14–2.02] and ≤ 10 years: HR, 1.73 [95% CI, 1.20–2.48], respectively), high-sensitivity CRP (hsCRP; ≤ 0.6 mg/dL: HR, 1.67 [95% CI, 1.22–2.28] and ≤ 0.21 mg/dL: HR, 1.67 [95% CI, 1.15–2.42], respectively), Parent/Patient Global Assessment of well-being (≤ 35.86: HR, 1.88 [95% CI, 1.41–2.51] and ≤ 43.16: HR, 2.05 [95% CI, 1.35–3.10], respectively), and Childhood HAQ-DI (CHAQ-DI; ≤ 1.63: HR, 2.23 [95% CI, 1.47–3.39] and ≤ 0.75: HR, 1.84 [95% CI, 1.24–2.73], respectively) (remission data shown in Figure 1). Disease duration ≤ 2 years from baseline (HR, 1.66 [95% CI, 1.25–2.21]) and SC route of administration (HR, 2.05 [95% CI, 1.45–2.91]) also predicted ID. Among the post-baseline factors, ACR50 at days 57 and 85 predicted both ID (HR, 1.57 [95% CI, 1.04–2.36] and HR, 1.88 [95% CI, 1.41–2.51], respectively) and remission (HR, 1.96 [95% CI, 1.11–3.45] and HR, 3.05 [95% CI, 1.47–6.34], respectively); ACR70 at day 57 also predicted ID (data not shown). Patients with predictive factors for age, hsCRP, Parent/Patient Global Assessment of well-being, and CHAQ-DI, and with lower disease activity achieved ID and/or remission earlier than patients with high disease activity.ConclusionWe identified baseline and post-baseline factors that predicted JADAS10-CRP ID and remission in patients with pJIA treated with abatacept for 2 years. Screening of abatacept-treated patients with pJIA for such factors may help predict earlier achievement of ID and/or remission.References[1]Ringold S, et al. Arthritis Rheumatol 2019;71:846–63.[2]Brunner HI, et al. Arthritis Rheumatol 2018;70:1144–54.[3]Ruperto N, et al. Lancet 2008;372:383–91.[4]Trincianti C, et al. Arthritis Rheumatol 2021;73:1966–75.AcknowledgementsThis study was sponsored by Bristol Myers Squibb. Writing and editorial assistance were provided by Candice Judith Dcosta, MSc, of Caudex, funded by Bristol Myers Squibb. We would like to acknowledge Mara Becker, Duke Clinical Research Institute, Durham, NC, USA, for her contribution to the study analysis.Disclosure of InterestsNicolino Ruperto Speakers bureau: Honoraria for consultancies or speaker bureaus from the following pharmaceutical companies in the past 3 years: 2 Bridge, Amgen, AstraZeneca, Aurinia, Bayer, Brystol Myers Squibb, Cambridge Healthcare Research, Celgene, Domain Therapeutic, Eli Lilly, EMD Serono, GlaxoSmithKline, Idorsia, inMed, Janssen, Novartis, Pfizer, Sobi, UCB, Consultant of: Honoraria for consultancies or speaker bureaus from the following pharmaceutical companies in the past 3 years: 2 Bridge, Amgen, AstraZeneca, Aurinia, Bayer, Brystol Myers Squibb, Cambridge Healthcare Research, Celgene, Domain Therapeutic, Eli Lilly, EMD Serono, GlaxoSmithKline, Idorsia, inMed, Janssen, Novartis, Pfizer, Sobi, UCB, Hermine Brunner Speakers bureau: GlaxoSmithKline, Novartis, Pfizer, Consultant of: AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer, Bristol Myers Squibb, Celgene, Cerocor, Eli Lilly, EMD Serono, F. Hoffmann-La Roche, GlaxoSmithKline, Idorsia, Janssen, Merck, Novartis, R-Pharm, Sanofi, Grant/research support from: The Cincinnati Children’s Hospital, where HIB works as a full-time public employee, has received contributions from the following industries in the past 3 years: Bristol Myers Squibb, F. Hoffmann-La Roche, Janssen, Novartis, and Pfizer. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment to third parties, Alberto Berman Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Lilly, Novartis, Pfizer, Roche, Francisco Avila Zapata: None declared, Gerd Horneff Speakers bureau: AbbVie, Chugai, Janssen, Novartis, Pfizer, Grant/research support from: AbbVie, Chugai, MSD, Novartis, Pfizer, Roche, Linda Wagner-Weiner Grant/research support from: Abbott, Bristol Myers Squibb, Merck, Pfizer, UCB, Alexander Belot Speakers bureau: Chugai, GlaxoSmithKline, Novartis, Roche (punctual scientific intervention), Grant/research support from: Boehringer Ingelheim, Merck (joint research project), Ruben Burgos-Vargas: None declared, Maria Luz Gámir Gámir: None declared, Claudia Goldenstein-Schainberg Speakers bureau: AbbVie, Janssen, Novartis, Consultant of: AbbVie, Janssen, Novartis, Maria T. Terreri: None declared, Margarita Askelson Consultant of: Acerta Pharma, Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Robert Wong Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Alberto Martini Consultant of: AbbVie, Eli Lilly, EMD Serono, Idorsia, Janssen, Novartis, Pfizer, Daniel J Lovell Consultant of: AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffman LaRoche, Novartis, UBC (all contracts with employer, CCHMC), Grant/research support from: Bristol Myers Squibb, Janssen, Pfizer, Roche (all contracts with employer, CCHMC); NIH grants: NIAMS, NICHD

Objective. To describe the distribution and severity of muscle weakness using manual muscle testing (MMT) in 172 patients with PM, DM and juvenile DM (JDM). The secondary objectives included characterizing individual muscle group weakness and determining associations of weakness with functional status and myositis characteristics in this large cohort of patients with myositis. Methods. Strength was assessed for 13 muscle groups using the 10-point MMT and expressed as a total score, subscores based on functional and anatomical regions, and grades for individual muscle groups. Patient characteristics and secondary outcomes, such as clinical course, muscle enzymes, corticosteroid dosage and functional status were evaluated for association with strength using univariate and multivariate analyses. Results. A gradient of proximal weakness was seen, with PM weakest, DM intermediate and JDM strongest among the three myositis clinical groups (P ≤ 0.05). Hip flexors, hip extensors, hip abductors, neck flexors and shoulder abductors were the muscle groups with the greatest weakness among all three clinical groups. Muscle groups were affected symmetrically. Conclusions. Axial and proximal muscle impairment was reflected in the five weakest muscles shared by our cohort of myositis patients. However, differences in the pattern of weakness were observed among all three clinical groups. Our findings suggest a greater severity of proximal weakness in PM in comparison with DM.

Batches of two winter wheat cultivars (Riband and Apollo) were inoculated with conidia of Mycosphaerella graminicola at weekly intervals over a 2 year period. Following 72 h incubation, plants were placed in ambient temperatures ranging between -7 and 32degreesC with mean batch temperatures of 2.9-20.2degreesC. Latent period until the first visible symptoms ranged between 11 and 42 days. The relationship between development of lesions and accumulated thermal time was described using a shifted cumulative gamma distribution model. The model provided good estimates of lesion development with r(2)>0.92 for both cultivars. Base temperatures, below which the pathogen did not develop, were estimated from the model as approximately -2.4degreesC for the two cultivars. Latent period was estimated as being 250 and 301 degree-days above the estimated base temperature, when defined as time from inoculation to first lesion and time to 50% of maximal lesions, respectively, for cv. Riband. The values for cv. Apollo were similar, but with estimates of thermal time periods c. 5% higher. The relationship between mean temperature and inverse latent period, expressed as days either to first lesion or to 50% of maximal lesions, was best described by a linear regression with r(2)>0.96 for both cultivars. The opportunity for plants to outgrow disease was reduced when prolonged periods of cold temperature occurred, because the base temperature for growth of the pathogen was less than that for the crop.

Several wheat genotypes, including eight with known field responses, were evaluated for their reaction to Soil-borne cereal mosaic virus (SBCMV, genus Furovirus) by growing in naturally infested soil under controlled environment conditions. Virus antigen titres in the foliage 8–9 weeks after sowing mostly reflected the field responses, showing that growth chamber-based tests can be used to improve the speed and reliability of germplasm screening. Such tests were used to determine the mode of inheritance of the SBCMV resistance in cv. Cadenza, commonly used in UK wheat-breeding programmes. One hundred and eleven doubled haploid (DH) lines derived from an F1 of a cross between cvs Cadenza (resistant) and Avalon (susceptible) were evaluated. This DH population segregated for the reaction to SBCMV in a ratio of 1 : 1 (resistant : susceptible). This suggests that the SBCMV resistance is controlled by a single gene locus. As a first step towards identification of new sources of improved SBCMV resistance (e.g. immunity) as well as sources of the resistance to the virus vector, Polymyxa graminis, a set of 26 Triticum monococcum lines of diverse geographical origin was also screened. Most lines were susceptible to SBCMV, but one line of Bulgarian origin was resistant to the virus and possibly partially resistant to the virus vector.

An electronic sensor, based on a piezoelectric transducer, was tested in the laboratory using simulated raindrops, and in natural rainfall. Data were also collected for splash dispersal using tracer dyes in laboratory experiments and the Long Ashton splashmeter in field experiments. Droplets impacting on sensor produce sound waves that are detected by an omnidirectional microphone sealed within an acoustic chamber. An electrical charge, proportional to the sound wave, is produced by the microphone and is converted to a categorical scale and then stored to provide an accumulation of impacts over a specified period of time. Calibration of the sensor was done using single-droplet impacts of known mass and impacting velocity. A linear relationship was shown between the categorical scale and the kinetic energy of impacting droplets (adjusted r2 = 0.99). The best relationship fitted between splash dispersal from dye cup, and kinetic energy was a second-order polynomial (adjusted r2 > 0.99). Splash height, recorded by the Long Ashton splashmeter during 41 natural rainfall events, was correlated closely with sensor output (adjusted r2 = 0.87). Our studies indicate that the sensor provides quantitative data which could be incorporated into disease management systems to provide estimates of inoculum dispersal gradients within crop canopies.

Summary 1 The weather is believed to affect the establishment of insect biological control agents in the field, in particular heavy rainfall immediately after release, but few studies have quantified this impact. 2 A rain simulator was used to quantify the effect of rainfall duration and intensity on the post-release survivorship of a gorse biological control agent, the thrips Sericothripsstaphylinus. This information was then used to predict the effect of rainfall on the establishment of thrips in the field. 3 Rainfall significantly decreased the numbers of thrips remaining on the plants, but significantly increased the numbers of thrips found dead and missing. As rain duration increased, the numbers of thrips remaining on the plants decreased. However, the relationship was not linear: the majority of thrips were washed off the plants within 30 min of the 120-min experiment. 4 Thrips survivorship was significantly affected by rainfall intensity (moderate, heavy and violent rainfall). Increasing rainfall intensity caused a significant decrease in the numbers of thrips remaining on the plants and significant increases in the numbers missing or found dead. 5 The relationship between rainfall, thrips release size and their probability of establishment was determined by combining published data on their probability of establishment with the results of our experiments. Rainfall is likely to change the relationship between the release size and the probability of establishment. 6 We advocate that biological control practitioners should be cognisant of weather conditions prior to any release. Control agents at risk from rain might be released in protective cages, while smaller sequential releases might be preferable to single large releases if adverse conditions are likely. This study demonstrates the value of controlled environments in understanding the effects of weather on biocontrol, and for invasion ecology more generally.

A multiplex Polymerase Chain Reaction (PCR) assay was developed to detect and quantify four fungal foliar pathogens in wheat. For Septoria tritici (leaf blotch) and Stagonospora nodorum (leaf and glume blotch), the β-tubulin gene was used as the target region. Diagnostic targets for Puccinia striiformis (stripe or yellow rust) and P. recondita (brown rust) were obtained from PCR products amplified with β-tubulin primer sequences. Final primer sets were designed and selected after being tested against several fungi, and against DNA of infected and healthy wheat leaves. For detection of the four pathogens, PCR products of different sizes were amplified simultaneously, whereas no products were generated from wheat DNA or other non-target fungi tested. The presence of each of the diseases was wheat tissue- and cultivar specific. Using real-time PCR measurements with the fluorescent dye SYBR Green I, PCR-amplified products could be quantified individually, by reference to a standard curve generated by adding known amounts of target DNA. Infection levels for each of the diseases were measured in the flag leaf of 19 cultivars at Growth Stage (GS) 60–64 in both 1998 and 1999. The infection levels for the cultivars were ranked, and showed, with a few exceptions, a good correlation with the NIAB Recommended List for winter wheat, which is based on visual assessment of symptoms. With PCR, the presence of the different pathogens was accurately diagnosed and quantification of pre-symptomatic infection levels was possible. Although sampling and DNA detection methods need further optimisation, the results show that multiplex PCR and quantitative real-time PCR assays can be used in resistance screening to measure the interaction between different pathogens and their hosts at different growth stages, and in specific tissues. This should enable an earlier identification of specific resistance mechanisms in both early-stage breeding material and field trials.

In order to detect and quantify Septoria tritici infection levels in wheat leaves, a polymerase chain reaction (PCR) assay was developed using the β-tubulin gene as target. Specific PCR primers were designed by aligning and comparing β-tubulin sequences from other fungi. The final primer set was selected after being tested against several fungi, and against S. tritici-infected and uninfected wheat leaves from different localities. A single DNA fragment (496 bp) was amplified from S. tritici, whereas no products were generated from DNA of the host plant or other micro-organisms associated with wheat leaves. Using agarose gel analysis, approximately 2 pg S. tritici genomic DNA could be detected in each assay. However, for rapid quantification of PCR-amplified products, a fluorometric microtitre plate-formatted PicoGreen assay was used; this could detect as little as 10 pg S. tritici DNA in the presence of 200 ng wheat leaf DNA. The PCR/PicoGreen assay was applied successfully to study the colonization, infection and subsequent disease development of S. tritici on wheat, both under controlled conditions in the glasshouse and in the field.

Generally, it is recognized that inocula of Septoria tritici present on the basal leaves of winter wheat crops are spread towards the top of the canopy by splashy rainfall. This mechanism of inoculum dispersal is commonly accepted to be a key limit on disease progression. Therefore, attempts to forecast epidemics of S. tritici often quantify rainfall by some means, but largely ignore measurement of pathogen and host variables. In the present study, we show that new wheat leaves emerge initially at a height below established leaves that can contain sporulating lesions of S. tritici. This presents the possibility of horizontal inoculum transfer, even without splashy rainfall. The extent and duration of overlap between emergent and established leaves was found to differ considerably with cultivar and sowing date. Nitrogen application had little effect on overlap, because differences in crop phenology, e.g. leaf area and nodal length, were relative. However, estimates of raindrop penetration to the base of crop canopies suggested that vertical movement of inoculum is affected by nitrogen application. Crops receiving more nitrogen are denser, and therefore less rainfall reaches the base of the canopy. The interactions between crop and pathogen development are discussed with reference to the implications for predicting disease risk. In particular, cultivar traits that promote disease escape are quantified.

Obwohl bereits eindeutig gezeigt wurde, dass kognitive Verhaltenstherapie (CBT) die Funktionsbeeintrachtigung chronischer Schmerzzustande bei Jugendlichen mit Fibromyalgie signifikant verbessert, profitieren doch nicht alle Behandelten davon. Daruber hinaus bedeutet nicht jede Funktionsverbesserung auch einen klinisch relevanten Vorteil.

Objective This study was undertaken to evaluate the long-term safety and effectiveness of etanercept alone or in combination with methotrexate (MTX) in children with selected categories of juvenile idiopathic arthritis (JIA). Methods Patients ages 2–18 years with rheumatoid factor (RF)–positive or RF-negative polyarthritis, systemic JIA, or extended oligoarthritis were eligible for the study. Patients received MTX alone (≥10 mg/m2/week [∼0.3 mg/kg/week], maximum dosage 1 mg/kg/week), etanercept alone (0.8 mg/kg/week, maximum dose 50 mg), or etanercept plus MTX for 3 years in an open-label, nonrandomized study. Safety was assessed by measuring rates of adverse events, and effectiveness was assessed using the physician's global assessment of disease activity and the pediatric total joint assessment. Results A total of 197, 103, and 294 patients were enrolled in the MTX, etanercept, and etanercept plus MTX groups, respectively. Exposure-adjusted rates of adverse events were similar among the 3 treatment groups (18.3, 18.7, and 21.6 per 100 patient-years in the MTX, etanercept, and etanercept plus MTX groups, respectively). Respective rates per 100 patient-years of serious adverse events (4.6, 7.1, and 6.0) and medically important infections (1.3, 1.8, and 2.1) were also similar among the 3 treatment groups. Scores for physician's global assessment and total active joints improved from baseline, and improvement was maintained for the duration of the study. Conclusion These data confirm the findings of other long-term studies and suggest that etanercept or etanercept plus MTX has an acceptable safety and effectiveness profile in children with selected categories of JIA. Improvement was maintained for 3 years in those continuing to receive medication.

Strobilurin fungicides or quinone outside inhibitors (QoIs) have been used successfully to control Septoria leaf blotch in the United Kingdom since 1997. However, QoI-resistant isolates of Mycosphaerella graminicola were reported for the first time at Rothamsted during the summer of 2002. Sequence analysis of the cytochrome b gene revealed that all resistant isolates carried a mutation resulting in the replacement of glycine by alanine at codon 143 (G143A). Extensive monitoring using real-time polymerase chain reaction (PCR) testing revealed that fungicide treatments based on QoIs rapidly selected for isolates carrying resistant A143 (R) alleles within field populations. This selection is driven mainly by polycyclic dispersal of abundantly produced asexual conidia over short distances. In order to investigate the role of sexually produced airborne ascospores in the further spread of R alleles, a method integrating spore trapping with real-time PCR assays was developed. This method enabled us to both quantify the number of M. graminicola ascospores in air samples as well as estimate the frequency of R alleles in ascospore populations. As expected, most ascospores were produced at the end of the growing season during senescence of the wheat crop. However, a rapid increase in R-allele frequency, from 35 to 80%, was measured immediately in airborne ascospore populations sampled in a wheat plot after the first QoI application at growth stage 32. After the second QoI application, most R-allele frequencies measured for M. graminicola populations present in leaves and aerosols sampled from the treated plot exceeded 90%. Spatial sampling and testing of M. graminicola flag leaf populations derived from ascospores in the surrounding crop showed that ascospores carrying R alleles can spread readily within the crop at distances of up to 85 m. After harvest, fewer ascospores were detected in air samples and the R-allele frequencies measured were influenced by ascospores originating from nearby wheat fields.

To investigate if the persistence of systemic features is longer in Hispanic children with systemic juvenile idiopathic arthritis (S-JIA) than in non-Hispanic children with S-JIA and to determine early predictors of systemic and articular disease.We performed a multi-center retrospective chart review of patients followed in six pediatric rheumatology centers with onset of S-JIA from 1974 to 2004. Patients were included in the study if they had been followed foror = 1 year after disease onset. Information collected included demographic, clinical, laboratory and treatment data. Systemic features included fever, rash, lymphadenopathy, hepatosplenomegaly, pericarditis, and pleuritis.Of the 159 S-JIA patients screened, 120 (75%) met our inclusion criteria. There were 65 boys and 55 girls. The mean follow-up period for Hispanic patients was 5.7 years (SD 4.0) and for non-Hispanic patients was 8.6 years (SD 7.2). There was no significant difference in the presence of systemic features between Hispanic and non-Hispanic patients at 0.5, 1, 2, 4, 6, 8, and 10 years of follow-up. Polyarthritis at the 6-month visit was predictive of systemic features (OR 9.7, 95% CI 1.16-81.35, p = 0.036) and polyarthritis (OR 5.6, 95% CI 1.42-21.8, p = 0.014) at last follow-up.In children with S-JIA, Hispanics did not demonstrate longer persistence of systemic features than non-Hispanics. Polyarthritis at 6 months strongly predicted the development of persistent systemic features and chronic polyarticular disease.

Here, the aim was to understand the cellular and genetic basis of the Triticum monococcum-Mycosphaerella graminicola interaction. Testing for 5 yr under UK field conditions revealed that all 24 T. monococcum accessions exposed to a high level of natural inocula were fully resistant to M. graminicola. When the accessions were individually inoculated in the glasshouse using an attached leaf seeding assay and nine previously characterized M. graminicola isolates, fungal sporulation was observed in only three of the 216 interactions examined. Microscopic analyses revealed that M. graminicola infection was arrested at four different stages post-stomatal entry. When the inoculated leaves were detached 30 d post inoculation and incubated at 100% humidity, abundant asexual sporulation occurred within 5 d in a further 61 interactions. An F(2) mapping population generated from a cross between T. monococcum accession MDR002 (susceptible) and MDR043 (resistant) was inoculated with the M. graminicola isolate IPO323. Both resistance and in planta fungal growth were found to be controlled by a single genetic locus designated as TmStb1 which was linked to the microsatellite locus Xbarc174 on chromosome 7A(m). Exploitation of T. monococcum may provide new sources of resistance to septoria tritici blotch disease.

To correlate disease course and complications in children with juvenile dermatomyositis (JDM) and polymyositis (JPM) with specific features of muscle pathology on biopsy.This is a retrospective cohort analysis of 59 children diagnosed with JDM or JPM between 1965 and 1998 and followed at the Cincinnati Children's Hospital Medical Center (CCHMC) for a mean duration of 7.3 years (range 1.1-24.5 years). Disease course was characterized as limited, chronic non-ulcerative or chronic ulcerative, similar to previously defined disease course subtypes reported by Crowe et al.(1). All subjects had diagnostic muscle biopsies performed at CCHMC and had disease for at least two years' duration in order to classify their disease course as either limited or chronic. Features of muscle histopathology that were evaluated included loss of the intramuscular capillary bed, infarct, perifascicular myopathy, direct immunofluorescence (DIF) staining of the intramuscular vasculature and specifically, the locale of DIF staining, i.e., small arteries or capillaries. Disease complications that were assessed included calcinosis, contractures, muscle atrophy, lipodystrophy, gastrointestinal ulceration, cutaneous ulceration and death. Data analysis was completed using Chi-square or Fisher's exact tests and logistic regression modeling.Twenty-two children (37%) had limited disease, 24 (41%) had chronic non-ulcerative disease and 13 (22%) had chronic ulcerative disease. Neither loss of the intramuscular capillary bed nor perifascicular myopathy on muscle biopsy significantly correlated with disease course or the various complications evaluated in this study. DIF staining of intramuscular vessels overall was not significantly associated with clinical disease course, but the localization of DIF staining to intramuscular arteries (rather than to capillaries) was significantly associated with the outcome of chronic ulcerative disease. Nine of the 13 children with chronic ulcerative disease had DIF-arterial staining on muscle biopsy (69%), significantly greater than DIF-arterial staining in children with limited disease (32% had DIF-arterial staining) (p = 0.04), chronic non-ulcerative disease (8% had DIF-arterial staining) (p = 0.0002), and non-ulcerative disease overall (limited + chronic non-ulcerative disease groups combined) (20% had DIF-arterial staining), with p = 0.001. Additionally, lack of DIF-arterial staining on biopsy was significantly correlated with patients not having gastrointestinal ulceration (p = 0.002), cutaneous ulceration (p = 0.004) and/or death (p = 0.02) as disease-related complications. Infarct on muscle biopsy was significantly associated with the development of chronic ulcerative disease (p = 0.02), being present on biopsy in 23% of children with chronic ulcerative disease compared with none of the patients with chronic non-ulcerative disease and 4% of those with limited disease. Infarct on muscle biopsy correlated with the outcomes of death (p = 0.01) and gastrointestinal ulceration (p = 0.03), but not with the development of cutaneous ulceration (p = 0.18).DIF-arterial staining and infarct on muscle biopsy are significantly associated with the development of chronic ulcerative disease in JDM and JPM, while perifascicular myopathy and loss of the intramuscular capillary network are not associated with disease course. The presence of DIF-arterial staining and infarct on biopsy should suggest early use of second-line therapeutic agents to more quickly bring disease activity under control.

To investigate the clinical use patterns, clinical effect and safety of cyclosporine A (CSA) in juvenile idiopathic arthritis (JIA) in the setting of routine clinical care.An open-ended, phase IV post marketing surveillance study was conducted among members of the Pediatric Rheumatology Collaborative Study Group (PRCSG) and of the Paediatric Rheumatology International Trials Organisation (PRINTO) to identify patients with polyarticular course JIA who had received CSA during the course of their disease.A total of 329 patients, half of whom had systemic JIA, were collected in 21 countries. Data were collected during 1240 routine clinic visits. CSA was started at a mean of 5.8 years after disease onset and was given at a mean dose of 3.4 mg/kg/day. The drug was administered in combination with MTX in 61% and along with prednisone in 65% of the patients who were still receiving CSA. Among patients who were still receiving CSA therapy at the last reported visit, remission was documented in 9% of the patients, whereas in 61% of the patients the disease activity was rated as moderate or severe. The most frequent reason for discontinuation of CSA was insufficient therapeutic effect (61% of the patients); only 10% of the patients stopped CSA because of remission. In 17% of the patients, side effects of therapy was given as the primary reason for discontinuation.This survey suggests that CSA may have a less favourable efficacy profile than MTX and etanercept, whereas the frequency of side effects may be similar. The exact place of CSA in the treatment of JIA can only be established via controlled clinical trial.

The growth and development of plant pathogens and their hosts generally respond strongly to the temperature of their environment. However, most studies of plant pathology record pathogen/host measurements against physical time (e.g. hours or days) rather than thermal time (e.g. degree-days or degree-hours). This confounds the comparison of epidemiological measurements across experiments and limits the value of the scientific literature.

Sharp eyespot, caused by the soil-borne fungus Rhizoctonia cerealis Van der Hoeven (teleomorph: Ceratobasidium cereale D. Murray & L.L. Burpee), is a common disease of Graminaceae plants including wheat, barley, oats, and rye. The fungus is prevalent throughout the major wheat growing regions of the world and is sometimes associated with pre- and post-emergence damping off and shoot death of seedlings. Accepted for publication 16 June 2003. Published 17 July 2003.

Macrophage activation syndrome (MAS), a recognized complication of systemic juvenile rheumatoid arthritis (sJRA), has been associated with significant morbidity and mortality. Dysregulation of macrophage-lymphocyte interactions leading to uncontrolled proliferation of highly activated macrophages and massive release of proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) appears to be central to the pathogenesis of this syndrome. Until now the mainstay of therapy has been corticosteroids and cyclosporin A. We describe a patient with MAS and sJRA successfully treated with the anti-TNF agent etanercept. The outcome in this patient suggests etanercept might be an effective therapeutic agent in MAS.

Rain splash is the most important factor in the spread of epidemics of many plant pathogens. Splash height is highly dependent on the kinetic energy of impacting drops. However, direct measurements of rain such as the duration, the amount or the intensity are not related to splash height. We derive a mechanistic model that describes the trajectory of the splashing droplets in terms of the kinetic energy. Experimental data from controlled indoor experiments were used to estimate model parameters and predict the whole distribution of splashes given the kinetic energy of impacting drops. A separate data set from 21 natural rain events was used to verify the model. The maximum splash height was well estimated and the overall splash distribution was well predicted except for lower heights. Three reasons for these differences are discussed: they may be due to (1) ‘secondary’ splashes, (2) the distance between the drop impacting point and the centre of the ‘Precipitation Impact Sensor’ and (3) sampling differences. Different impacting surfaces may have an effect on the model; its robustness is, therefore, discussed. As a first approximation, this model could be used for droplets splashing from leaves within a crop if the structure of the model can be assumed to remain unchanged for different impacting surfaces.

To determine the extent of low total-body bone mineral content (BMC) in non-corticosteroid-treated white postpubertal females with juvenile rheumatoid arthritis (JRA) compared with healthy age- and race-matched female controls, and to identify variables that significantly contribute to total-body BMC.Thirty-six females with definite JRA who had never received corticosteroids and 51 healthy female controls were evaluated. All subjects had had their first menstrual period at least 2 years prior to enrollment. Total-body BMC, lumbar spine bone mineral density, and body composition were determined by dual x-ray absorptiometry. Total-body BMC Z-scores were calculated for JRA patients using data from controls. JRA patients were dichotomized into those with "normal" bone mass (total-body BMC at or above the mean or no more than 1 SD below the mean) and those with "low" bone mass (total-body BMC more than 1 SD below the mean). Comparisons of anthropometric measurements, laboratory measurements of bone metabolism, disease activity, dietary intake, and physical activity were performed. Stepwise logistic regression was utilized to determine the presence or absence of low total-body BMC and to identify associated contributing factors.Total-body BMC was 4.5% lower in JRA patients than in controls (mean +/- SD 2,050 +/- 379 gm versus 2,143 +/- 308 gm; P = 0.21). Twenty-five of 36 patients (69.4%) had "normal" and 11 of 36 (30.6%) had "low" total-body BMC. Comparison of JRA patients with "normal" versus those with "low" total-body BMC revealed significant differences in disease characteristics, anthropometric and physical development characteristics, laboratory measures of bone mineralization, and dietary intake. The final regression model contained only lean mass (P = 0.01), which accounted for 76.3% of the variance in total-body BMC. The odds ratio for lean mass was 0.4451 (95% confidence interval 0.2374-0.8348).In this study, approximately 30% of the subjects in a sample of postpubertal female patients with mild-to-moderate, non-corticosteroid-treated JRA had low bone mass. The predictor variable that significantly contributed to total-body BMC was lean mass, which demonstrated a protective effect of 0.56 risk reduction for low total-body BMC.

We evaluated the safety and efficacy of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein, in children with polyarticular juvenile rheumatoid arthritis who did not tolerate or had an inadequate response to methotrexate.Patients 4 to 17 years old received 0.4 mg of etanercept per kilogram of body weight subcutaneously twice weekly for up to three months in the initial, open-label part of a multicenter trial. Those who responded to treatment then entered a double-blind study and were randomly assigned to receive either placebo or etanercept for four months or until a flare of the disease occurred. A response was defined as an improvement of 30 percent or more in at least three of six indicators of disease activity, with no more than one indicator worsening by more than 30 percent.At the end of the open-label study, 51 of the 69 patients (74 percent) had had responses to etanercept treatment. In the double-blind study, 21 of the 26 patients who received placebo (81 percent) withdrew because of disease flare, as compared with 7 of the 25 patients who received etanercept (28 percent) (P=0.003). The median time to disease flare with placebo was 28 days, as compared with more than 116 days with etanercept (P0.001). In the double-blind study, there were no significant differences between the two treatment groups in the frequency of adverse events.Treatment with etanercept leads to significant improvement in patients with active polyarticular juvenile rheumatoid arthritis. Etanercept is well tolerated by pediatric patients.

To develop, validate, and determine the measurement characteristics of a quantitative tool for assessing the severity of muscle involvement in children with idiopathic inflammatory myopathies.The Childhood Myositis Assessment Scale (CMAS) was developed from 2 existing observational functional assessment tools to assess muscle function in the areas of strength and endurance across a wide range of ability and ages. The 14 ordinal items included were chosen to assess primarily axial and proximal muscle groups and are ranked with standard performance and scoring methods. Following the development of the CMAS, a training video and written instructions were developed and reviewed by the physicians participating in this study. Subsequently, utilizing a randomized block design, 12 physicians independently scored 10 children (9 with dermatomyositis, 1 with polymyositis; ages 4-15 years) twice in one day (morning and afternoon) on the CMAS. A pediatric physical therapist performed quantitative manual muscle strength testing (MMT) twice on each child (morning and afternoon), including the neck, trunk, and proximal and distal extremity muscle groups.The CMAS has a potential range of 0-51, with higher scores indicating greater muscle strength and endurance. The observed mean for the 10 patients was 36.4 (median 44, SD 14.1, observed range 5-51). The total score for the CMAS correlated with the physician's global assessment (by visual analog scale) of disease activity, the MMT score, serum creatine kinase level, and the Juvenile Arthritis Functional Assessment Report score. The score on the CMAS was not correlated with patient age. Interrater reliability (Kendall's coefficient of concordance) ranged from 0.77 to 1.0 for individual items (all P0.001), and overall, it was 0.95 (P0.001). Intrarater reliability for the individual physicians was measured by correlation of the CMAS scores for each patient on 2 separate evaluations and ranged from 0.97 to 0.99, with an overall correlation for all physicians of 0.98 (all P0.001).The CMAS demonstrated an acceptable range of observed scores, excellent convergent validity, and excellent inter- and intrarater reliability. The CMAS is validated to quantitatively assess muscle function in the areas of strength and endurance in children with idiopathic inflammatory myopathies. It can be used in routine clinical care as well as therapeutic trials.

To assess bone mineral density (BMD) and bone turnover in adults with a history of juvenile chronic arthritis (JCA) or persistent JCA, and to identify predictors of reduced BMD.Sixty-five white patients (mean age 32.2 years) with a history of JCA and 65 age-, sex-, height-, and weight-matched healthy control subjects participated in the study. Densitometry of the left hip and the lumbar spine was performed, and osteocalcin (bone formation marker) and crosslinks (bone resorption marker) were measured. In addition, bone-related clinical parameters were assessed in the JCA group.BMD in the hip and lumbar spine was significantly lower in the JCA group than in the controls. Levels of osteocalcin and crosslinks were significantly increased in the JCA group. According to WHO definitions, significantly more subjects in the JCA group had "osteopenia" and "osteoporosis" than would be expected in a normal population sample. Active disease at the time of the study (1996-1997), baseline erosions evaluated in 1979, Steinbrocker functional class in 1996-1997, polyarticular course of JCA, and history of systemic steroid treatment for more than 1 year were significantly associated with reduced BMD. In linear regression analysis including both the JCA and control groups, presence of JCA proved to be the factor most strongly associated with reduced BMD, explaining approximately 20% of its variation.Reduced BMD and evidence of increased bone turnover suggest that JCA patients may be at risk of developing premature osteoporosis and associated fractures later in life. The data are consistent with the concept that BMD in JCA is determined by many factors.

Outcome assessment has been a focus of recent research in rheumatic diseases and in pediatric rheumatology. The establishment of a preliminary core set of outcome variables for juvenile rheumatoid arthritis patients and a preliminary definition of improvement using these variables have been important steps toward standardization of outcome assessment. A population-based epidemiologic study has added to our knowledge of long-term outcome in juvenile arthritis and confirms the chronicity of disease that was found in previous studies. Standardization of outcome assessment in pediatric systemic lupus erythematosus has not been achieved to the same extent as in juvenile rheumatoid arthritis, but renal survival and overall mortality are important outcomes in this disease that are easily quantified. Recent studies of pediatric systemic lupus erythematosus demonstrate similarities with respect to organ involvement and overall survival between adult and pediatric lupus patients.

To identify a core set of outcome variables for the assessment of children with juvenile arthritis (JA), to use the core set to develop a definition of improvement to determine whether individual patients demonstrate clinically important improvement, and to promote this definition as a single efficacy measure in JA clinical trials.A core set of outcome variables was established using a combination of statistical and consensus formation techniques. Variables in the core set consisted of 1) physician global assessment of disease activity; 2) parent/patient assessment of overall well-being; 3) functional ability; 4) number of joints with active arthritis; 5) number of joints with limited range of motion; and 6) erythrocyte sedimentation rate. To establish a definition of improvement using this core set, 21 pediatric rheumatologists from 14 countries met, and, using consensus formation techniques, scored each of 72 patient profiles as improved or not improved. Using the physicians' consensus as the gold standard, the chi-square, sensitivity, and specificity were calculated for each of 240 possible definitions of improvement. Definitions with sensitivity or specificity of80% were eliminated. The ability of the remaining definitions to discriminate between the effects of active agent and those of placebo, using actual trial data, was then observed. Each definition was also ranked for face validity, and the sum of the ranks was then multiplied by the kappa statistic.The definition of improvement with the highest final score was as follows: at least 30% improvement from baseline in 3 of any 6 variables in the core set, with no more than 1 of the remaining variables worsening by30%. The second highest scoring definition was closely related to the first; the third highest was similar to the Paulus criteria used in adult rheumatoid arthritis trials, except with different variables. This indicates convergent validity of the process used.We propose a definition of improvement for JA. Use of a uniform definition will help standardize the conduct and reporting of clinical trials, and should help practitioners decide if a child with JA has responded adequately to therapy. We are in the process of prospectively validating this definition and several others that scored highly.

We describe a 6-year-old female patient with systemic lupus erythematosus (SLE) manifested mainly as steroid-dependent thrombocytopenia who developed a vasculitic appearing rash on her palms and soles following treatment with intravenous immunoglobulin (IVIg) (1 gm/kg/infusion x 2, 1 day apart). Vascular occlusion resulting in ischemic gangrene of the fore and midfeet eventually developed, necessitating bilateral amputation. This and other side effects described in SLE indicate that exacerbation of SLE, with the possibility of vasculitis, may occur following IVIg therapy.

To obtain preliminary information about the safety and efficacy of intravenous immune globulin (IVIG: Iveegam, Immuno AG, Vienna) in the treatment of polyarticular juvenile rheumatoid arthritis (poly-JRA) resistant to other forms therapy.We used a multicentered, phase I/II blinded-withdrawal design with stratified entry. All patients began by receiving open infusions of IVIG at a dose between 1.5 and 2.0 g/kg/infusion (100 g maximum) bimonthly for the first 2 months, then monthly for up to 6 months. Beginning at Month 3, those who met the criteria for "clinically important improvement" were randomized to receive monthly infusions for 4 months of either placebo or IVIG in a double blind (DB) phase. Patients were permitted nonsteroidal antiinflammatory drugs, slow acting antirheumatic drugs, and low dose (10 mg/day) prednisone at constant doses. An "early escape" provision in the DB allowed those who showed "clinically important worsening" to again receive IVIG (if taking placebo) or a higher dose of IVIG (if taking the lower dose of IVIG).Efficacy. Twenty-five children entered the trial and 19 (76%) met the criteria for "clinically important improvement" during the open phase (OP) and entered the DB. Three patients completed the OP but failed to meet the criteria for response, and 3 patients dropped out of the OP, none of whom showed benefit from IVIG. Treatment effect sizes produced by IVIG were moderate to large for all variables in the OP. Patients who continued IVIG in the DB continued to show improvement over that achieved in the OP. Those given placebo showed a rapid loss of efficacy, suggesting IVIG has a limited duration of effect after discontinuation. Safety. No patient developed serious or unexpected adverse side effects in the open or DB phases, and none dropped out of the study due to toxicity or side effects.Substantial clinical improvement from IVIG is produced in about three-fourths of patients with poly-JRA during open administration, but the duration of the beneficial effect is short after discontinuation. Those with disease3 years' duration may be more likely to respond than those who have had their disease for5 years. Short term safety is excellent.

The presence of clonally expanded T lymphocytes appears to be a characteristic feature of autoimmune diseases, including juvenile rheumatoid arthritis (JRA), although the relevance of such clones to immunopathogenesis is not clear. Identification of clones specific for a disease and/or particular MHC haplotypes should help differentiate those of pathogenic importance.A reverse transcriptase polymerase chain reaction assay for T cell receptor (TCR) complementarity determining region 3 (CDR3) length heterogeneity and cDNA sequencing were used to identify clonal expansion in synovial fluid (SF) samples obtained from 36 patients with JRA.The majority of patients had multiple synovial T cell clones using different TCR V beta families. Fifty-eight percent of these clonally expanded T cell populations used one of six TCR V beta families (V beta 2, V beta 8, V beta 14, V beta 16, V beta 17, and V beta 20). Patients with polyarticular, as opposed to pauciarticular, JRA had higher numbers of clones in joints. TCR V beta 8, V beta 14, V beta 16, and V beta 17 families were most frequently found in these clones. Overall, the most frequently used V beta family was V beta 20, which was observed in 18 of 36 SF samples. Of 18 patients exhibiting TCR V beta 20 clonal expansion, 14 (78%) had pauciarticular onset JRA. The V beta 20 association was especially strong in patients who possessed HLA-DR8+ haplotypes (p = 0.01, Fisher's exact test). SF from the patients who had other types of JRA (and other MHC haplotypes) did not show this association.The distinct clinical subtypes of JRA are characterized by different patterns of synovial T cell clonality. These findings imply that different molecular pathways underlie the development of arthritis in each subtype of JRA.

To assess the efficacy and safety of intravenous immunoglobulin (IVIG) in juvenile rheumatoid arthritis (JRA).Thirty-one children with active, refractory, systemic JRA were randomized into a multicentered, double blinded, placebo controlled trial. Patients received infusions of 1.5 g/kg of IVIG or placebo (0.1% albumin) every 2 weeks for 2 months, then monthly for 4 months (total: up to 9 infusions over 6 months). Twenty-nine of the 31 patients were included in the efficacy subset.Fourteen patients discontinued prematurely from study, 7 in each treatment group. A higher proportion of patients in the IVIG group improved (50 vs 27%) as assessed by the physician's global assessment. However, the sample size was small and this difference was not statistically significant. IVIG was not more effective than placebo in reducing the number of days with fever or other systemic manifestations. Changes from baseline in the joint count, hemoglobin, albumin, platelet count, and erythrocyte sedimentation rate did not differ between treatment groups.Our results suggest that high dose IVIG has limited clinical utility in systemic JRA. However, this trial failed to enroll adequate numbers of patients to permit valid statistical intergroup comparisons, and the results must be considered nondefinitive.

Protein-energy malnutrition (PEM) has been demonstrated in about 35% of patients with juvenile rheumatoid arthritis (JRA), but fewer than 8% of children with rheumatic diseases were reported in a national survey to have been seen by a pediatric dietitian. We demonstrate the development of a nutritional screening test for PEM in patients with JRA for use by all health care professionals. Nutritional assessment of 74 patients with JRA was conducted using a standardized 11 variable profile comprised of upper body anthropometric and biochemical measurements. The sensitivity, specificity, predictive values and index of validity were calculated for individual and selected clusters of nutritional variables to predict the need for referral for PEM compared to the independent review by 2 pediatric dietitians to refer or not refer to a dietitian for further evaluation or care. Arm circumference less than or equal to 10th percentile for age and sex matched norms was selected as the screening test for PEM in patients with JRA due to a combination of excellent measurement characteristics (sensitivity 0.80, specificity 0.86, positive predictive value 0.90, negative predictive value 0.73, index of validity 0.88) and ease of measurement.

Patients with systemic juvenile rheumatoid arthritis (JRA) are often poorly responsive to existing therapeutic modalities. We evaluated the effectiveness of pulse therapy consisting of methylprednisolone 30 mg/kg/day for 3 consecutive days combined with cyclophosphamide 0.4 g/m2 body surface area on the 3rd day, for 18 patients with definite systemic JRA, who were enrolled in an open trial of 12 months' duration. The children received pulse therapy every 3 months; oral methotrexate 10 mg/m2 was started after the first pulse. A rapid and clinically significant suppression of systemic and articular manifestations was seen in all patients. Significant decreases in laboratory indices of disease activity were also observed. Side effects were minor and reversible. The results of our preliminary trial support the development of a controlled study to evaluate the efficacy of pulse therapy in systemic JRA.

Development of health status questionnaires for pediatric patients with rheumatic disease presents special challenges. At this time, several investigators are actively involved in development of health status instruments which have demonstrated reliability and internal validity. I review these instruments and outline future studies needed for these instruments.

The risk of iridocyclitis in children with early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) has been shown to be associated with certain HLA haplotypes. Our report contains an actuarial analysis, using one-year intervals, of 161 subjects and estimates haplotype specific risks. Individuals who possess the major susceptibility haplotype HLA-DR5 (11) developed eye disease earlier and with a greater frequency than did those with the protective HLA-DR1 haplotype. Highly significant differences were found between the resulting life-table curves for HLA-DR5 and HLA-DR1 positive subjects (p = 0.00003). These time oriented risk estimates may aid clinicians in determining more precisely the probability of iridocyclitis throughout the course of the disease in children with EOPA-JRA.

This article focuses on the factors contributing to increased risk for malnutrition in juvenile rheumatoid arthritis patients, the methods of identifying and treating nutritional problems (including protein-energy malnutrition and obesity), and outlines national statistics demonstrating that the pediatric rheumatic patient population is nutritionally underserved. The dietitian, in conjunction with the interdisciplinary treatment team, should be involved in the initial evaluation of all juvenile rheumatoid arthritis patients to facilitate early detection of nutritional problems and initiate nutritional intervention strategies.

A juvenile rheumatoid arthritis-like arthropathy has previously been documented in 12 patients with Down syndrome. An additional 9 patients are described and the literature is reviewed. It is unknown whether these patients have juvenile rheumatoid arthritis or a unique arthropathy in light of the genetic and immunologic abnormalities associated with Down syndrome. Most of the patients had a progressive course with polyarticular disease complicated by subluxations and a long lag time to diagnosis. The purpose of reporting these children is to increase awareness of this association and facilitate more appropriate and timely diagnosis of arthritis in Down syndrome patients.

SUMMARY Standard specimens were examined in a transmission electron microscope with a top entry stage. Using a range of objective focal lengths, measurements of contrast, resolution and magnification range were made. Focal lengths up to 14 mm were examined. The contrast was found to increase with increasing focal length, being twelve and a half times greater at 14 mm focal length than at the normal high resolution mode of 2 mm focal length. Resolution, determined by the fresnel fringe method decreased from 0·3 nm to 3·5 nm. The photographic image magnification was reduced from × 1000– × 500,000 at 2 mm focal length to ×100-× 50,000 at 14 mm focal length.

Infantile-onset multisystem inflammatory disease (IOMID) is a newly recognized disease that is similar to systemic-onset juvenile rheumatoid arthritis (JRA). The clinical symptoms of IOMID include rash, fever, lymphadenopathy, chronic meningitis, uveitis, and a distinct arthropathic condition. Skeletal involvement is surprisingly constant. The long bones become short, bowed, and widened. The metaphyses flare and simulate rickets. Grotesque epiphyses appear fragmented early in the course of the disease but are gradually incorporated into the widened shafts. We observed these and other radiologic findings in the four cases described in the present study. The findings are distinctive and allow for a specific diagnosis.

The colonization and survival of Bacillus species, members of the cutaneous microbial community of humans, were investigated by applying spores of Bacillus licheniformis to the forearms of volunteers. Four strains were tested, including the bacitracin producer ATCC 10716 and its bacitracin-negative mutant. Germination occurred within 24 h. Significant differences in survival population and duration were found among the test strains; however, ATCC 10716 and its mutant produced statistically similar survival curves. In general, an inoculum density of 10(4) colony-forming units per cm2 allowed survival for at least 2 weeks. Individual variation was extreme, for one subject harbored bacilli for over 2 months and another eliminated the microorganism within 3 days. Individuals could be differentiated into long-term (greater than 21 days) and short-term (less than 14 days) carriers. Eight of the 11 volunteers (73%) inoculated with ATCC 10716 carried it for 2 weeks, and 5 subjects (45%) continued to support the bacilli for 3 weeks. Spreading of the organism to other regions of the body occurred, but bacilli were not detected in these areas beyond 6 days.

In 1930, a meeting to discuss photoelectric cells indicated that photoconductive cells were of marginal value. In 1954, interest in photoconductivity was sufficient to warrant a meeting to discuss that topic exclusively. The impetus for this change came largely from the military in its desire to develop a sensitive, reliable infrared detector. The varied investigations involve both German and U. S. A. wartime efforts and subsequent efforts in such diverse laboratories as university, military, and commercial. It is doubtless this diversification that has enabled so many successes to be achieved.