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OBJECTIVES: Measurement of serum biomarkers at disease onset may improve prediction of disease course in patients with early rheumatoid arthritis (RA). We evaluated the multi-biomarker disease activity (MBDA) score and early changes in MBDA score for prediction of 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) remission and radiographic progression in the double-blinded OPERA trial.METHOD: Treatment-naïve RA patients (N = 180) with moderate or high DAS28 were randomized to methotrexate (MTX) + adalimumab (n = 89) or MTX + placebo (n = 91) in combination with glucocorticoid injection into swollen joints. X-rays of hands and feet were evaluated at months 0 and 12 (n = 164) by the total Sharp van der Heijde score (TSS). The smallest detectable change (1.8 TSS units) defined radiographic progression (∆TSS ≥ 2). Clinical remission (DAS28-CRP < 2.6) was assessed at baseline and 6 months. MBDA score was determined at 0 and 3 months and tested in a multivariable logistic regression model for predicting DAS28 remission at 6 months and radiographic progression at 1 year.RESULTS: Baseline MBDA score was independently associated with radiographic progression at 1 year [odds ratio (OR) = 1.03/unit, 95% confidence interval (CI) = 1.01-1.06], and changes in MBDA score from baseline to 3 months with clinical remission at 6 months [OR = 0.98/unit, 95% CI 0.96-1.00). In anti-cyclic citrullinated peptide antibody (anti-CCP)-positive patients, 35 of 89 with high MBDA score (> 44) showed radiographic progression (PPV = 39%), compared with 0 of 15 patients (NPV = 100%) with low/moderate MBDA score (≤ 44) (p = 0.003).CONCLUSION: Early changes in MBDA score were associated with clinical remission based on DAS28-CRP at 6 months. In anti-CCP-positive patients, a non-high baseline MBDA score (≤ 44) had a clinical value by predicting very low risk of radiographic progression at 12 months.

OBJECTIVE: To investigate serum interleukin-6 (IL-6), serum chitinase-3-like protein-1 (YKL-40), and plasma vascular endothelial growth factor (VEGF) as measures of disease activity and predictors of clinical remission and radiographic progression in two early rheumatoid arthritis (RA) randomized controlled trials (RCTs).METHOD: Treatment-naïve patients with early RA (< 6 months' duration) and active disease, participating in two investigator-initiated RCTs, were treated according to a predefined treat-to-target algorithm aiming at inflammatory control, using methotrexate (MTX) + cyclosporine versus MTX + placebo (CIMESTRA study, n = 150, 5 year follow-up) or MTX + adalimumab versus MTX + placebo (OPERA study, n = 180, 2 year follow-up). The 28-joint Disease Activity Score (DAS28) and conventional radiography [bilateral hands and feet at baseline, 2 years and 5 years (only CIMESTRA)] were obtained at baseline and during follow-up. Serum IL-6, serum YKL-40, and plasma VEGF were measured in baseline blood samples and during follow-up. Hypotheses regarding the biomarkers' relation with DAS28 and ability to predict clinical remission (DAS28 < 2.6) and radiographic progression (change in total Sharp van der Heijde score ≥ 2) were generated in CIMESTRA and validated in OPERA, by Spearman's correlation and logistic regression analyses.RESULTS: Baseline IL-6, YKL-40, and VEGF correlated significantly with DAS28 in CIMESTRA (r = 0.50, r = 0.36, r = 0.36, respectively, all p < 0.01) and these results were confirmed in OPERA patients (r = 0.52, p < 0.01; r = 0.18, p = 0.01; r = 0.23, p = 0.002, respectively). None of the biomarkers (absolute values or change) was predictive of clinical remission or radiographic progression at 2 or 5 years in either study.CONCLUSION: Serum IL-6, serum YKL-40, and plasma VEGF were significantly correlated with DAS28 at baseline, but did not have consistent predictive value for clinical remission or radiographic progression in two early RA RCTs.

OBJECTIVE: Intestinal inflammation is frequent in patients with spondyloarthritis (SpA). Here, we test the validity of faecal calprotectin as a marker of intestinal inflammation in SpA patients and evaluate the response of adalimumab in patients with and without intestinal lesions.METHOD: Patients were included on the basis of active SpA with a Bath Ankylosing Spondylitis Disease Activity Index ≥ 4. After a 4 week non-steroidal anti-inflammatory drug washout period, patients were divided into two groups based on faecal calprotectin level (> 100 mg/kg, n = 15, and < 50 mg/kg, n = 15). Adalimumab 40 mg every other week was initiated. Patients with calprotectin >100 mg/kg received an additional 40 mg of adalimumab at baseline. Patients were followed with clinical examination at weeks 12, 20, and 52; magnetic resonance imaging (MRI) at weeks 0, 20, and 52; and endoscopy at weeks 0 and 20.RESULTS: The groups were similar with regard to clinical disease activity measures at baseline. Faecal calprotectin above 100 mg/kg accurately identified patients with intestinal inflammation. Twelve of the 15 patients with elevated calprotectin had bowel lesions, compared to only one patient in the control group. On MRI, the group with elevated calprotectin had more inflammation in the sacroiliac joints. Finally, the group with intestinal inflammation had a better clinical response to adalimumab, as evaluated by the Ankylosing Spondylitis Disease Activity Score.CONCLUSION: Elevated faecal calprotectin accurately identified SpA patients with bowel inflammation and more inflammation on MRI. Elevated faecal calprotectin at baseline may predict a better treatment response.

Background Studies in established rheumatoid arthritis (RA) have shown that radiographic progression is associated with increasing health assessment questionnaire (HAQ) score. However, most studies have failed to demonstrate this association at the early stage of the disease. In addition, little is known about how specific pathologies, e.g. joint inflammation, tenosynovitis and joint damage, contribute to different patient-reported outcomes (PROs). Objectives To examine the association between MRI wrist inflammation and damage with PROs in patients with early RA. Methods MRIs of the wrist and hand were obtained from 210 early RA patients participating in two investigator-initiated, randomized, controlled studies (CIMESTRA/OPERA), which aimed at achieving inflammatory control by use of conventional and/or biologic drugs combined with intra-articular injection of glucocorticoids. The image-sets were assessed according to the RA MRI scoring system (RAMRIS) for inflammation (synovitis, tenosynovitis, osteitis) and damage (bone erosions, joint space narrowing) at baseline (n=210), 1 (n=206) and 5 (n=113) years follow-up. Data from the two studies were pooled and assessed for associations between MRI features and HAQ, patient global visual analogue scales (VAS-PtGlobal) and VAS pain using Spearman correlation for status and change scores, univariate and multivariable linear regression analyses for change scores and generalized estimating equations for status and change scores. MRI features were further tested for trends against specific hand-related HAQ questions using the Jonckheere trend test. Results MRI inflammation, but not damage, showed statistically significant associations with HAQ, VAS-PtGlobal and VAS pain for status and change scores, independently of swollen joint count and level of C-reactive protein. Synovitis and tenosynovitis were the MRI features most consistently associated with PROs, particularly VAS-PtGlobal and VAS pain (Table 1). MRI synovitis and tenosynovitis mean scores increased with the level of difficulty to cut meat and open a milk carton (p Conclusions MRI-assessed inflammation, but not damage, in the early RA wrist is associated with patient-reported physical impairment, global disease activity and pain, and the amount of wrist inflammation influences physical hand function. Disclosure of Interest D. Glinatsi: None declared, J. Baker: None declared, M. Hetland Grant/research support from: BMS, AbbVie, Pfizer, UCB-Nordic, MSD, K. Horslev-Petersen Consultant for: AbbVie and UCB, B. Ejbjerg: None declared, K. Stengaard-Pedersen: None declared, P. Junker: None declared, T. Ellingsen: None declared, H. Lindegaard: None declared, I. Hansen: None declared, T. Lottenburger: None declared, J. Moller: None declared, L. Ornbjerg: None declared, A. Vestergaard: None declared, A. G. Jurik: None declared, H. Thomsen: None declared, T. Torfing: None declared, S. Bisgaard: None declared, M. Axelsen Grant/research support from: Abbvie, M. Ostergaard Grant/research support from: Abbvie, BMS, Janssen and Merck, Consultant for: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Centocor, GSK, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB, and Wyeth

Capturing financial network linkages and contagion in stress test models are important goals for banking supervisors and central banks responsible for micro- and macroprudential policy. However, granular data on financial networks is often lacking, and instead the networks must be reconstructed from partial data. In this paper, we conduct a horse race of network reconstruction methods using network data obtained from 25 different markets spanning 13 jurisdictions. Our contribution is two-fold: first, we collate and analyze data on a wide range of financial networks. And second, we rank the methods in terms of their ability to reconstruct the structures of links and exposures in networks.

OBJECTIVES: To investigate whether a treat-to-target strategy based on methotrexate (MTX) and intra-articular (IA) betamethasone suppresses magnetic resonance imaging (MRI)-determined measures of disease activity and reduces joint destruction in early rheumatoid arthritis (eRA) patients, and to investigate whether concomitant cyclosporin A (CyA) provides an additional effect.METHOD: In the 2-year randomized, double-blind, treat-to-target trial CIMESTRA, 160 patients with eRA (< 6 months) were randomized to MTX, intra-articular betamethasone and CyA, or placebo CyA. A total of 129 patients participated in the MRI substudy, and had contrast-enhanced MR images of the non-dominant hand at months 0, 6, 12, and 24. MR images were evaluated for osteitis, synovitis, tenosynovitis, bone erosion, and joint space narrowing (JSN), using validated scoring methods.RESULTS: Significant reductions were seen at 6 months in all inflammatory parameters [synovitis, mean change -1.6 (p < 0.001, Wilcoxon), tenosynovitis, -3.5 (p < 0.001), and osteitis, -1.3 (p < 0.05)] and at 12/24 months in synovitis and tenosynovitis [-1.6/-2.2 and -3.6/-3.8, respectively; all p < 0.001]. MRI signs of inflammation were not fully eliminated, and increases in erosion and JSN scores were observed at 6 months [0.4 (p < 0.01)/0.1 (p < 0.05)], 12 months [0.8 (p < 0.001)/0.3 (p < 0.01)], and 24 months [1.0 (p < 0.001)/0.4 (p < 0.001)]. Clinical measures decreased significantly (p < 0.001) at all time points. There were no consistent statistically significant differences between treatment groups.CONCLUSIONS: In this eRA treat-to-target trial, MTX and intra-articular glucocorticoids markedly reduced, but did not eliminate, MRI osteitis, synovitis, and tenosynovitis. Accordingly, minimal but statistically significant increases in bone erosion and JSN were observed. No additional effect of CyA was demonstrated.

Objective To investigate the short-term and long-term efficacy of intra-articular betamethasone injections, and the impact of joint area, repeated injections, MRI pathology, anticyclic citrullinated peptide (CCP) and immunoglobulin M rheumatoid factor (IgM-RF) status in patients with early rheumatoid arthritis (RA). Methods During 2 years of follow-up in the CIMESTRA trial, 160 patients received intra-articular betamethasone in up to four swollen joints/visit in combination with disease-modifying antirheumatic drugs. Short-term efficacy was assessed by EULAR good response. Long-term efficacy by Kaplan–Meier plots of the joint injection survival (ie, the time between injection and renewed flare). Potential predictors of joint injection survival were tested. Results 1373 Unique joints (ankles, elbows, knees, metacarpophalangeal (MCP), metatarsophalangeal, proximal interphalangeal (PIP), shoulders, wrists) were injected during 2 years. 531 Joints received a second injection, and 262 a third. At baseline, the median numbers of injections (dose of betamethasone) was 4 (28 mg), declining to 0 (0 mg) at subsequent visits. At weeks 2, 4 and 6, 50.0%, 58.1% and 61.7% had achieved a EULAR good response. After 1 and 2 years, respectively, 62.3% (95% CI 58.1% to 66.9%) and 55.5% (51.1% to 60.3%) of the joints injected at baseline had not relapsed. All joint areas had good 2-year joint injection survival, longest for the PIP joints: 73.7% (79.4% to 95.3%). 2-Year joint injection survival was higher for first injections: 56.6% (53.7% to 59.8%) than for the second: 43.4% (38.4% to 49.0%) and the third: 31.3% (25.0% to 39.3%). Adverse events were mild and transient. A high MRI synovitis score of MCP joints and anti-CCP-negativity were associated with poorer joint injection survival, whereas IgM-RF and C-reactive protein were not. Conclusion In early RA, intra-articular injections of betamethasone in small and large peripheral joints resulted in rapid, effective and longlasting inflammatory control. The cumulative dose of betamethasone was low, and the injections were well tolerated.

Objective To investigate the possibility that inhalation of raspberry powder at work can cause occupational asthma. Methods We report the case of a 35-year-old, nonsmoking woman who complained of hay fever symptoms, wheezing, and shortness of breath two or three times a month exclusively in association with coating chewing gum with raspberry powder. Prick test extracts with the five types of fruit powder were produced. Peak expiratory flow rate monitoring five times daily was performed for an 8-week period while the patient was at work. Specific IgE and histamine release tests for raspberry powder were performed. Breathing zone dust measurements were taken. Results Baseline lung function and histamine provocation test results were normal. During the 8-week monitoring period, 5 episodes of reduced peak expiratory flow rate were demonstrated. Each period was directly related to working with raspberry powder. A 9-mm prick test result positive for raspberry powder was seen (histamine control, 9 mm). In addition, the result of a radioallergosorbent test for raspberry was positive (0.84 kUA/L). The result of a histamine release test with raspberry powder from work was negative. Breathing zone total dust measurement was 5.9 mg/m 3 . Conclusions To our knowledge, this is the first description of occupational asthma due to the inhalation of raspberry powder. The symptoms of the patient described herein disappeared after she was moved to another part of the factory. Hygienic improvements were performed at the workplace to reduce the sensitization risk of other workers.

Following oral administration of trimethoprim (TMP) in doses varying from 5.7 to 9.8 mg TMP per kg body weight per 24 h over a period of 1–22 days, the concentration was determined in normal and patho

10 of 20 workers in an envelope-making factory developed contact dermatitis. The cause was dibutyl maleinate, which was added to a polyvinylacetate glue. Dibutyl maleinate is a strong sensitizer and should be withdrawn from industrial use.

The penetration of lincomycin into normal bone was studied in 10 patients with fracture of the neck of the femur, a separate determination being made of the lincomycin concentration in serum, bone marrow, spongy bone and compact bone. The concentration of lincomycin in bone marrow was found to be at the same level as that in the serum. The concentration in spongy bone amounted in most cases to 50 to 75 percent of the concentration in the serum, whereas the concentration in compact bone varied from 0 to 15 percent of that in the serum.

Following the administration of trimethoprim (TMP) by mouth in doses varying from 5.0 to 8.1 mg TMP per kg body weight per 24 hours over a period of 24–48 hours, the concentration was examined in either the prostatic tissue or the prostatic secretion, in a total of 13 patients. A microbiological method was employed to determine the concentration, using B. ptrmilis as test organism. A method of collecting the prostatic secretion was used which excluded the admixture of urine with higher antibiotic content than that of the secretion. Tissue was examined which was obtained both by open and closed (transperineal) biopsy. The concentrations of TMP found in both the secretion and the tissue (9–12 hours after the last administration of TMP) were at a thera-peutically active level (≥MIC × 5) with respect to the majority of those bacteria usually occurring in urinary tract infection.