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Background Few RCTs have investigated long-term (>10 years (yrs)) outcomes of goal-directed synovitis suppression in early rheumatoid arthritis (RA). The CIMESTRA trial was a 2-year double-blinded Danish multicenter study on aggressive treatment with csDMARDS (methotrexate (MTX) versus MTX and cyclosporine) in combination with intra-articular glucocorticoids (1+2). Disease control after 2 yrs was excellent with $≈ $50% in remission and halted radiographic progression in both groups. We present 11 yr follow-up data. Objectives The aims were to 1) investigate the clinical and radiographic status and 2) identify baseline predictors of functional status and erosive progression. Methods Of 160 patients (pts) included, 130 pts also had MRI of the wrist performed at baseline. 17 pts had died since baseline. All living pts were contacted and 120 signed informed consent to participate in a 11 yrs9 follow-up visit assessing e.g. treatment, disease activity (DAS28, CRP, 4 variables), physical function (HAQ), X-ray of hands and feet. Baseline MRI was scored by OMERACT rheumatoid arthritis MRI scoring (RAMRIS) system, X-rays by Sharp-van der Heijde total Sharp Score (TSS). Multivariable linear regression analyses of a panel of baseline variables (see foot note in table) with backward selection were performed with HAQ at 11 yrs (HAQ 11 ) and radiographic progression since baseline (ΔTSS 0–11 ) as dependent variables. Results 120 of 160 pts (75%) completed the 11 yrs visit. 96 pts with available baseline MRI and X-rays of both time points were included in the prediction models. Withdrawal analysis comparing the 160 pts with the 40 and 64 pts who were not included showed similar baseline characteristics except for higher DAS28 and HAQ score for withdrawers. Follow-up was after 11.6 yrs (10.7–12.2) (median (IQR)). Pts were 63 yrs (55–72) and 70% females. 20% received biologics (+/- csDMARD), 53% csDMARD alone, 27% were in drug free remission. DAS28 was 2.0 (1.5–2.6); pain score: 1 cm (0.3–3); pt. global: 1.1 cm (0.2–2.9); swollen joint count (28SJC): 0 (0–0); tender joint count (28TJC): 0 (0–1). 76% of pts were in DAS28 remission; HAQ-score was 0.25 (0–0.75); ΔTSS 0–11 (median (IQR)):4 (0–13); ΔTSS 0–11 (mean±SD): 10.9±16.9). The annual progression rate since baseline was median (IQR):0.4 (0–1.1); mean±SD:0.96±1.52. Multivariable linear regression analyses are shown in Table. Conclusions 11 years after diagnosis 75% were in DAS28 remission. HAQ-score was low, and mean radiographic progression was References Arthritis Rheum 2006; 54: 1401–9. Ann Rheum Dis 2008; 67: 815–22. Disclosure of Interest M. L. Hetland Grant/research support from: AbbVie, BMS, MSD, Pfizer, Orion, Novartis, Biogen, Eli Lilly, K. Stengaard-Petersen: None declared, P. Junker: None declared, H. Lindegaard: None declared, T. Ellingsen: None declared, J. Podenphant: None declared, H. Skjodt: None declared, A. Vestergaard: None declared, B. Ejbjerg: None declared, S. Jacobsen: None declared, N. S. Krogh: None declared, M. Ostergaard Grant/research support from: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Centocor, GSK, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB, K. Horslev-Petersen: None declared

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

Background IgG4-related disease (IgG4-RD) is a recently recognized systemic disease of unknown etiology and prevalence [1]. Retrospective single center series have provided evidence that 13–63% of patients with idiopathic retroperitoneal fibrosis (IRPF) could be reclassified as IgG4-RD. Since immunesuppressants or B-cell targeted therapies may halt or reverse progression, early diagnosis and treatment is important to prevent terminal fibrosis. Objectives To estimate the occurrence of IgG4 related retroperitoneal fibrosis (RPF) in Danish patients diagnosed with IRPF. Methods The National Danish Pathology Register was searched for biopsy codes relating to retroperitoneal tissue and inflammation from 01.01.2004 through 31.12.2013. Patients below 18 years of age, secondary causes, malignancies, infections, and specimens with multinucleated giant cells or granulomas were excluded. Among 724 candidate cases 68 were identified with IRPF. Among these 25 were left out due to small tissue samples, unavailable patient files or lack of consent. Clinical, laboratory data and imagings were reviewed. Paraffin-embedded tissue blocks were retrieved from 18 pathology departments. Four sections were prepared and stained with hematoxylin-eosin, Weigerts elastin and IgG4 immunostaining. Histopathologic features suggesting an IgG4-RD background were recorded (table). Cut-off levels for IgG4 positive cells at ≥30 per HPF and IgG4: total IgG ratio at ≥40% were applied. Patients were categorized as IRPF, definite or possible IgG4-RD according to international consensus [2]. Intergroup comparisons were done using Mann-Whitney U test or Chi square test. Results Forty three patients (29 males), median age 56 years were included among which 19 (44%) met the criteria for IgG4-RD comprising 7 with definite, 12 with possible IgG4-RD and 24 with IRPF. Biopsies were available from all participants. Extraretroperitoneal manifestations, standard laboratory measures and serum IgG4 (in 5 individuals) did not differ significantly between RPF subsets. Patients with an IgG4: total IgG ratio ≥40% had significantly more histopathologic features of IgG4-RD compared to a ratio Conclusions A total of 44% of IRPF patients was diagnosed with IgG4-RD, 16% with definite and 28% with possible IgG4-RD. This estimate may be conservative because specimens with multinucleated giant cells or granulomas were excluded. The closer association of IgG4: total IgG ratio ≥40 vs. lower ratios with histopathologic findings supports a direct pathogenic role by IgG4 bearing cells or IgG4 in IgG4 RPF. References Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366 6: 539–51. Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012;25 9: 1181–92. Disclosure of Interest None declared

Background Undifferentiated arthritis (UA) is a label applied to patients with joint complaints which cannot be classified according to current criteria, which implies a need for precision diagnostic technologies. We studied serum galectin-3, a proinflammatory mediator, and seromarkers of structural joint elements in patients with early, UA and their associations with disease profile and biochemical and imaging findings. Methods One hundred and eleven UA patients were followed-up for at least 12 months and reclassified according to appropriate criteria (TUDAR). At baseline, demographics and laboratory and clinical disease measures, as well as wrist magnetic resonance imaging (MRI) synovitis, erosion, and bone marrow edema scorings, were recorded. Galectin-3, the type IIA collagen N-terminal propeptide (PIIANP), which is a marker of regenerative cartilage formation, and hyaluronan (HYA), which is prevalent in synovial tissue swellings, were measured by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) curve analysis was carried out to assess the discriminant capacity of galectin-3 against arthritis subsets. Results Galectin-3 was increased in pre-rheumatoid arthritis (RA) (4.6 μg/l, interquartile range (IQR) 3.8–5.5) versus non-RA (4.0 μg/l, IQR 3.1–4.9; p = 0.03) and controls (3.8 μg/l, IQR 3.0–4.8; p = 0.009). PIIANP was equally depressed in either subset (p

INTRODUCTION: Cardiovascular morbidity and mortality is increased in patients with rheumatoid arthritis (RA), and among these patients, the prevalence of hypovitaminosis D is high. Moreover, low vitamin D levels have been associated with increased cardiovascular risk in healthy subjects.OBJECTIVE: To evaluate the long-term risk of cardiovascular events in patients having low total 25-hydroxyvitamin D levels at baseline compared with patients with normal levels, in an efficiently treated, closed cohort of patients with an early diagnosis of RA.METHODS AND ANALYSIS: This study is a prospective, closed, blinded endpoint cohort study, based on secondary analyses from a previous randomised trial (CIMESTRA study; NCT00209859, approved September 1999) including 160 patients with an early diagnosis of RA from Danish University clinics. Primary outcome will be the proportion of patients with any cardiovascular event in the follow-up period, evaluated using systematic journal audits. Logistic regression models will test the hypothesis that there are more cardiovascular events in enrolled patients with a low level of vitamin D (< 50 nmol/L). Secondarily, Cox regression models, based on survival analysis, will determine the extent to which independent variables (including different levels of vitamin D at baseline) predict whether a cardiovascular event will occur, and also when this will be.ETHICS AND DISSEMINATION: All patients have received verbal and written information before enrolment, and have given written consent at baseline. To disseminate comprehension of factors of prognostic importance to cardiovascular outcome in RA, we will attempt to have a first draft ready no later than 1 year after the adjudication process has finished. If low vitamin D levels can predict cardiovascular events in RA, it is relevant to take into account in a prediction model, to be considered by patients, physicians and other decision-makers.TRIAL REGISTRATION NUMBER: The parental controlled trial is registered as NCT00209859.

OBJECTIVES: To investigate whether antibody response patterns against Klebsiella pneumoniae capsular serotypes can discriminate patients with axial spondyloarthritis (axSpA) from patients with non-specific low back pain (LBP).METHOD: Immunoglobulin (Ig)G and IgA antibodies against K. pneumoniae capsular serotypes K2, K26, K36, and K50 were measured, and antibody seropositivity compared between groups and analysed for patient correlation in five different groups: (a) 96 patients fulfilling the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axSpA; (b) 38 patients with either a positive magnetic resonance imaging (MRI) scan as defined by ASAS or a positive human leucocyte antigen (HLA)-B27 status plus one clinical SpA feature, characterized as 'non-axSpA'; (c) 82 non-specific LBP patients; (d) 40 healthy blood donors and (e) 43 patients with diagnosed ankylosing spondylitis (AS) served as the negative and positive control groups.RESULTS: There was no difference in IgG and IgA seropositivity against all serotypes between the axSpA, non-axSpA, and LBP groups. No significant correlations were found between anti-Klebsiella antibodies and age, gender, HLA-B27, or high-sensitivity C-reactive protein (hsCRP). IgG seropositivity against K50 was more frequent in AS (25.6%) than in axSpA (13.5%, p < 0.05). axSpA patients with radiographic sacroiliitis and AS controls concordantly had the highest frequency of seropositivity for ≥ 2 serotypes (21%).CONCLUSIONS: The antibody patterns against K. pneumoniae serotypes K2, K26, K36, and K50 did not discriminate between early axSpA and non-specific LBP.

Rheumatoid arthritis (RA) is characterized by chronic joint inflammation and infiltration by activated macrophages. TNFα is a central mediator in this process. The mannose receptor, CD206, is a scavenger receptor expressed by M2A-macrophages and dendritic cells. It is involved in collagen internalization and degradation. The soluble form has been suggested as a biomarker of M2A-macrophage activation. The aim of this study was to investigate sCD206 plasma levels in early RA patients initiating anti-TNFα treatment. Plasma levels of sCD206 were measured by ELISA in samples from 155 early RA patients with an average symptom duration of 3 months. Patients were randomized to 12 months' methotrexate and placebo (PLA) or methotrexate and adalimumab (ADA) treatment, followed by open-label treatment with disease-modifying anti-rheumatic drugs (DMARD) and if needed, ADA. Disease activity was assessed at baseline and after 3, 6, 12 and 24 months. Baseline plasma level of sCD206 in treatment naïve RA patients was 0.33 mg/L (CI: 0.33-0.38 mg/L) corresponding to the upper part of the reference interval for healthy controls (0.10-0.43 mg/L). In the PLA group, sCD206 levels decreased after 3 months, but did not differ from baseline after 6 months. In the ADA group, however, levels remained lower than baseline throughout the treatment period. In conclusion, initially, plasma sCD206 in early RA patients decreased in accordance with disease activity and initiation of DMARD treatment. Treatment with anti-TNFα preserved this decrease throughout the study period.

This study aims to investigate 1-year hand bone loss (HBL 1-year) in early rheumatoid arthritis (RA) patients treated with a methotrexate (MTX) and intra-articular triamcinolone treat-to-target strategy +/− adalimumab and to determine if HBL 6months is associated with radiographic progression after 2 years. In a clinical trial (OPERA) of 180 treatment-naive early RA patients, bone mineral density (BMD) was estimated from hand radiographs with digital X-ray radiogrammetry (DXR) at baseline, after 6 (n = 90) and 12 months (n = 70) of follow-up. Baseline and 2-year radiographs were scored according to the Sharp/van der Heijde method. Baseline characteristics and HBL 6months (0–6 months changes in DXR-BMD) were investigated as predictors of structural damage by univariate linear (∆ total Sharp/van der Heijde score (TSS) as dependent variable) and logistic (+/−radiographic progression (∆TSS >0) as dependent variable) regression analyses. Variables with p 1-year data, HBL 1-year was median (interquartile range (IQR)) −1.9 (−3.3; −0.26 mg/cm 2) in the MTX + placebo group and −1.8 (−3.6; 0.06) mg/cm 2 in the MTX + adalimumab group, p = 0.98, Wilcoxon signed-rank. Increased HBL (compared to general population reference values) was found in 26/37 and 23/33 patients in the MTX + placebo and MTX + adalimumab groups, chi-squared = 0.99. In 90 patients with HBL 6months data and 2-year radiographic data, HBL 6months was independently associated with ∆TSS after 2 years (β = −0.086 (95% confidence interval = −0.15; −0.025) TSS unit/mg/cm 2 increase, p = 0.006) but not with presence of radiographic progression (∆TSS >0) (OR 0.96 (0.92–1.0), p = 0.10). In early RA patients treated with a methotrexate-based treat-to-target strategy, the majority of patients had increased HBL 1-year, irrespective of adalimumab; HBL 6months was independently associated with ∆TSS after 2 years.

OBJECTIVE: The aim of this investigation was to estimate the heritability of circulating collagen IIA N-terminal propeptide (PIIANP) by studying mono- and dizygotic healthy twin pairs at different age and both genders.DESIGN: 598 monozygotic (MZ) and dizygotic (DZ) twin individuals aged 18-59 years were recruited from the Danish Twin Registry. PIIANP was measured by competitive ELISA. The similarity of circulating PIIANP among MZ and DZ twins was assessed by intraclass correlations according to traits. The heritability was estimated by variance component analysis accounting for additive and dominant genetic factors as well as shared and non-shared environment but ignoring epistasis (genetic inter-locus interaction) and gene-environment interaction.RESULTS: The intraclass correlation of PIIANP in MZ and DZ twins was 0.69 (0.60-0.76) and 0.46 (0.34-0.58) respectively indicating a significant genetic impact on PIIANP in serum. Additive genetic effects explained 45% (21-70%), shared environment 24% (7-53%) and non-shared environment 31% (24-39%) of the total variance. The heritability estimate did not differ across ages and between genders.CONCLUSIONS: The study shows that approximately 45% of the collagen IIA synthesis as assessed by the collagen IIA N-terminal propeptide in serum is attributable to genetic effectors while individual and shared environment account for 24% and 31% respectively. The heritability does not differ between genders or according to age. OBJECTIVE: The aim of this investigation was to estimate the heritability of circulating collagen IIA N-terminal propeptide (PIIANP) by studying mono- and dizygotic healthy twin pairs at different age and both genders.DESIGN: 598 monozygotic (MZ) and dizygotic (DZ) twin individuals aged 18-59 years were recruited from the Danish Twin Registry. PIIANP was measured by competitive ELISA. The similarity of circulating PIIANP among MZ and DZ twins was assessed by intraclass correlations according to traits. The heritability was estimated by variance component analysis accounting for additive and dominant genetic factors as well as shared and non-shared environment but ignoring epistasis (genetic inter-locus interaction) and gene-environment interaction.RESULTS: The intraclass correlation of PIIANP in MZ and DZ twins was 0.69 (0.60-0.76) and 0.46 (0.34-0.58) respectively indicating a significant genetic impact on PIIANP in serum. Additive genetic effects explained 45% (21-70%), shared environment 24% (7-53%) and non-shared environment 31% (24-39%) of the total variance. The heritability estimate did not differ across ages and between genders.CONCLUSIONS: The study shows that approximately 45% of the collagen IIA synthesis as assessed by the collagen IIA N-terminal propeptide in serum is attributable to genetic effectors while individual and shared environment account for 24% and 31% respectively. The heritability does not differ between genders or according to age.

OBJECTIVES: To investigate whether a treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid injections suppresses MRI inflammation and halts structural damage progression in patients with early rheumatoid arthritis (ERA), and whether adalimumab provides an additional effect.METHODS: In a double-blind, placebo-controlled trial, 85 disease-modifying antirheumatic drug-naïve patients with ERA were randomised to receive methotrexate, intra-articular glucocorticosteroid injections and placebo/adalimumab (43/42). Contrast-enhanced MRI of the right hand was performed at months 0, 6 and 12. Synovitis, osteitis, tenosynovitis, MRI bone erosion and joint space narrowing (JSN) were scored with validated methods. Dynamic contrast-enhanced MRI (DCE-MRI) was carried out in 14 patients.RESULTS: Synovitis, osteitis and tenosynovitis scores decreased highly significantly (pCONCLUSIONS: A treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid in patients with ERA effectively decreased synovitis, osteitis and tenosynovitis and halted structural damage progression as judged by MRI. The findings suggest that addition of adalimumab is associated with further suppression of osteitis and tenosynovitis.

Objective To assess plasma M-ficolin concentrations in disease-modifying antirheumatic drug (DMARD)–naive patients with early rheumatoid arthritis (RA), to investigate the correlation of M-ficolin concentrations with disease activity markers, and to determine the predictive value of M-ficolin with respect to the Disease Activity Score in 28 joints (DAS28). Methods The study group included 180 DMARD-naive patients with early RA who participated in a randomized controlled trial of methotrexate and intraarticular glucocorticoids plus either adalimumab or placebo/adalimumab. One hundred healthy control subjects and 51 patients with chronic RA were also assessed. A sandwich-type time-resolved fluorometric immunoassay was used for quantification of plasma M-ficolin. Results At baseline, M-ficolin levels were highest in the group of DMARD-naive patients with newly diagnosed active RA, and the level in these patients decreased 26% after 1 year of aggressive treatment. The baseline M-ficolin level correlated with 5 of 7 disease activity markers, including the DAS28 and the Health Assessment Questionnaire (HAQ), and a similar pattern of correlations was observed at 1 year. Multiple logistic regression analysis showed that an elevated M-ficolin level at baseline was the strongest predictor of not achieving either DAS28 remission (odds ratio [OR] 4.18, 95% confidence interval [95% CI] 2.02–8.63) or low disease activity (OR 2.45, 95% CI 1.13–5.28) at 1 year. The presence of a baseline M-ficolin level in the lowest quartile resulted in sensitivity of 29%, specificity of 93%, and positive predictive value of 95% for low disease activity at 1 year. Conclusion In patients with early RA, elevated plasma M-ficolin levels correlated with a high DAS28 and a high HAQ score at baseline and 1 year. A low M-ficolin level was the strongest predictor of remission and low disease activity in a multivariate analysis.

Low birth weight has been proposed as a risk factor for rheumatoid arthritis (RA). The twin-control study design provides an opportunity to investigate the significance of potential prenatal determinants for adult morbidity by accounting for maternal characteristics and early environmental and genetic factors. We investigated the association between birth weight and RA in a sample of 42 twin pairs discordant for rheumatoid arthritis in which valid information on birth weight, birth length, and order was available from midwife records. Difference plot and conditional logistic regression were used to investigate the relationship between RA and birth weight or birth order adjusting for birth length and sex. The intra-pairwise birth weight differences, i.e., RA twin minus co-twin, ranged from -750 to 1,100 g, mean 78 g (95 % CI -13 to 70), 146 g (95 % CI (-36 to 329) in monozygotic, 32 g (95 % CI -90 to 154) in dizygotic, same sex and 69 g (95 % CI -122 to 260) in dizygotic, opposite sex twin pairs. The odds ratio for birth weight as risk factor for RA was 1.00 (95 % CI 0.997-1.003) when adjusting for birth length, birth order, and sex, irrespective of ACPA status. The odds ratio for developing RA as first born twin was 2.33 (95 % CI 0.97-5.60) when adjusting for birth length, birth weight, and sex, irrespective of ACPA status. In this twin-control study, birth weight was not associated with the development of RA in adult life. Being born first may predispose to RA. Low birth weight has been proposed as a risk factor for rheumatoid arthritis (RA). The twin-control study design provides an opportunity to investigate the significance of potential prenatal determinants for adult morbidity by accounting for maternal characteristics and early environmental and genetic factors. We investigated the association between birth weight and RA in a sample of 42 twin pairs discordant for rheumatoid arthritis in which valid information on birth weight, birth length, and order was available from midwife records. Difference plot and conditional logistic regression were used to investigate the relationship between RA and birth weight or birth order adjusting for birth length and sex. The intra-pairwise birth weight differences, i.e., RA twin minus co-twin, ranged from -750 to 1,100 g, mean 78 g (95 % CI -13 to 70), 146 g (95 % CI (-36 to 329) in monozygotic, 32 g (95 % CI -90 to 154) in dizygotic, same sex and 69 g (95 % CI -122 to 260) in dizygotic, opposite sex twin pairs. The odds ratio for birth weight as risk factor for RA was 1.00 (95 % CI 0.997-1.003) when adjusting for birth length, birth order, and sex, irrespective of ACPA status. The odds ratio for developing RA as first born twin was 2.33 (95 % CI 0.97-5.60) when adjusting for birth length, birth weight, and sex, irrespective of ACPA status. In this twin-control study, birth weight was not associated with the development of RA in adult life. Being born first may predispose to RA.

OBJECTIVES: An investigator-initiated, double-blinded, placebo-controlled, treat-to-target protocol (Clinical Trials:NCT00660647) studied whether adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment in early rheumatoid arthritis (ERA) increased the frequency of low disease activity (DAS28CRPMETHODS: In 14 Danish hospital-based clinics, 180 disease-modifying anti-rheumatic drugs (DMARD)-naïve ERA patients (RESULTS: Baseline characteristics were similar between groups. In the adalimumab group/placebo group the 12-month cumulative triamcinolone doses were 5.4/7.0 ml (p=0.08). Triple therapy was applied in 18/27 patients (p=0.17). At 12 months, DAS28CRPCONCLUSIONS: Adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment did not increase the proportion of patients who reached the DAS28CRP

Objectives: In an explorative epigenome-wide association study (EWAS) to search for gene independent, differentially methylated DNA positions (DMPs) and regions (DMRs) associated with rheumatoid arthritis (RA) by studying monozygotic (MZ) twin pairs discordant for rheumatoid arthritis. Methods: Genomic DNA was isolated from whole blood samples from 28 monozygotic (MZ) twin pairs discordant for RA. DNA methylation was measured using the HumanMethylation450 BeadChips. Smoking, anti-cyclic citrullinated peptide antibodies and immunosuppressive treatment were included as covariates. Pathway analysis was performed using GREAT. Results: Smoking was significantly associated with hypomethylation of a DMR overlapping the promoter region of the RNF5 and the AGPAT1, which are implicated in inflammation and autoimmunity, whereas DMARD treatment induced hypermethylation of the same region. Additionally, the promotor region of both S100A6 and EFCAB4B were hypomethylated and both genes have previously been associated with RA. We replicated several candidate genes identified in a previous EWAS in treatment naive RA singletons. Gene set analysis indicated the involvement of immunologic signatures and cancer-related pathways in RA. Conclusion: We identified several differentially methylated regions associated with RA which may represent environmental effects or consequences of the disease and plausible biological pathways pertinent to the pathogenesis of rheumatoid arthritis

Background: Psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) are chronic inflammatory rheumatic diseases with complex origins. Both are characterized by altered extracellular matrix remodeling in joints and entheses that results in destructive and osteochondral proliferative lesions. There is a need for biomarkers reflecting core disease pathways for diagnosis and disease mapping. Pro-C2 reflects mature cartilage collagen type IIB formation, while C-Col10 represents turnover of type X collagen, which is exclusively expressed by hypertrophic chondrocytes. The objectives of this study were to study cartilage metabolism in axSpA and PsA by assessing Pro-C2 and C-Col10 and to evaluate their diagnostic utility against a healthy reference population.Methods: Patients with PsA (n = 101) or axSpA (n = 110) were recruited consecutively from three rheumatology outpatient clinics. Demographic and clinical disease measures were recorded. Pro-C2 and C-Col10 were quantified in serum by using newly developed and specific competitive enzyme-linked immunosorbent assays based on monoclonal antibodies. One-way analysis of variance and Tukey’s multiple comparison tests were performed on log-transformed data. ROC curve analysis was carried out to evaluate their discriminative power.Results: Pro-C2 levels in serum were significantly increased in both axSpA (median concentration 1.11 ng/ml, 0.67–1.64) and PsA (median concentration 1.03 ng/ml, 0.53–1.47) compared with healthy controls (median concentration 0.30 ng/ml, 0.16–0.41) (p Conclusions: These findings indicate that cartilage collagen metabolism was enhanced in the axSpA and PsA groups compared with the healthy control group. The lower C-Col10 level in patients with axSpA undergoing TNFi treatment may reflect that hypertrophic chondrocytes in axSpA are targeted by TNFi. ROC curve analysis showed a diagnostic potential for Pro-C2 in axSpA and PsA.

BACKGROUND: Rheumatoid arthritis (RA) is often characterized by the presence of rheumatoid factor, anti-citrullinated protein antibodies, and bone erosions. Current therapies can compromise immunity, leading to risk of infection. The interleukin-20 receptor (IL-20R) axis comprising IL-19, IL-20, and IL-24 and their shared receptors activates tissue homeostasis processes but not the immune system. Consequently, modulation of the IL-20R axis may not lead to immunosuppression, making it an interesting drug target. We evaluated the role of the IL-20R axis in RA and associations between plasma cytokine levels and clinical disease.METHODS: Plasma IL-19, IL-20, and IL-24 levels were measured in early RA patients during a treat-to-target strategy by enzyme-linked immunosorbent assays. The IL-20R1 and IL-22R1 levels in paired peripheral blood mononuclear cells and synovial fluid mononuclear cells from a different cohort of RA patients were evaluated by flow cytometry and confocal microscopy. Monocytes/macrophages were stimulated with heat-aggregated human immunoglobulin immune complexes and immune complexes containing citrullinated fibrinogen, and osteoclasts were incubated with IL-19, IL-20, and IL-24.RESULTS: The plasma concentrations of IL-20 and IL-24 (but not IL-19) were increased in early RA patients compared with healthy controls (both P CONCLUSIONS: This study suggests that IL-20 and IL-24 link RA-associated autoantibodies with radiographic progression via the IL-22R1. Modulation of this axis holds promise as feasible anti-erosive treatment modalities in seropositive RA.

To assess the incidence of chronic persistent rheumatoid arthritis (RA) in a population-based cohort of twins and to determine the impact of smoking.In a historical cohort study on twins born in 1920 to 1982, we identified 157 cases of RA among 45,280 responders (response rate 80%). Information on smoking was obtained by questionnaire and interview. A mixed-effects Poisson regression model was used to estimate incidence rate ratios with age, sex, smoking duration, and smoking intensity as covariates. We used the SplitLexis procedure in the Epi R package to study a possible effect of period or cohort in addition to age on the variation of the incidence.The annual incidence of chronic persistent RA was 18.8 per 100,000 person-years, ages 15-73 years (females 25.2, males 12.0), increasing with age to a maximum at age 60 years in females and age 70 years in males. The incidence rate ratio among ever-smoking patients was 1.96 (95% confidence interval [95% CI] 1.43-3.76), 1.93 (95% CI 1.00-3.7) after 30 pack-years, and 1.034 (P 0.001) per year of smoking, implying a doubling of risk after 20 years regardless of sex and smoking intensity. We did not detect significant period or cohort effects.The incidence of chronic persistent RA is lower than the incidence figures reported in inception cohorts. Smoking duration, but not intensity, doubled the risk of RA after 20 years of smoking in both sexes.

INTRODUCTION: In rheumatoid arthritis (RA) immune activation and presence of autoantibodies may precede clinical onset of disease, and joint destruction can progress despite remission. However, the underlying temporal changes of such immune system abnormalities in the inflammatory response during treat-to-target strategies remain poorly understood. We have previously reported low levels of the soluble form of CD18 (sCD18) in plasma from patients with chronic RA and spondyloarthritis. Here, we study the changes of sCD18 before and during treatment of early RA and following arthritis induction in murine models of rheumatoid arthritis.METHODS: The level of sCD18 was analyzed with a time-resolved immunoflourometric assay in 1) plasma from early treatment naïve RA patients during a treat-to-target strategy (the OPERA cohort), 2) plasma from chronic RA patients, 3) serum from SKG and CIA mice following arthritis induction, and 4) supernatants from synovial fluid mononuclear cells (SFMCs) and peripheral blood mononuclear cells (PBMCs) from 6 RA patients cultured with TNFα or adalimumab.RESULTS: Plasma levels of sCD18 were decreased in chronic RA patients compared with early RA patients and in early RA patients compared with healthy controls. After 12 months of treatment the levels in early RA patients were similar to healthy controls. This normalization of plasma sCD18 levels was more pronounced in patients with very early disease who achieved an early ACR response. Plasma sCD18 levels were associated with radiographic progression. Correspondingly, the serum level of sCD18 was decreased in SKG mice 6 weeks after arthritis induction compared with healthy littermates. The sCD18 levels in both SKG and CIA mice exhibited a biphasic course after arthritis induction with an initial increase above baseline followed by a decline. Shedding of CD18 from RA SFMC and RA PBMC cultures was increased by TNFα and decreased by adalimumab.CONCLUSIONS: The plasma sCD18 levels were altered in patients with RA, in mice with autoimmune arthritis and in cell cultures treated with TNFα and adalimumab. Decreased levels of plasma sCD18 could reflect autoimmunity in transition from early to chronic disease and normalization in response to treatment could reflect autoimmunity in remission.

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.

Autoimmune diseases encompass a plethora of conditions in which the immune system attacks its own tissue, identifying them as foreign. Multiple factors are thought to contribute to the development of immune response to self, including differences in genotypes, hormonal milieu, and environmental factors. Viruses including human endogenous retroviruses have long been linked to the occurrence of autoimmunity, but never proven to be causative factors. Endogenous viruses are retroviral sequences embedded in the host germline DNA and transmitted vertically through successive generations in a Mendelian manner. In this study by means of genetic epidemiology, we have searched for the involvement of endogenous retroviruses in three selected autoimmune diseases: multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. We found that at least one human endogenous retroviral locus was associated with each of the three diseases. Although there was a significant overlap, most loci only occurred in one of the studied disease. Remarkably, within each disease, there was a statistical interaction (synergy) between two loci. Additional synergy between retroviral loci and human lymphocyte antigens is reported for multiple sclerosis. We speculate the possibility that recombinants or mixed viral particles are formed and that the resulting viruses stimulate the innate immune system, thereby initiating the autoimmune response. Electronic supplementary material The online version of this article (doi:10.1007/s12026-015-8671-z) contains supplementary material, which is available to authorized users.

A 69-year-old female was admitted due to progressive loss of muscle strength following addition of fluconazole to long-term simvastatin treatment. Rhabdomyolysis was suspected and both drugs were discontinued. Forced diuresis was initiated together with a short course of prednisolone. After 21 weeks the patient had regained normal muscle strength and endurance. The favourable course and the absence of antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase suggest that the condition was due to interaction between the two drugs, which are both metabolized via the CYP3A4 pathway.

ObjectivesTo study clinical and radiographic outcomes after withdrawing 1 year's adalimumab induction therapy for early rheumatoid arthritis (eRA) added to a methotrexate and intra-articular triamcinolone hexacetonide treat-to-target strategy (NCT00660647).MethodsDisease-modifying antirheumatic drug (DMARD)-naive patients with eRA started methotrexate (20 mg/week) and intra-articular triamcinolone (20 mg/ml) for 2 years. In addition, they were randomised to receive placebo adalimumab (DMARD group, n=91) or adalimumab (40 mg/every other week) (DMARD+adalimumab group, n=89) during the first year. Sulfasalazine and hydroxychloroquine were added if disease activity persisted after 3 months. During year 2, synthetic DMARDs continued. Adalimumab was (re)initiated if active disease reoccurred. Clinical response, remission, disability, quality of life and radiographic changes were assessed.ResultsOne year after adalimumab withdrawal, treatment profiles and clinical responses did not differ between groups. In the DMARD/DMARD+adalimumab groups, the median 2-year methotrexate dose was 20/20 mg/week (p=0.45), triple DMARD therapy had been initiated in 33/27 patients (p=0.49), adalimumab was (re)initiated in 12/12 patients and cumulative triamcinolone dose was 160/120 mg (p=0.15). The treatment target (disease activity score, 4 variables, C-reactive protein (DAS28CRP) ≤3.2 or DAS28>3.2 without swollen joints) was achieved at all visits in ≥85% of patients in year 2; remission rates were DAS28CRPConclusionsAn aggressive triamcinolone and synthetic DMARD treat-to-target strategy in eRA provided excellent 2-year clinical and radiographic disease control independent of adalimumab induction therapy. ES progression was slightly less during and following adalimumab induction therapy.Trial registration numberNCT00660647.

This study assessed the grade of bone marrow (BM) fibrosis and its association with a seromarker for collagen-III formation and fibrosis-related cytokines in 25 immune thrombocytopenia (ITP) patients treated with thrombopoietin receptor agonists (Tpo-RA) who had at least one BM biopsy. Assessment of 8 pre- and on-treatment BM biopsies revealed statistically significant increases in reticulin. Reticulin in biopsies performed after a median of 1·4 years of treatment was graded: MF-0 in 3 (12%), MF-1 in 19 (76%), MF-2 in 2 (8%) and MF-3 in 1 (4%). No cytogenetic or flow-cytometric abnormalities were detected. Median pretreatment Procollagen III N-propeptide (PIIINP) (6·6 μg/l) was significantly higher than on-treatment levels (5·6 μg/l); both were higher than controls (3·4 μg/l; P < 0·001). PIIINP was negatively correlated with treatment duration (r = -0·49) suggesting a decelerated reticulin production over time. There was a trend towards an association between grade of reticulin and PIIINP. Transforming growth factor (GF)-beta and basic-Fibroblast GF were not different between patients and controls but Hepatocyte GF (HGF), an anti-fibrotic cytokine, was significantly elevated in patients. In conclusion, low-grade BM reticulin fibrosis is seen in most ITP patients on Tpo-RA. The novel findings of decreasing PIIINP and elevated HGF need further investigation to explore their significance in BM fibrogenesis.

Objective.To investigate by magnetic resonance imaging (MRI) which bones in wrists and metacarpophalangeal (MCP) joints most frequently show bone erosions, and which most frequently demonstrate erosive progression, in early and established rheumatoid arthritis (RA).Methods.MRI datasets from 258 RA patients [126 with early RA (disease duration < 6 months)] were analyzed, of whom 223, including 126 with early RA, had 1-year followup MRI. All patients had MRI of one wrist, whereas 86 patients had additional images of 2nd–5th MCP joints, and 46 patients additional images of the contralateral wrist. MRI were evaluated blinded by one reader, according to the OMERACT RA MRI scoring system (RAMRIS) for erosions, and presence/absence of erosions was noted in each bone, as was presence/absence of erosive progression.Results.The capitate, ulna, lunate, triquetrum, and scaphoid were the 5 bones with both most frequent baseline erosions and most frequently demonstrated erosive progression. No bones were without erosions. Patterns of erosions and progression were similar in early and established RA. No major difference between dominant and nondominant wrists was detected. In the fingers, the 2nd–3rd MCP joint most frequently displayed erosions and erosive progression.Conclusion.The distribution and frequency of bone erosion and erosive progression as detected by MRI in RA wrists and MCP joints were identified. No pattern differences between early versus established disease and dominant versus nondominant sides were detected. No bones showed erosive progression. Thus, no self-evident simplification of the RAMRIS erosion score was identified. Bone involvement patterns may be considered, when joints are selected for MRI protocols for clinical trials and practice.

To study the circadian variability of circulating connective tissue metabolites in patients with very early (VERA) and long-standing rheumatoid arthritis (LRA) and in healthy control individuals.Eleven patients with newly diagnosed, untreated RA, disease duration6 months, and 10 patients with LRA were included, together with 16 healthy control subjects. Seven blood samples were drawn serially from each participant at 3-hourly intervals from 10.00-22.00 h, fasting at 07.00 h the following day and finally at 10.00 h. Cartilage oligomeric matrix protein (COMP) and hyaluronan (HYA) were quantified by enzyme-linked immunosorbent assay (ELISA) and the N-terminal propeptide of collagen type III (PIIINP) was determined by radioimmunoassay (RIA).The two RA subsets did not differ with respect to age, gender distribution, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), immunoglobulin M rheumatoid factor (IgM-RF) status, global health status and pain. Healthy controls were younger than both VERA and LRA patients. At baseline, PIIINP, HYA, and COMP were increased significantly in both RA cohorts compared with controls. No circadian rhythmicity was recorded with respect to HYA and PIIINP. By contrast, COMP was decreased at 07.00 h in all three study groups; this decline was particularly prominent in LRA.Within-day changes of PIIINP, HYA, and COMP are qualitatively similar in RA at different stages and in healthy individuals, indicating that the connective tissue responses to rhythmic physiological signals are not abolished by disease-modifying anti-rheumatic drug (DMARD) therapy. Serum for measurement of HYA and COMP should be collected between 10.00 and 20.00 h.

Aims Transient elastography (TE) is a non-invasive sensitive tool for diagnosing cirrhosis in hospital-based cohorts. This study aimed to evaluate TE as a screening tool for cirrhosis among drug users. Design Cross-sectional study. Setting All treatment centres in the county of Funen, Denmark. Participants Drug users attending treatment centres during the presence of the study team. Measurements Liver stiffness measurements (LSM) by transient elastography using the Fibroscan device; blood tests for viral hepatitis, HIV infection and hyaluronic acid (HA) levels; and routine liver tests. Individuals with LSM ≥ 8 kPa were referred to the hospital for treatment evaluation. Individuals with LSM ≥ 12 kPa were recommended a liver biopsy. Findings Among 175 drug users negative for hepatitis C, 13% had LSM = 8–11.9 kPa and 4% had LSM ≥ 12 kPa; elevated LSM was associated with a body mass index (BMI) > 30. Among 128 drug users with chronic hepatitis C, 19.5% had LSM = 8–11.9 kPa and 21.1% had LSM ≥ 12 kPa (P

Udgivelsesdato: Jun-18 Surfactant protein D (SP-D) is an oligomeric calcium-dependent lectin with important roles in innate host defence against infectious microorganisms. Several studies have shown that patients with inflammatory lung disease have elevated levels of circulating SP-D, and serum SP-D has been suggested to be used as a biomarker for disease e.g. in COPD. We aimed to investigate the variation of circulating SP-D in healthy individuals in and between days for 6 months. In addition, we studied the SP-D response to a standardized physical exercise programme. SP-D was measured in serum using a 5-layered ELISA technique. We found that circulating SP-D remained constant over a 6-month period. However, during the course of one day SP-D varied significantly. Median SP-D peaked at 10 a.m. at 1009ng/ml (95% CI: 803-1497), subsequently decreasing to nadir at 10 p.m. at 867ng/ml (95% CI: 650-1148)(P

In 1995 all systemic lupus erythematosus (SLE) patients in the county of Funen were retrieved from four separate and independent sources as part of an 8-year prospective study to determine the pattern of disease activity and damage accumulation in a community based lupus cohort of predominantly Scandinavian ancestry. Incident cases were subsequently identified by surveillance of these sources. Established and new cases underwent annual, structured interviews, clinical examination and blood sampling. The Systemic Lupus Erythematosus Diseases Activity Index SLEDAI and Systemic Lupus International Collaborating Clinics SLICC scores were calculated. Flares were defined as modified — SLEDAI ≥ 4. The annual flare rate in definite SLE (D-SLE) was 0.21 (95%CI 0.18—0.24) versus 0.03 (95%CI 0.01—0.07) in incomplete SLE (I-SLE). Forty-three per cent of the entire study population had no disease exacerbations. Infections requiring hospital admission and thrombocytopenia were significantly more frequent among patients with relapsing disease (p < 0.04—0.01). Patients with flares had slightly shorter disease duration and were younger at disease onset than patients with a quiescent course. The most recently diagnosed patients had the lowest annual rate of damage accrual. According to flare rate, two major subsets of almost equal size were identified — one having a long quiescent course, the other exhibiting relapses alternating with remissions. An increased risk of flares was associated with short disease duration and younger age at disease onset, infections requiring hospital admission and thrombocytopenia. Temporal damage increment was the lowest in the most recently diagnosed patients. Lupus (2010) 19, 239—246.

Male Sprague-Dawley rats were treated with D-penicillamine (D-pen) 500 mg/kg/day for 10 or 42 days. Pair fed rats served as controls. Changes in aortic morphology were examined by light- and transmission-electron microscopy (TEM). In addition, the endothelial permeability and the penetration through the aortic wall of albumin were studied 10 minutes, 24 and 48 hours after i. v. injection of human serum 131I-albumin (131I-HSA). TEM revealed extensive elastolysis in the arterial wall of D-pen-treated rats, consistent with an inhibitory effect on crosslink formation. In experimental animals excess deposition of collagen and glycoaminoglycans was observed in the subendothelial and medial layer of the aortic wall, together with prominent basal membrane substance around aortic smooth muscle cells. The aorta/serum-ratio and the radioactive build-up 24 and 48 hours after injection of 131I-HSA was reduced in animals treated with D-pen for 42 days, indicating an impeded transmural transport of tracer which may be caused by a steric exclusion effect of abundant hyaluronate. The endothelial ultrastructure was unaffected by D-pen, and no differences in aortic 131I-HSA radioactivity or aorta/serum-ratio were recorded between experimental and control groups 10 minutes after tracer injection, indicating that the permeability of the endothelial barrier to albumin remained unaffected by D-pen treatment. These observations support the hypothesis that treatment with high doses of D-pen may induce a fibroproliferative response in rat aorta, possibly by an inhibitory effect on the cross-linking of collagen and elastin.

A comparison was made between the granulation tissue formation in two different synthetic sponge types. Visella and Ivalon, of different sizes. The granulation tissue formed in the two sponge types did not differ qualitatively, and had the character of wound tissue and inflammatory tissue in man. The rate of tissue formation in the Visella sponges was faster and the tissue was more homogenous than in the Ivalon sponges. Fourteen-day-old Visella implants of either size contained more granulation tissue than Ivalon sponges, probably owing to the smaller pore size of the former material. This may also account for the more frequent occurrence of giant cells in the Visella implants. In contrast to the Visella sponges, the trabeculae of the Ivalon polymer showed calcification and positive staining properties with histological staining procedures, and deformation was frequent among the Ivalon implants. Thin sponges of either type closed in about 21 days, thick ones after about 42 days of implantation. Calculated per 2 cm3 of implant, thin sponges produced more tissue after 14 days of implantation than thick noes. It is concluded that the Visella sponge type is best suitable for this experimental model of inflammation.

D-penicillamine (D-pen) in doses of 20, 100 and 500 mg/kg/day or D-pen 100 mg/kg/day plus methylprednisolone (MP) 2.0 mg/kg/day was administered daily for 42 days to rats implanted with viscose-cellulose sponges. Operated, pairfed rats served as controls. D-pen increased the DNA content of granulation tissue, but had no effect on the amount of tissue produced. In contrast, high dose D-pen reduced the content of DNA and collagen in skin. A dose related inhibition of collagen crosslink formation occurred in all tissues, particularly in skin, as indicated by increased proportions of extractable collagen with increased alpha/beta chain ratio and aldehyde content. Moreover, low doses of D-pen increased the hydroxyproline/proline ratio of acid soluble skin collagen, presumably due to solubilization of type III collagen as demonstrated by SDS-polyacrylamide gel electrophoresis in the presence of 3.6 M urea. These changes were associated with increased skin fragility and edema plus excess elastin deposition in the aorta after high dose D-pen treatment. Low dose D-pen stimulated the 35S-sulphate uptake into the sulphated glycosaminoglycans (GAGs) of granulation tissue without altering their relative amounts, whereas high dose D-pen reduced the concentration of chondroitin-4/6-sulphate in skin. MP antagonized the solubilizing effect of D-pen on collagen, probably by inhibition of the collagen synthesis. In addition, MP inhibited the cell proliferation and GAG metabolism. Food restriction reduced the DNA content of granulation tissue. The inhibitory effect of D-pen on the formation of granuloma collagen crosslinks in the presence of unaltered rate of collagen biosynthesis may diminish the amount of fibrotic tissue due to increased degradability of crosslink deficient collagen. Simultaneous administration of MP may facilitate this effect by inhibiting the biosynthesis of collagen. However, long-term D-pen treatment seems to increase the susceptibility of normal tissues to mechanical injury.

Granulation tissue was produced by subcutaneous implantation of viscose-cellulose sponges on rats. The effect of D-penicillamine 500 mg/kg/day for 10 days on granulation tissue and the connective tissue of skin, bone and aorta was studied ny comparison of treated animals with operated and unoperated controls. In addition, the effect of sponge implantation on intact tissues was studied by comparison between the control groups. The amount of granulation tissue was not affected by D-penicillamine, and the granulomas-DNA content even increased. D-penicillamine increased the amount of salt soluble collagen in all tissues consistent with an inhibition of collagen crosslinking as reflected by increased aldehyde content and alpha/beta chain ratio in soluble skin collagen. Skin appeared to be most sensitive. The content of free hydroxyproline and RNA and the RNA/DNA ratio in skin decreased suggesting a decreased collagen biosynthesis. The hydroxylation of proline and lysine was not affected by the treatment. The water percentage of aorta increased during D-penicillamine treatment, and the 35S-sulphate uptake in the sulphated glycosaminoglycans was stimulated in all tissues, in granulation tissue mainly in the chondroitin-4/6-sulphate fraction. No quantitative glycosaminoglycan changes occurred in granulation tissue. Sponge implantation caused an increase in the amount of salt soluble skin collagen without any change in alpha/beta chain ratio and aldehyde content of purified, soluble collagen. D-penicillamine plus operation reduced the collagen content of aorta. The effects of D-penicillamine on connective tissue compounds may be of importance for its antirheumatic efficacy, but the accompanying effect on normal tissues may imply side effects.

Objective.To study the association between polymorphisms in the mannose-binding lectin gene (MBL2)and disease activity, physical disability, and joint erosions in patients with newly diagnosed rheumatoid arthritis (RA).Methods.Patients with early RA (n = 158) not previously treated with disease modifying antirheumatic drugs, participating in a treatment trial (CIMESTRA study) were examined at inclusion forMBL2pooled structural genotypes (O/O, A/O, A/A), regulatoryMBL2promoter polymorphism in position −221 (XX, XY, YY), anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2), disease activity by Disease Activity Score-28 (DAS28 score), physical disability by Health Assessment Questionnaire (HAQ) score, and erosive changes in hands and feet (Sharp-van der Heijde score).Results.Eight patients were homozygousMBL2defective (O/O), 101 belonged to an intermediate group, and 49 wereMBL2high producers (YA/YA). Anti-CCP was present in 93 patients (59%). High scores of disease activity, C-reactive protein-based DAS28 (p = 0.02), and physical disability by HAQ (p = 0.01) were associated with highMBL2expression genotypes in a gene-dose dependent way, but only in anti-CCP-positive patients. At this early stage of the disease there was no association with erosion score from radiographs.Conclusion.The results point to a synovitis-enhancing effect of MBL in anti-CCP-positive RA, whereas such an effect was not demonstrated for joint erosions.

The development of chronic viral liver disease is associated with increased deposition of connective tissue in the liver. The aminoterminal propeptide of procollagen type III (P-III-NP) is considered to reflect the metabolism of collagen type III, one of the major collagen types in liver fibrosis. The purpose of the present study was to elucidate, whether S-P-III-NP in patients with viral hepatitis was related to injury and repair processes in the liver. S-P-III-NP was determined in a prospective longitudinal study of 63 patients with acute viral hepatitis followed to healing or development of chronic liver disease. Two assays were applied. The P-III-NP Ria-gnost assay, which measures mainly the intact propeptide, and the P-III-NP Fab-assay, in which the antibody exhibits equal affinity to the intact propeptide as well as the degradation product col 1. At the onset of viral hepatitis, S-P-III-NP determined in either assay was equally elevated in the two groups. From the second month of follow-up, significantly higher levels in both assays were observed in patients developing chronic disease. During follow-up, the highest P-III-NP RIA-gnost values were seen in patients with chronic active hepatitis, and active cirrhosis. S-P-III-NP decreased towards normal levels during development of inactive cirrhosis. In the individual patient, S-P-III-NP Ria-gnost was positively related to transaminases. During follow-up of uncomplicated hepatitis a normalization of transaminases occurred before normalization of S-P-III-NP RIA-gnost. Considering, that S-P-III-NP, in contrast to the conventional laboratory variables, reflects the metabolism of type III collagen, it is assumed that determination of S-P-III-NP may provide new information on fibrogenesis in viral liver disease.

To apply and compare different classification criteria on a representative nationwide sample of psoriatic arthritis (PsA) twins and to estimate the prevalence and incidence of PsA.The study comprised three Danish nationwide twin cohorts. In 1994 37 388 Danish twin individuals and in 2002 46 418 twin individuals received a questionnaire, including questions on rheumatic diseases. Twins reporting PsA and their co-twins were classified according to the Moll and Wright and CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria based on interview, clinical examination and scrutiny of medical records.228 twin individuals reported PsA and 164 (72%) participated in clinical validation. By using the Moll and Wright and CASPAR criteria, 54 and 50 cases were diagnosed with PsA respectively. The positive predictive value of self-reported PsA was 31%. According to the Moll and Wright and CASPAR criteria the prevalence was 0.15% (95% CI: 0.13%, 0.22%) and 0.14% (95% CI: 0.11%, 0.19%) respectively. The annual incidence rate based on new self-reported cases in 2002 was 6/100 000 person-years (95% CI: 3/100 000 person-years, 11/100 000 person-years).The positive predictive value of self-reported PsA was 31%. The prevalence and incidence figures of PsA were equivalent to the previously reported occurrence in population- and hospital-based studies.

OBJECTIVE: To estimate the influence of genetic effects in the aetiology and pathogenesis of ankylosing spondylitis (AS). METHODS: The study comprised one Norwegian and two Danish nationwide twin surveys. In 1994 and 2002, respectively, 37,388 and 46,331 Danish twin individuals were asked by questionnaire if they had AS. Similarly, in 1998, 12,718 Norwegian twins were asked if they had AS using a questionnaire phrased according to the Danish survey. Twins reporting AS were categorized according to the modified New York criteria. RESULTS: A total of 113 twin individuals reported AS, of whom 81 (72.3%) participated in validation of the diagnosis. After validation, 39 probands were diagnosed with AS. Subsequent invitation of co-twins resulted in 27 complete pairs. The point prevalence and the annual incidence of AS was 0.1% and 3/100,000 person-years (pyr) among the Danish twins. The positive predictive value of self-reported AS was 49.3%. Probandwise concordance rates on AS were (2/5) 40% in monozygotic (MZ) and (1/23) 4% in dizygotic (DZ) twins [difference 35% (95% CI 2.9-72.8), p = 0.26]. Heredity analysis including previously published and the present HLA-B27-positive twin pairs indicated that additive genetic effects account for 94% (95% CI 0.56-0.99) of the variance in the causation of AS. CONCLUSION: Self-reported AS needs careful validation. The occurrence of AS in a Danish twin population was 0.1% and accords well with previous studies on singletons in hospital settings. The present study adds to previous evidence of a major genetic effect in the pathogenesis of AS.

Innate immune system abnormalities, e.g., mannan-binding lectin (MBL) genotype variants, have been demonstrated to modify the disease course of rheumatoid arthritis (RA). Surfactant protein D (SP-D) shares important structural and functional properties with MBL suggesting that SP-D may be an additional RA disease modifier. The Met11Thr polymorphism in the N-terminal part of SP-D is an important determinant for the SP-D serum level, but this polymorphism is also essential to the function and assembly into oligomers. We aimed to compare the serum levels of SP-D in a cohort of newly diagnosed untreated RA patients with healthy matched controls, and to investigate if there was an association to core measures of disease activity within the first year after disease onset. Secondly, we aimed to investigate whether the Met11Thr polymorphism was associated with RA. Serum SP-D was significantly lower in DMARD naive RA patients compared with healthy controls (P = 0.016). Median SP-D concentration at inclusion was 878 ng/ml (95% CI: 730-1033) and 1164 ng/ml (95% CI: 1093-1366) in RA patients and matched controls, respectively. SP-D increased during Methotrexate treatment (P < 0.0001), and at 1-year follow-up median SP-D was 1032 ng/ml (95% CI: 777-1255). SP-D levels did not correlate with traditional disease activity measures. The Thr11/Thr11 genotype and the Thr11 allele tended to be more frequent in RA patients. In conclusion, the low serum level of SP-D and the lack of correlation with traditional disease activity measures indicate that SP-D reflects a distinctive aspect in the RA pathogenesis.

OBJECTIVE: Co-stimulatory T cell cytokines are important in the progression of RA. This study investigates the interplay between 4-1BB, a disintegrin and metalloprotease-17 (ADAM17) and galectin-9 (Gal-9) in RA.METHODS: Stimulated mononuclear cells from patients with chronic RA (n = 12) were co-incubated with tissue inhibitor of metalloproteinase, 4-1BB ligand and Gal-9. Plasma samples were examined for soluble 4-1BB (s4-1BB) in newly diagnosed, treatment-naïve patients with RA (n = 97). The 28-joint DAS with CRP (28DAS-CRP), total Sharp score, erosion score and joint space narrowing were used to evaluate treatment outcome serially over a 2-year period.RESULTS: RA CD4(+) and CD8(+) synovial T cells express high levels of 4-1BB. The addition of TNF-α to cultured synovial mononuclear cells increased shedding of 4-1BB. 4-1BB ligand only increased TNF-α shedding in combination with Gal-9. RNA interference-mediated knockdown of ADAM17 or the addition of an ADAM17 inhibitor reduced the 4-1BB shedding. Shedding of 4-1BB was not influenced by Gal-9. Plasma levels of s4-1BB were increased in early RA and correlated with the number of swollen joints at baseline. After 3 months of treatment, the plasma levels of s4-1BB were equal to those of the controls. Baseline plasma levels of s4-1BB were inversely correlated with DAS28-CRP after 2 years of treatment, but not with total Sharp score, erosion score or joint space narrowing.CONCLUSION: ADAM17 induces 4-1BB shedding in RA. Gal-9 is pivotal for the function of 4-1BB and induction of TNF-α. Furthermore, high plasma levels of s4-1BB were associated with the number of swollen joints, but also with a low DAS28-CRP after 2 years treatment in early RA.

The aim of the study was to assess the possible association between type II collagen turnover seromarkers and disease profile in patients with axial spondyloarthritis (SpA) and psoriatic arthritis (PsA). Outpatients with axial SpA (n = 110) or PsA (n = 101) underwent clinical examination including disease activity measures and HLA-B27 typing. The procollagen IIA N-terminal peptide (PIIANP) and a matrix metalloproteinase-generated type II collagen fragment (C2M) were quantified in serum by ELISA. C2M was higher in SpA than in controls, 0.41 versus 0.36 ng/ml (p = 0.004), while PIIANP did not differ between patients and healthy subjects, 2252 versus 2142 ng/ml (p = 0.13). However, DMARD-naïve SpA patients had higher PIIANP, 2461 ng/ml (p = 0.01) and C2M, 0.44 ng/ml (p = 0.0007) levels than controls, and PIIANP correlated with CRP (ρ = 0.34). C2M was lower in SpA smokers, 0.36 ng/ml versus non-smokers, 0.43 ng/ml (p = 0.02), while PIIANP was higher in HLA-B27 positive, 2312 ng/ml versus negative patients, 2021 ng/ml (p = 0.03). In PsA, PIIANP and C2M did not differ between patients and controls, but PIIANP was elevated in patients not receiving DMARDs, 2726 ng/ml. In PsA, PIIANP and C2M did not differ according to smoking and HLA-B27. Cartilage degradation assessed by C2M is increased in SpA irrespective of treatment but not in PsA. Cartilage synthesis reflected by PIIANP is increased in untreated SpA and PsA. PIIANP correlates with CRP in SpA while not in PsA. In DMARD-naïve SpA but not in PsA, HLA-B27 positivity and smoking are associated with a chondro-proliferative metabolic pattern.

Galectin-3 has been suggested as a pro-inflammatory mediator in rheumatoid arthritis (RA). Previous studies have reported overexpression of Galectin-3 in RA synovitis and increased levels in synovial fluid and serum in long-standing RA compared with osteoarthritis and healthy controls. Our objectives were to study whether serum Galectin-3 (1) exhibits circadian variation and/or (2) responds to exercise in RA and controls. The study on circadian patterns (1) comprised eleven patients with newly diagnosed RA, disease duration less than 6 months (ERA), 10 patients with long-standing RA [5-15 years (LRA)] and 16 self-reportedly healthy control subjects. During 24 h, 7 blood samples were drawn at 3-h intervals starting at 10 a.m. through 10 p.m. and at 7 and 10 a.m. on the following day. The study on the effect of physical activity (2) included 10 patients with ERA, 10 with LRA and 14 controls. The participants underwent a standardized exercise programme and four blood samples were drawn before, during and after exercise. Serum Galectin-3 was quantified by ELISA (R&D systems). (1) Galectin-3 was increased at baseline in both RA subsets (P = 0.08). There were no diurnal oscillations (P = 0.85). Day-to-day variation amounted to 3%. (2) Baseline Galectin-3 was increased in LRA versus controls and ERA (P < 0.01 and 0.05). Physical exercise induced 10-15% Galectin-3 increments in RA and controls (P < 0.001) peaking after 1-3 h. To conclude, Galectin-3 did not exhibit circadian variation. Day-to-day variation was 3%. Exercise elicited comparable increments in patients with RA of short and long duration and controls, approaching normal after 1-3 h.

OBJECTIVES: To determine to what extent shared epitopes, smoking, and anti-cyclic citrullinated peptide (anti-CCP) antibodies are associated with disease activity and erosive disease in patients with rheumatoid arthritis (RA) at disease onset.METHOD: RA patients not previously treated with disease-modifying anti-rheumatic drugs (DMARDs) and with a disease duration of < 6 months (CIMESTRA study) were examined for shared epitopes, anti-CCP antibodies, immunoglobulin M rheumatoid factor (IgM-RF) and IgA-RF, radiographic erosive changes in hands and feet, and clinical disease activity.RESULTS: The study comprised 153 patients, of whom 104 (68%) were ever-smokers. The prevalence of patients with 0, 1, or 2 shared epitopes was 40 (48%), 71 (49%), and 33 (23%), respectively. Anti-CCP antibodies, IgM-RF, and IgA-RF were present in 89 (58%), 99 (65%), and 82 (54%) patients, respectively. Among smokers, erosive disease was associated with anti-CCP antibodies [odds ratio (OR) 3.9, 95% confidence interval (CI) 1.6-9.3], IgM-RF (OR 4.9, 95% CI 1.9-12), and IgA-RF (OR 2.8, 95% CI 1.2-6.4) but absent with regard to shared epitopes. Among never-smokers, erosive disease was not associated with either shared epitopes or antibodies. All antibody levels measured were associated with smoking and shared epitopes.CONCLUSIONS: Shared epitopes and smoking were associated with the production of anti-CCP antibodies and rheumatoid factors of IgM and IgA isotypes, which again were associated with erosive disease at presentation only in smokers. As shared epitopes and smoking were not directly associated with erosive disease, smoking may enhance the development of erosive disease in RA at different levels or through separate pathways.

OBJECTIVES: To investigate the levels of interleukin (IL)-23 in patients with early rheumatoid arthritis (eRA) and the effect of anti-tumour necrosis factor (anti-TNF)-α treatment on IL-23 levels.METHOD: Treatment-naïve eRA patients from the OPERA cohort were included (n = 151). Patients were randomized to methotrexate (MTX) plus adalimumab (ADA; n = 75) or MTX plus placebo-ADA (PLA; n = 76). Plasma samples were obtained at baseline and at months 3, 6, and 12 together with values for C-reactive protein (CRP), the 28-joint Disease Activity Score based on CRP (DAS28CRP), scores on the Clinical Disease Activity Index (CDAI) and the Simplified Disease Activity Index (SDAI), visual analogue scale (VAS) for pain/fatigue/physician global and total Sharp/van der Heijde score (TSS). IL-23 was measured at each time point.RESULTS: IL-23 levels decreased significantly in the ADA group from 20.6 pg/mL (IQR 13.1-32.7 pg/mL) at baseline to 18 pg/mL (IQR 7.2-25.0 pg/mL) at 12 months (p < 0.01). No significant decrease in IL-23 level was observed in the PLA group. No associations between baseline IL-23 levels and measures of disease activity (DAS28CRP, CRP, CDAI, or SDAI) at 12 or 24 months were present in the treatment groups. Baseline IL-23 correlated inversely with changes in TSS and symptom duration before diagnosis.CONCLUSIONS: Our data show increased baseline levels and a significant decrease in IL-23 levels in eRA patients treated with anti-TNF-α. The inverse correlation with duration of symptoms before diagnosis supports the importance of IL-23 in the preclinical disease development of RA.

Summary objective To establish the optimum GH dose for restoring bone mineral density (BMD) in adult-onset GH deficiency (GHDA). design Two separate randomized, controlled clinical trials. patients Fifty-eight adults aged 45·1 (20–64) years with severe GHDA were followed in two 12-month studies. In the first study, patients were randomized to placebo or GH 1·7 IU/m2/day and in the second study GH 0·5 IU/m2/day or 1·0 IU/m2/day. measurements BMD of the spine, hip, forearm and whole body was measured at 0 and 12 months. Alkaline phosphatase (AP) and collagen markers serum C-terminal propeptide of type I collagen (PICP), type I collagen telopeptide (ICTP) and N-terminal propeptide of type III collagen (PIIINP) were measured at baseline and every 3 months. results Biochemical markers of skeletal and soft tissue collagen increased significantly and remained elevated throughout the study period. BMD changes depended on site, dose and gender. In placebo-treated patients, spinal BMD declined by 2·5%. At the low and medium doses, BMD increased by 2·4 and 3·1%, respectively, while a nonsignificant 0·2% decrease was seen with high dose. Forearm BMD decreased by 4·9% (P

Rheumatoid arthritis (RA) is a chronic autoimmune disease where TNF-α is a central mediator of inflammation, and is cleaved from the cell surface by TACE/ADAM17. This metalloproteinase is also responsible for the release of soluble (s) CD163. Soluble CD163 reflects macrophage activation. In RA, sCD163 has been suggested as a marker of disease activity and progression. Our aim is to investigate sCD163 levels in early RA patients.Soluble CD163 was measured by ELISA from 150 RA plasma samples from the OPERA trial. Averaged disease duration was three months, prior to randomisation with methotrexate (MTX) and adalimumab (DMARD+ADA) or MTX and placebo (DMARD+PLA). Soluble CD163 levels were evaluated in relation to clinical disease parameters.Plasma sCD163 at baseline was 2.39 mg/l (1.74 mg/l-3.18 mg/l), mean (95% CI), vs healthy controls: 1.63 mg/l (1.54 mg/l - 1.73 mg/l), (p0.001). After three months of treatment sCD163 levels decreased significantly (average 23.5%) in both treatment groups. Significant incremental sCD163 levels followed withdrawal of ADA after 12 months of treatment. Baseline sCD163 correlated with CRP and all investigated disease activity markers (ρ=0.16-0.28, p0.05). In the DMARD+PLA group baseline sCD163 also correlated with CRP during the follow-up period.Soluble CD163 correlated with disease activity markers in early RA before treatment. Plasma sCD163 may add to currently available disease measures by specifically reflecting changes in macrophage activity as evidenced by increasing levels following anti-TNF withdrawal, despite maintenance of a stable clinical condition achieved by conventional remedies. It remains to be determined whether sCD163 is an early predictor of disease flare.

At least 30% of patients with rheumatoid arthritis (RA) do not respond to biologic agents, which emphasizes the need of predictive biomarkers. We aimed to identify microRNAs (miRNAs) predictive of response to adalimumab in 180 treatment-naïve RA patients enrolled in the OPtimized treatment algorithm for patients with early RA (OPERA) Study, an investigator-initiated, prospective, double-blind placebo-controlled study. Patients were randomized to adalimumab 40 mg (n=89) or placebo-adalimumab (n=91) subcutaneously in combination with methotrexate. Expressions of 377 miRNAs were determined using TaqMan Human MicroRNA LDA, A Card v2.0 (Applied Biosystems). Associations between miRNAs and treatment response were tested using interaction analyses. MiRNAs with a P-value

BACKGROUND: It has been suggested that polymorphisms in Toll-like Receptors (TLRs) are associated with Rheumatoid Arthritis (RA), but the implicated alleles have differed between studies. The aim of this investigation was to explore whether polymorphisms of TLR genes are associated with RA in a predominantly Caucasian population from Denmark using a case-control approach.FINDINGS: DNA samples (3 university hospital outpatient clinics) were obtained from patients with RA (n = 704) and healthy controls (n = 639) in a Danish population. TLR single nucleotide polymorphisms (SNPs) were selected based on the previously reported associations with chronic autoimmune diseases. Genotyping for the TLR SNPs was performed using Sequenom Multiplex technology.We identified one SNP in TLR3, [(rs3775291, P = 0.02, OR (95% CI) 1.31 (1.1087-1.5493)] significantly associated with the whole RA cohort. Subgroup analysis according to IgM rheumatoid factor (RF) and anti-cyclic citrinullated peptide (CCP) status suggested a significant association of sero-negative RA with the rs3775291 A allele and disease activity in this subset.CONCLUSION: These observations on a RA population of Danish ancestry suggest that variations in the TLR3 locus may be implicated in the pathogenesis of sero-negative RA. Since this TLR3 SNP has previously been associated with systemic lupus erythematous (SLE), the present findings support the notion that TLR3 genetic variants may represent a common risk factor in different chronic inflammatory conditions, including RA and SLE.