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To compare changes in low-density lipoprotein cholesterol and other lipids in patients with rheumatoid arthritis (RA) randomised to a 1-year treat-to-target strategy with either adalimumab plus methotrexate or placebo plus methotrexate. Prespecified secondary analyses from the OPERA trial, where 180 early and treatment-naïve RA patients received methotrexate 20 mg once weekly in combination with either placebo or subcutaneous adalimumab 40 mg every other week. Serum lipid levels were measured at baseline and after 1 year. Changes in lipid levels were analysed using mixed linear models based on the intention-to-treat (ITT) population. Overall, 174 patients were included in the ITT population (adalimumab plus methotrexate n = 86; placebo plus methotrexate n = 88). Differences between changes in lipid levels were low-density lipoprotein cholesterol 0.18 mmol/l [95% CI − 0.05 to 0.42], total cholesterol 0.27 mmol/l [− 0.002 to 0.54], high-density lipoprotein cholesterol 0.05 mmol/l [− 0.06 to 0.15], triglycerides 0.11 mmol/l [− 0.08 to 0.29], very-low-density lipoprotein cholesterol 0.03 mmol/l [− 0.05 to 0.12], and non-high-density lipoprotein cholesterol 0.22 mmol/l [− 0.02 to 0.46]. In early RA patients treated to tight control of inflammation over a period of 1 year with either adalimumab plus methotrexate or placebo plus methotrexate, changes in lipid levels were similar. Trial registration number: NCT00660647.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic autoimmune disease, that involves both pro- and anti-inflammatory mechanisms. The purpose of the present study is to investigate T-cell immunoglobulin and mucin domain 3 (Tim-3) in RA.METHODS: Plasma levels of soluble (s) Tim-3 in early RA (n=98), were followed, to evaluate association with treatment and disease activity, acquired from a prospective collected biobank (clinicaltrials.gov (NCT00660647)). We also investigate the influence of Tim-3 on spontaneous cytokine production in synovial fluid mononuclear cells (SFMC) from RA patients after addition of neutralizing anti-Tim-3's antibodies, either alone or in combination with neutralizing anti-Programmed Cell death protein 1 (PD-1) antibodies.RESULTS: Long-time stimulated CD4 T-cells expressed high levels of Tim-3, but tended to decrease their PD-1 expression. Tim-3 expression was exclusively seen co-expressed with PD-1 by CD3, CD4, CD45RO positive cells in the inflamed RA joint. Addition of neutralizing Tim-3 antibodies increased the secretion of IFNγ and MCP-1, in SFMC cultures from RA. Whereas neutralizing anti-PD-1 antibodies showed a broader impact on cytokine production. Finally, we observed that soluble Tim-3 is increased in plasma and is associated with disease activity in early RA.CONCLUSION: Taken together, our findings indicate disease-suppressive functions of Tim-3 in RA.

Objectives Identification of RA patients at a high risk of joint destruction remains challenging. The C-X-C motif chemokine 13 (CXCL13) has previously been suggested as a marker of disease activity in RA. Here, we investigate the potential of plasma CXCL13 as a marker of long-term radiographic status and progression. Methods CXCL13 was measured in plasma from treatment-naïve RA patients (n = 158) with an 11-year follow-up. At baseline, clinical and biochemical DASs were obtained; among these CRP, ESR, DAS in 28 joints with CRP (DAS28CRP), number of swollen joints (SJC28) and radiographic status, evaluated by total Sharp score (TSS). Age- and gender-matched healthy controls (HCs) were included. Results CXCL13 was significantly increased at baseline and decreased during treatment; however, it was not reduced to the level in HCs. At baseline, CXCL13 was associated with both CRP and ESR, but not with other markers of disease activity. Baseline CXCL13 was correlated with both TSS and radiographic progression (ΔTSS) at 11 years. With an 89% probability, levels of CXCL13 above 85 pg/ml predicted the risk of a TSS of 5 or above, after 11 years of treatment. Compared with CRP, DAS28CRP, SJC28 and ACPA status, CXCL13 was superior in predicting 11-year joint destruction. Conclusion In early RA, one single measurement of plasma CXCL13 at baseline is superior to currently used clinical and serological disease markers in the prediction of long-term radiographic status and progression.

Microfibrillar associated protein 4 (MFAP4) is a non-structural matrix protein with cell regulatory activities and a potential as seromarker for fibrosis. We aimed to study the occurrence of MFAP4 in the synovial membrane from patients with rheumatoid arthritis (RA) versus osteoarthritis (OA). Formaldehyde-fixed synovial tissue sections, from patients with RA (N=6) and OA (N=6) undergoing total hip arthroplasty, were deparaffinized and immunostained with monoclonal antibodies against MFAP4. Elastin was detected using ElastiKit. MFAP4 in serum (sMFAP4) and synovial fluid was measured by an immunoassay. MFAP4 was present in synovial biopsies from both RA and OA patients, particularly prominent in deep arterioles where it colocalized with elastin. Notably however, MFAP4 was absent from the internal elastic lamina in RA arterioles irrespective of disease duration and synovitis activity, while present although with irregular staining patterns in OA specimens. sMFAP4 was increased in RA and OA serum versus healthy controls: median (interquartile range) 29.8 (25.3-39.1) and 25.5 U/l (18.1-43.3) versus 17.7 U/l (13.7-21.2), p=0.006 and p=0.02, respectively The concentration of synovial fluid was lower than in serum in both RA and OA. These findings may suggest that MFAP4 is involved in adaptive vessel wall remodeling associated with chronic joint disease. This article is protected by copyright. All rights reserved.

Objectives: IgG4-related disease (IgG4-RD) may present as ‘idiopathic’ retroperitoneal fibrosis (IRPF). We aimed to determine the occurrence of IgG4-retroperitoneal fibrosis (IgG4-RPF) in a nationwide study on patients with newly diagnosed IRPF, and to compare histopathological, imaging, and clinical features in the IgG4-RPF and non-IgG4-RPF subsets. Method: The National Danish Pathology Register was searched for biopsy codes relating to retroperitoneal tissue from 1 January 2004 to 31 December 2013. Secondary causes of RPF were excluded. Among 724 candidate cases, 68 were identified with IRPF. Clinical, laboratory, and imaging recordings were reviewed, and tissue blocks were scrutinized for IgG4-RPF features according to international consensus. Results: Forty-two patients (28 males), median age 56 (25–74) years were included. Nineteen (45%) met the criteria for IgG4-RPF, seven with definite and 12 with possible IgG4-RPF, while 23 had non-IgG4-RPF. Local manifestations and laboratory measures did not differ between RPF subsets. Arterial hypertension (p = 0.037) and periaortic fibrosis (p = 0.024) were more common in IgG4-RPF vs non-IgG4-RPF. Plasma cell IgG4/total IgG ratios ≥ 40% were associated more with core histopathological features of IgG4-RD compared to ratios

Objective.The RAMRIS [Outcome Measures in Rheumatology rheumatoid arthritis (RA) magnetic resonance imaging (MRI) Scoring system] is used in clinical RA trials. We have investigated methods to combine the RAMRIS features into valid and responsive scores for inflammation and joint damage.Methods.We used data from 3 large randomized early RA trials to assess 5 methods to develop a combined score for inflammation based on RAMRIS bone marrow edema, synovitis, and tenosynovitis scores, and a combined joint damage score based on erosions and joint space narrowing. Methods included unweighted summation, normalized summation, and 3 different variants of weighted summation of the RAMRIS features. We used a derivation cohort to calculate summation weights to maximize the responsiveness of the combined score. Construct validity of the combined scores was examined by assessing correlations to imaging, clinical, and biochemical measures. Responsiveness was tested by calculating the standardized response mean (SRM) and the relative efficiency of each score in a validation cohort.Results.Patient characteristics, as well as baseline and followup RAMRIS scores, were comparable between cohorts. All combined scores were significantly correlated to other imaging, clinical, and biochemical measures. Inflammation scores combined by normalized and weighted summation had significantly higher responsiveness in comparison to unweighted summation, with SRM (95% CI) for unweighted summation 0.62 (0.51–0.73), normalized summation 0.73 (0.63–0.83), and weighted summation 0.74 (0.64–0.84). For the damage score, there was a trend toward higher responsiveness for weighted summation.Conclusion.Combined MRI scores calculated by normalized or weighted summation of individual MRI pathologies were valid and responsive.

Serum microfibrillar-associated protein 4 (sMFAP4) has been investigated as a biomarker for various diseases and is demonstrated to show significant gradual increase with severity of liver fibrosis. Ideal biomarkers used for disease diagnosis or prognosis should display deviating levels in affected individuals only and be robust to factors unrelated to the disease. Here we show the impact of normal physiological variation of sMFAP4 by characterizing the circadian variation, week-to-week variation, and physical exercise-induced levels. Serum samples from 3 groups of healthy volunteers were drawn: 7 times during a 24-hour period, 5 times during a 3-week period, and before and after a standardized physical exercise challenge. sMFAP4 was determined by AlphaLISA. Statistical analysis was performed using mixed effects modeling of repeated measurements. Circadian variation of sMFAP4 was demonstrated, with time of peak and nadir values depending on age and gender. For males, the peak values were observed during nighttime whereas for females, peak values were observed in the morning. Individual sMFAP4 levels remained stable over a period of 3 weeks and physical exercise inferred a mild negative influence. In conclusion, the circadian sMFAP4 variation was significant, and the levels could be influenced by physical activity. However, these variations were of limited magnitude relative to previously observed disease-induced levels in support of the biomarker potential of sMFAP4.K Serum microfibrillar-associated protein 4 (sMFAP4) has been investigated as a biomarker for various diseases and is demonstrated to show significant gradual increase with severity of liver fibrosis. Ideal biomarkers used for disease diagnosis or prognosis should display deviating levels in affected individuals only and be robust to factors unrelated to the disease. Here we show the impact of normal physiological variation of sMFAP4 by characterizing the circadian variation, week-to-week variation, and physical exercise-induced levels. Serum samples from 3 groups of healthy volunteers were drawn: 7 times during a 24-hour period, 5 times during a 3-week period, and before and after a standardized physical exercise challenge. sMFAP4 was determined by AlphaLISA. Statistical analysis was performed using mixed effects modeling of repeated measurements. Circadian variation of sMFAP4 was demonstrated, with time of peak and nadir values depending on age and gender. For males, the peak values were observed during nighttime whereas for females, peak values were observed in the morning. Individual sMFAP4 levels remained stable over a period of 3 weeks and physical exercise inferred a mild negative influence. In conclusion, the circadian sMFAP4 variation was significant, and the levels could be influenced by physical activity. However, these variations were of limited magnitude relative to previously observed disease-induced levels in support of the biomarker potential of sMFAP4.

The study evaluates associations between serum vitamin D metabolites at diagnosis and one-year remission, in early diagnosed rheumatoid arthritis(RA). The CIMESTRA-cohort comprised 160 newly diagnosed RA patients, treated aiming at remission. Vitamin D supplementation was recommended according to national guidelines. Dtotal(25OHD2 + 25OHD3) was dichotomized at 50 nmol/L, 1,25(OH)2D was categorized in tertiles. Primary outcome was remission(DAS28-CRP ≤ 2.6) after one year. Associations were evaluated using logistic regression, further adjusted for pre-specified potential confounders: Age, sex, symptom-duration before diagnosis, DAS28-CRP and season of diagnosis. Results are presented as Odds Ratios(OR) with 95% Confidence Intervals(95%CIs). In univariate analyses, neither Dtotal nor 1,25(OH)2D were associated with remission. In adjusted analyses, low Dtotal was associated with higher odds for remission; OR 2.6, 95%CI (1.1; 5.9) p = 0.03, with season impacting results the most. One-year remission was lower in patients with diagnosis established at winter. In conclusion, low Dtotal at diagnosis was associated with increased probability of achieving one-year remission in early RA when adjusting for covariates. Diagnosis in winter was associated with lower odds for one-year remission. Results suggest that season act as a contextual factor potentially confounding associations between vitamin D and RA disease-course. The finding of low Dtotal being associated with higher one-year remission remains speculative.

To compare changes in low-density lipoprotein cholesterol and other lipids in patients with rheumatoid arthritis (RA) randomised to a 1-year treat-to-target strategy with either adalimumab plus methotrexate or placebo plus methotrexate. Prespecified secondary analyses from the OPERA trial, where 180 early and treatment-naïve RA patients received methotrexate 20 mg once weekly in combination with either placebo or subcutaneous adalimumab 40 mg every other week. Serum lipid levels were measured at baseline and after 1 year. Changes in lipid levels were analysed using mixed linear models based on the intention-to-treat (ITT) population. Overall, 174 patients were included in the ITT population (adalimumab plus methotrexate n = 86; placebo plus methotrexate n = 88). Differences between changes in lipid levels were low-density lipoprotein cholesterol 0.18 mmol/l [95% CI - 0.05 to 0.42], total cholesterol 0.27 mmol/l [- 0.002 to 0.54], high-density lipoprotein cholesterol 0.05 mmol/l [- 0.06 to 0.15], triglycerides 0.11 mmol/l [- 0.08 to 0.29], very-low-density lipoprotein cholesterol 0.03 mmol/l [- 0.05 to 0.12], and non-high-density lipoprotein cholesterol 0.22 mmol/l [- 0.02 to 0.46]. In early RA patients treated to tight control of inflammation over a period of 1 year with either adalimumab plus methotrexate or placebo plus methotrexate, changes in lipid levels were similar. Trial registration number: NCT00660647.

Rheumatoid arthritis (RA) is an autoimmune disease which may lead to severe disabilities due to structural joint damage and extraarticular manifestations The dendritic cell marker CD83 belongs to the immunoglobulin superfamily and has previously been associated with autoimmune diseases. In RA the levels of soluble CD83 (sCD83) are elevated in synovial fluid, however little is known about CD83 expression and regulation in RA. Therefore, we studied how CD83 is expressed in RA and further evaluated the effect of anti-TNF-alpha therapy hereon. Early RA patients were randomized to conventional disease modifying anti-rheumatic drugs with or without additional anti-TNF-alpha, therapy. Rheumatoid arthritis patients had increased levels of sCD83 in plasma compared with healthy volunteers. The increase in sCD83 plasma levels were unaffected by anti-TNF-alpha therapy. In chronic RA patients the levels of sCD83 were higher in synovial fluid than in plasma, and only a limited amount of membrane bound CD83 expression was detected on the surface of cells from peripheral blood and synovial fluid. Finally, confocal microscopy of RA synovial membranes revealed that CD83 was mainly localized intracellularly in a group of cells with diverse morphology including both antigen-presenting cells and non-antigen-presenting cells. Our findings demonstrate that early-stage RA patients have elevated levels of sCD83 in plasma and that anti-TNF-alpha treatment has no effect on the sCD83 plasma level. This suggest that in RA patients sCD83 regulation is beyond control of TNF-alpha. (C) 2017 Elsevier Ltd. All rights reserved.

OBJECTIVES: To examine whether MRI assessed inflammation and damage in the wrist of patients with early rheumatoid arthritis (RA) are associated with patient-reported outcomes (PROs).METHODS: Wrist and hand MRIs of 210 patients with early RA from two investigator-initiated, randomised controlled studies (CIMESTRA/OPERA) were assessed according to the Outcome Measures in Rheumatology RA MRI score (RAMRIS) for synovitis, tenosynovitis, osteitis, bone erosions and joint space narrowing (JSN) at baseline, 1 and 5 years follow-up. These features, and changes therein, were assessed for associations with health assessment questionnaires (HAQ), patient global visual analogue scales (VAS-PtGlobal) and VAS-pain using Spearman's correlations, generalised estimating equations and univariate/multivariable linear regression analyses. MRI features were further tested for trends against specific hand-related HAQ items using Jonckheere trend tests.RESULTS: MRI inflammation, but not damage, showed statistically significant associations with HAQ, VAS-PtGlobal and VAS-pain for status and change scores, independently of C reactive protein and swollen joint count. MRI-assessed synovitis was most consistently associated with PROs, particularly VAS-PtGlobal and VAS-pain. MRI-assessed synovitis and tenosynovitis mean scores were positively associated with patient-reported difficulty to cut meat and open a milk carton (pCONCLUSIONS: MRI-assessed inflammation, but not damage, in early RA wrists is associated with patient-reported physical impairment, global assessment of disease activity and pain and influences the physical function in the hand.TRIAL REGISTRATION NUMBER: NCT00660647.

Objective: A reduction in haemoglobin level is a frequent complication among rheumatoid arthritis (RA) patients. Hepcidin has been linked to disturbed erythropoiesis. The objective of this study was to investigate the longitudinal changes in hepcidin in patients with early RA. Method: Hepcidin plasma concentrations were measured by enzyme-linked immunosorbent assay in patients with early RA (n = 80) and healthy volunteers (HV, n = 40). Haemoglobin and other iron-related proteins were also measured. At baseline, all patients had active disease and were treatment naïve. Patients were treated with disease-modifying anti-rheumatic drugs (DMARDs) and with additional adalimumab (ADA, n = 42) or placebo (PLA, n = 38) during 52 weeks, using a treat-to-target strategy, aiming for a 28-joint Disease Activity Score (DAS28)

Objective: To assess the incidence of chronic persistent rheumatoid arthritis (RA) in a population based cohort of twins and to determine the impact of smoking. Methods: In a historical cohort study on twins born 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 effect 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. Results: The annual incidence of chronic persistent RA was 18.8 per 100,000 person years aged 15-73 years (females 25.2, males 12.0), increasing with age to a maximum at sixty years in females and seventy years in males. The incidence rate ratio among ever smoking patients was 1.96 (95% CI: 1.43 – 3.76), 1.93 (95% CI: 1.00 – 3.7) after 30 pack-years, and 1.034 (p

Background Vitamin D is often low in Rheumatoid Arthritis(RA), and immunomodulatory properties of vitamin D might be associated with disease-course in RA.(1) Objectives To evaluate association between baseline vitamin D metabolites and one-year remission, in newly diagnosed, treatment-naive RA patients, aggressively treated during follow-up. Methods The CIMESTRA-cohort comprises 160 newly diagnosed RA patients, treated aiming at remission with methotrexate and intraarticular steroid, further randomized 1:1 to ciclosporine or placebo-ciclosporine.(2) A total of 158 patients had vitamin D metabolites measured at time of diagnosis. Dietary vitamin D supplementation was recommended in accordance with the national guidelines. Serum vitamin Dtotal (sum of 25OHD2 and 25OHD3) and 1,25(OH)2D at time of diagnoses were measured by LC-MS/MS or RIA. Dtotal were dichotomized at 50 nmol/l, and 1,25(OH)2D categorized in tertiles. Primary outcome was remission (DAS28-CRP ≤ 2.6) after one year. Associations were calculated using logistic regression, presented as Odds Ratios with 95% Confidence Intervals (95%CIs). Adjustment of analyses included sex, age, symptom duration prior to diagnosis, DAS28-CRP and season of diagnosis. Results In univariate analyses, neither Dtotal nor 1,25(OH)2D at time of diagnosis predicted remission at year one. In adjusted analysis, Dtotal Conclusion Low Dtotal at time of diagnosis is associated to increased odds for achieving remission at year one in early, treatment naive RA patients, treated aggressively during follow-up. References [1] Jeffery LE, et al. Vitamin D in rheumatoid arthritis-towards clinical application. NatRevRheumatol. 2015. [2] Hetland ML, et al. Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Arthritis Rheum. 2006;54:1401-9. Acknowledgement Soren Moller, biostatistician at OPEN, Odense, for statistical support Disclosure of Interests Mette Herly Grant/research support from: Pfizer Denmark, unrestricted grant, used for salary. The Danish Rheumatism Association, patient association, 6 months salary as part of PHD study, Speakers bureau: The Danish Rheumatism Association, patient association, speakers Fee 500 Euro, Kristian Stengaard-Pedersen: None declared, Peter Vestergaard Speakers bureau: Amgen, Eli Lilly, Novartis, MSD, Servier, Robin Christensen Grant/research support from: AbbVie Inc, and the Oak Foundation, Speakers bureau: Roche, Mikkel Ostergaard Grant/research support from: Abbvie, Celgene, Centocor, Merck, Novartis, Consultant for: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, and UCB, Speakers bureau: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, and UCB, Peter Junker: None declared, Merete L. Hetland Grant/research support from: BMS, MSD, AbbVie, Roche, Novartis, Biogen, Pfizer, Consultant for: Eli Lilly, Speakers bureau: Orion Pharma, Biogen, Pfizer, CellTrion, Merck, Samsung Bioepis, Kim Horslev-Petersen Grant/research support from: AbbVie during the conduct of the study, Torkell Ellingsen: None declared

Background: Co-inhibitory receptors are important for the regulation of inflammation in autoimmune diseases. Among these, T-cell Immunoglobulin and mucin domain-3 (Tim-3) has recently gained attention, as it is expressed on exhausted T cells co-expressing PD-1 (1). Objectives: To investigate Tim-3’s role in rheumatoid arthritis (RA). Methods: Early RA (eRA) patients were randomized to conventional methotrexate (MTX) treatment + placebo or MTX + adalimumab (ADA) (2). Plasma were analysed by ELISA at baseline (n=98) and after 3 and 12 months of treatment. Clinical follow up including 28-joint Disease Activity Score with CRP (DAS28CRP) and Total Sharp Score (TSS) were available. Intrasubject differences in sTim-3 between baseline and 3 months were assessed by parametric paired t tests and compared with plasma from HV (n=44) by parametric unpaired t tests. Spearman correlation and Mann-Whitney test were used to investigate relations between sTim-3 and clinical follow up. From chronic RA (cRA) patients (n=17) plasma and synovial fluid were analysed by ELISA and peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) (n=8) were analysed by flow cytometry. Intrasubject differences were assessed by paired parametric t tests, and comparison with PBMC from HV (n=6) by unpaired parametric t test. Parametric data are reported as mean differences (MD) [95%CI]. P values Results: Among memory prone T cells (CD3+CD4+CD45RO+) in SFMC, the percentage of Tim-3+ cells were increased compared with similar gated PBMC from patients (MD 17.4%, [10.7;24.1], p Conclusion: Tim-3 expression is upregulated in memory prone T cells in RA joints and the majority co-express PD-1. Levels of sTim-3 are increased in SF. In eRA, baseline sTim-3 plasma levels are elevated and correlate with DAS28CRP. Decrease of sTim-3 during treatment associates with future radiographic progression. We suggest, that Tim-3 expression and sTim-3 plasma and SF levels reflect ongoing immune response, thus immune regulation in RA. These data indicate that maintenance of sTim-3 plasma levels during treatment is favourable, consistent with Tim-3 being a co-inhibitory receptor. Reference [1] Ana C. et al. Immunity 2016;44:989-1004, 2 Horslev-Petersen K, et al. Ann Rheum Dis 2014;73:654-661. Disclosure of Interests: Caecilie Skejo: None declared, Morten Aagaard Nielsen: None declared, Malene Hvid: None declared, Aida Solhoj Hansen: None declared, Kristian Stengaard-Pedersen: None declared, Merete L. Hetland Grant/research support from: BMS, MSD, AbbVie, Roche, Novartis, Biogen, Pfizer, Consultant for: Eli Lilly, Speakers bureau: Orion Pharma, Biogen, Pfizer, CellTrion, Merck, Samsung Bioepis, Kim Horslev-Petersen: None declared, Peter Junker: None declared, Mikkel Ǿstergaard Grant/research support from: Abbvie, Celgene, Centocor, Merck, Novartis, Consultant for: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, and UCB, Speakers bureau: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, and UCB, Stinne Ravn Greisen: None declared, Mette Deleuran: None declared, Bent Deleuran: None declared

Objective Cardiac events are a major cause of death in patients with idiopathic inflammatory myopathies. The study objective was in a controlled setting to describe cardiac abnormalities by noninvasive methods in a cohort of patients with polymyositis (PM) or dermatomyositis (DM) and to identify predictors for cardiac dysfunction. Methods In a cross-sectional study, 76 patients with PM/DM and 48 matched healthy controls (HCs) were assessed by serum levels of cardiac troponin I, electrocardiography, Holter monitoring, echocardiography with tissue Doppler imaging, and quantitative cardiac 99mTc-pyrophosphate (99mTc-PYP) scintigraphy. Results Compared to HCs, patients with PM/DM more frequently had left ventricular diastolic dysfunction (LVDD) (12% versus 0%; P = 0.02) and longer QRS and QT intervals (P = 0.007 and P < 0.0001, respectively). In multivariate analysis, factors associated with LVDD were age (P = 0.001), disease duration (P = 0.004), presence of myositis-specific or -associated autoantibodies (P = 0.05), and high cardiac 99mTc-PYP uptake (P = 0.006). In multivariate analysis of the pooled data for patients and HCs, a diagnosis of PM/DM (P < 0.0001) was associated with LVDD. Conclusion Patients with PM or DM had an increased prevalence of cardiac abnormalities compared to HCs. LVDD was a common occurrence in PM/DM patients and correlated to disease duration. In addition, the association of LVDD with myositis-specific or -associated autoantibodies and high cardiac 99mTc-PYP uptake supports the notion of underlying autoimmunity and myocardial inflammation in patients with PM/DM.

Background:Systemic inflammation in rheumatoid arthritis (RA) is associated with reduced serum lipid levels (LL) and treatment with disease modifying antirheumatic drugs has been associated with increased serum LL [1]. It is unclear whether the changes in serum LL reported in association with adalimumab (ADA) treatment are due to suppressed inflammation or the ADA treatmentper se.Objectives:The primary objective was to compare the effect of ADA + methotrexate (MTX) to placebo (PBO) + MTX on changes in low density lipoprotein cholesterol (LDL-C) from baseline to month 12 in patients with early- and treatment naïve RA. Secondary objectives were to compare the treatment groups on changes in total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglycerides, very low density lipoprotein cholesterol (VLDL-C) and non-HDL-C (=TC – HDL-C).Methods:We present secondary analyses from the OPERA trial, which was an investigator-initiated, multicenter double-blind, placebo-controlled, treat-to-target trial of 180 early and treatment naïve RA patients, who were randomized (1:1) to oral MTX 20 mg once a week in combination with either PBO or ADA 40 mg SC EOW [2]. Any swollen joint was injected with triamcinolone hexacetonide. Lipid profiles of each patient were assessed at baseline and 12 months. All randomized patients with available LDL-C at baseline were included in Intention To Treat (ITT) analysis. Sensitivity analyses were performed on the Per Protocol (PP) and the ITT population with baseline observations carried forward (BOCF). All analyses were based on repeated measurements using mixed linear models.Results:In total, 174 patients (97% of the original OPERA trial population) were included in ITT analysis (ADA n=86; PBO n=88) and 156 patients (ADA n=78; PBO n=78) completed the study with LDL-C measurements at both baseline and 12 months (PP). At baseline mean LDL-C was 2.9 mmol/L (SD 0.9) with 63 (36.2%) patients having an LDL-C above 3.0 mmol/L. There was no significant difference in LDL-C change between ADA+MTX and PBO+MTX groups after 12 months. A nearly statistically significant between-group difference in TC change was found. Other changes in LL were comparable across the two groups. Results in ITT, PP and ITT with BOCF populations were similar.Conclusion:In early RA patients treated to target with methotrexate and intra-articular triamcinolone, 12 months with the addition of adalimumab did not affect lipid levels.References:[1]England BRet al., Bmj2018;361:k1036[2]Hørslev-Petersen Ket al.,Ann Rheum Dis2014;73:654–61Disclosure of Interests:Dzenan Masic: None declared, Kristian Stengaard-Pedersen: None declared, Brian Bridal Løgstrup: None declared, Kim Hørslev-Petersen Grant/research support from: Pfizer (Travel expences), Merete L. Hetland Grant/research support from: BMS, MSD, AbbVie, Roche, Novartis, Biogen and Pfizer, Consultant of: Eli Lilly, Speakers bureau: Orion Pharma, Biogen, Pfizer, CellTrion, Merck and Samsung Bioepis, Peter Junker: None declared, Mikkel Ǿstergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Merck, and Novartis, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Christian Ammitzbøl: None declared, Sören Möller: None declared, Robin Christensen: None declared, Torkell Ellingsen: None declaredTable .Change in primary and secondary outcomes in the ITT analysis

Background:Collagen type IV and laminin are the main constituents of basement membranes (BMs). Epitopes on these molecules are targeted in various autoimmune diseases, systemic lupus erythematosus (SLE) in particular. Accelerated large vessel disease is a well-recognized cause of premature cardiovascular morbidity and mortality in SLE. Novel tools for quantification of soluble MMP-derived fragments of collagen type IV (C4M) and laminin (LG1M) have emerged as promising biomarkers for BM remodeling in atherosclerosis.Objectives:To study serum levels of collagen type IV and laminin metabolites in patients with SLE and in healthy controls. And to search for associations with disease activity, organ damage and cardiovascular comorbidity.Methods:One hundred and six SLE patients without and 20 with previous CVD events were included (1). One hundred and twenty male and female blood donors aged 20-65 years served as healthy reference. Disease activity (SLEDAI) and damage (SLICC) scores were calculated. Coronary artery calcification (CAC) was studied by CT scan and expressed as Agatston score. Carotid intima-media thickness (IMT) was measured by ultrasound (LOGIQ E9, GE Healthcare). In either subgroup atherosclerosis was defined as Agatston > 99 U and/or IMT>1 mm and/or presence of plaque. C4M and LG1M were measured by competitive ELISAs (2).Results:Patient characteristics are presented in Table 1. Overall, C4M and LG1M were significantly increased in the entire SLE cohort vs. healthy controls (35.7 ± 17.5 vs. 22.3 ± 9.4 ng/mL, pTable 1Characteristics for SLE patients with and without CVDPatients characteristicsAll (126)SLE + CVD (20)SLE without CVD (106)pFemales, no. (%)113 (89)18 (90)95 (89)0.95Age, yrs., mean ± SD50.6± 14.454.8 ± 15.346.8± 14.10.15Disease duration, yrs., mean ± SD13.9 ± 9.319.0± 11.313.0± 11.30.007SLEDAI, median, range4 (0-14)4 (0-10)4 (0-14)0.717SLICC, median, range1 (0-11)3 (1-11)1 (0-10)0.0001Atherosclerosis, no. (%)53 (42)14 (70)39 (37)0.0006LG1M (ng/ml), mean ± SD20.9± 21.234.5± 41.218.3 ± 13.60.0015C4M (ng/ml), mean ± SD35.7 ± 17.538.1± 20.635.3± 16.90.518Conclusion:Serological levels of collagen type IV and laminin biomarkers were elevated and interrelated in an unstratified SLE population. Moreover, LG1M but not C4M was significantly elevated in SLE patients with previous CVD events and in those with atherosclerosis by imaging. These findings indicate that LG1M may serve as a serological marker for SLE-related large vessel disease. However, additional extravascular sites of increased basement membrane remodeling may contribute to the abnormal biomarker pattern.References:[1]Kay SD, Poulsen MK, Diederichsen AC, Voss A. J Rheumatol 2016;43:315–22[2]Sand JM, Larsen L, Hogaboam C et al. PLoS One 2013;8:e84934Kay SD and Genovese F contributed equally to this work.Figure 1.Levels of C4M and LG1M in serum of patients with SLE and healthy controls; graphs are presented as box and whiskers plot (in the style of Tukey). Statistical significance: ****pFigure 2.Correlation plots (Spearman r) of C4M and LG1M in SLE patients and healthy controls.Disclosure of Interests:Susan Due Kay: None declared, Federica Genovese Shareholder of: Own Nordic Bioscience stocks, Employee of: Nordic Bioscience, Anne Sofie Siebuhr Employee of: Nordic Bioscience, Morten Karsdal Shareholder of: Nordic Bioscience A/S., Employee of: Full time employee at Nordic Bioscience A/S., Anne Voss: None declared, Peter Junker: None declared

Background:Low vitamin D levels are common in Rheumatoid Arthritis (RA)1, and possibly associated with disease course,2but data on vitamin D levels during long-term disease course has not been reported previously.Objectives:To describe vitamin D trajectories from time of diagnosis through 10 years follow-up in early diagnosed RA patients.Methods:The CIMESTRA trial included 160 newly diagnosed RA-patients, treated aiming at remission with methotrexate and intraarticular steroid, further randomized to ciclosporine or placebo. Vitamin D supplementation was recommended according to national guidelines. Vitamin Dtotalwas measured at diagnosis, and year 1, 5 and 10 using LC-MS/MS. 1,25(OH)2D was measured at diagnosis and year 1 using RIA. Linear mixed effects models were used to study vitamin D levels serially. We had fixed effects for time, and patients modelled as a random effect. We tested the hypothesis that percentage of patients achieving Dtotal≥ 50 nmol/l during follow-up was 90%. Analyses of associations between Dtotaland DAS28-CRP during the disease-course were adjusted for age, sex, symptom-duration prior to diagnosis and season of diagnosis.Results:Median Dtotalat baseline was 53 nmol/l (IQR 36-567.8). Dtotalincreased significantly during follow-up, independently of level at diagnosis (ptotal≥50nmol/l during follow-up was 80-87%, but not as high as 90% at year 1 and 5, ptotaltrajectories only in crude (β-coefficient (β) -0.0034, 95%CI (-0.007; -0.0002) p=0.039) and partially adjusted analyses (β -0.003, 95%CI (-0.007; -0.002) p=0.04). Estimate was left insignificant in fully adjusted analyses (β -0.003, 95%CI (-0.0006; 0.0001) p=0.06). 1,25(OH)2D levels did not change significantly during follow-up (p=1.00).Conclusion:Dtotalincreased significantly during follow-up, but fewer than 90% achieved the recommended 50 nmol/l at year 1 and 5. Disease activity during follow-up was associated with Dtotaltrajectories only in partially adjusted analyses, while adjustment for possible confounders left estimates insignificant. Results suggest vitamin D supplementation to be recommended in all RA patients.References:Reference List[1]Herly M, Stengaard-Pedersen K, Vestergaard P, et al. The D-vitamin metabolite 1,25(OH)2 D in serum is associated with disease activity and Anti-Citrullinated Protein Antibodies in active and treatment naive, early Rheumatoid Arthritis Patients.Scand J Immunol2018;88(3):e12704. doi: 10.1111/sji.12704[2]Mouterde G, Gamon E, Rincheval N, et al. Association between Vitamin D deficiency and disease activity, disability and radiographic progression in early rheumatoid arthritis. The ESPOIR cohort.J Rheumatol2019 doi: 10.3899/jrheum.190795Disclosure of Interests:Mette Herly Grant/research support from: Pfizer Denmark - “Unrestricted Grant” for PhD projectDanish Rheumatism Association, Research Grant, Speakers bureau: Speaker for Danish Rheumatism Association, Kristian Stengaard-Pedersen: None declared, Peter Vestergaard: None declared, Robin Christensen: None declared, Sören Möller: None declared, Mikkel Ǿstergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Merck, and Novartis, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Peter Junker: None declared, Merete L. Hetland Grant/research support from: BMS, MSD, AbbVie, Roche, Novartis, Biogen and Pfizer, Consultant of: Eli Lilly, Speakers bureau: Orion Pharma, Biogen, Pfizer, CellTrion, Merck and Samsung Bioepis, Kim Hørslev-Petersen Grant/research support from: Pfizer (Travel expences), Torkell Ellingsen: None declared

Objective Active rheumatoid arthritis (RA) is accompanied by increased appendicular and axial bone loss, closely associated to the degree of inflammation. The programmed death-1 (PD-1) pathway is important for maintaining peripheral tolerance, and its ligand PD-L2 has recently been associated with bone morphogenetic protein activity. Here, we report that PD-L2 plays a central role in RA osteoimmunology. Methods Femoral bone mineral density (BMD) and trabecular bone microstructure were evaluated by micro-CT in wild type (WT) and PD-L2−/− mice. Osteoclasts were generated from RA synovial fluid mononuclear cells and peripheral blood monocytes. The effects of recombinant PD-L2, was evaluated by tartrate-resistant acid phosphatase (TRAP) activity and the development of bone erosions in the presence of anti-citrullinated protein antibodies (ACPA). Plasma soluble (s)PD-L2 levels were measured in patients with early (e)RA (n ​= ​103) treated with methotrexate alone or in combination with the TNF inhibitor Adalimumab. Results PD-L2−/− mice had a decreased BMD and deteriorated trabecular bone microstructure that was not related to the RANKL/OPG pathway. PD-L2 decreased TRAP activity in osteoclasts and decreased ACPA-induced erosions. In the RA synovial membrane PD-L2 was highly expressed especially in the lining layer and plasma sPD-L2 levels were increased in eRA patients and decreased with treatment. One-year sPD-L2 correlated inversely with erosive progression two years after treatment initiation with methotrexate and placebo. Conclusion PD-L2 regulates bone homeostasis in RA. Our findings provide new insight into the relationship between the immune system and bone homeostasis, and suggest a potential therapeutic target for limiting inflammatory bone loss in RA., Highlights • PD-L2 is closely related to bone homeostasis in a mouse model. • PD-L2 inhibits osteoclastogenesis and osteoclast activation in vitro. • PD-L2 is highly expressed by cells in the synovial membrane of rheumatoid arthritis. • PD-L2 is associated with less radiographic progression in patients with early rheumatoid arthritis.

Objectives: Surfactant protein-D (SP-D), an innate immune defence molecule of the collectin family, is expressed in lungs and additional extrapulmonary epithelia. SP-D has immune modulatory and anti-microbial effects depending on its oligomerization. The ratio of high molecular weight (HMW): low molecular weight (LMW) SP-D in serum is mainly determined by the Met11Thr polymorphism (SNP rs721917). We aimed to study the SP-D serum level and the molecular size distribution in patients with untreated axial spondyloarthritis (axSpA) as compared with control subjects.Methods: Thirty-four patients with disease modifier untreated axSpA according to the ASAS criteria, age 19-63 years, disease duration 3.9 (2.2-5.6) years were included. Demographics, smoking habits, HLA-B27 status, ASDAS, BASDAI, BASFI, BASMI and visual analogue scale scores were recorded. SP-D in serum was measured by ELISA. DNA was isolated from whole blood and single nucleotide polymorphism rs721917 was genotyped. SP-D molecular size distribution was determined using gel filtration chromatography.Results: SP-D in serum did not differ between patients with axSpA and healthy controls, 1177 (869, 1536) vs 910 (494, 1682) (P = 0.35) and SP-D did not correlate with disease activity. However, the HMW/LMW ratio of SP-D in serum was significantly lower in axSpA, 0.38 (0.18, 0.53) compared with controls 1.49 (0.37, 3.24) when adjusting for the Met11Thr polymorphism, gender, age, BMI and smoking (P = 0.0004). There was no correlation between HMW/LMW ratio and CRP or composite diseases outcome measures.Conclusion: We suggest that predominance of LMW oligomeric variants of SP-D may enhance local or systemic inflammatory responses in axSpA.

Rationale: Sufficient levels of vitamin D seem to be essential for proper immune function, and low levels might be associated to disease activity in Rheumatoid Arthritis (RA). Most studies investigate only 25OHD and not the physiologically active vitamin D metabolite, 1,25(OH) 2D. Objective: To investigate associations between serum level of vitamin D metabolites and disease activity parameters in 160 inflammatory active and treatment naïve early RA patients. Serum level of vitamin D metabolites (25OHD 2, 25OHD 3 and 1,25(OH) 2D) was measured by isotope dilution mass spectrometry and radio-immunoassays at baseline. Disease characteristics were gender, number of tender joints, number of swollen joints, DAS28-CRP, HAQ, VAS-scores, CRP, erosive status (Total Sharp Score; TSS), ACPA and IgM-RF-status. Associations were evaluated using Spearman's and Wilcoxon rank-sum tests. The study was registered in clinical trials; trial registration number: NCT00209859. Findings: Statistically significant inverse associations were found between the active metabolite 1,25(OH) 2D and DAS28-CRP (P = 0.004, rho = −0.23), HAQ (P = 0.005, rho = −0.22), CRP (P = 0.001, rho = −0.25), VAS patient-pain (P = 0.008, rho = −0.21), and a positive association was found to ACPA-status (P = 0.04). Conclusion: The vitamin D metabolite 1,25(OH) 2D was inversely associated with disease activity and positively associated with ACPA in treatment naïve and inflammatory active early RA. The results indicate that in RA, both the degree of inflammatory activity, and the diagnostic sensitivity and specificity might affect—or might be affected by the level of vitamin 1,25(OH) 2D.

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.

Sufficient levels of vitamin D seem to be essential for proper immune function, and low levels might be associated to disease activity in Rheumatoid Arthritis (RA). Most studies investigate only 25OHD and not the physiologically active vitamin D metabolite, 1,25(OH)To investigate associations between serum level of vitamin D metabolites and disease activity parameters in 160 inflammatory active and treatment naïve early RA patients. Serum level of vitamin D metabolites (25OHDStatistically significant inverse associations were found between the active metabolite 1,25(OH)The vitamin D metabolite 1,25(OH)

Bone marrow (BM) fibrosis is a potential side effect of thrombopoietin receptor agonist (TPO-RA) treatment. We aimed to investigate stromal seromarker profiles and growth factors in order to elucidate pathogenic and dynamic aspects of immune thrombocytopenia (ITP)-related BM fibrosis before and during TPO-RA treatment. Connective tissue metabolites [procollagen I and III peptides (PINP/PIIINP); hyaluronan (HYA), C-terminal-telopeptide (ICTP), and fibrosis-related growth factors (transforming growth factor-beta (TGF-beta), HGF, basic fibroblast growth factor)] were measured in blood samples acquired before initiation of TPO-RA and subsequently at 6-month intervals for up to 2 years. BM fibrosis was graded MF-0 in 8 (18%), MF-1 30 (65%), and MF-2 8 (18%) in the last available BM biopsy. In the 21 patients having more than one biopsy, the grade of fibrosis from the first to the last available biopsy decreased in 2 (10%), remained unchanged in 15 (71%), and increased in 4 (19%). Pretreatment levels of PIIINP, PINP, ICTP, and HYA were significantly increased in ITP versus controls. PINP, PIIINP, and HYA decreased on TPO-RA; ICTP remained unchanged. PINP:ICTP was lower before and during treatment compared to controls. Pretreatment, TGF-beta was lower than in controls; HGF exhibited the opposite pattern. HYA, ICTP, and TGF-beta tended to increase while PINP and platelet-derived growth factor tended to decrease with increasing fibrosis grade. In conclusion, ITP is associated with deranged patterns of extracellular matrix seromarkers and growth factors, indicating that BM stromal remodeling is enhanced. During TPO-RA treatment for up to 2 years, this profile was partially reversed while mild BM reticulin fibrosis was still present in the majority of patients. These observations likely reflect a BM injury by autoimmunity that is modified by TPO-RA.

Objective To determine the occurrence of traditional cardiovascular (CV) risk factors and coronary artery calcification (CAC) in adults with polymyositis (PM) or dermatomyositis (DM) compared to healthy controls and to assess the association between CV risk factors, PM/DM, and CAC score. Methods Traditional CV risk factors were assessed in a cross-sectional, observational study of 76 patients with PM/DM and in 48 sex- and age-matched healthy controls. CAC was quantified by means of cardiac computed tomography scan and expressed in Agatston units. The associations between CV risk factors, PM/DM, and CAC were studied by multivariate analyses. Results Thirty-three percent of the patients were obese compared to 11% of the controls (P = 0.005). Hypertension and diabetes mellitus were more frequent in patients (71% versus 42%; P = 0.002, and 13% versus 0%; P = 0.007), and patients had higher levels of triglycerides (P = 0.0009). High CAC score occurred more frequently in patients (20% versus 4%; P = 0.04). In multivariate analysis of patient factors associated with CAC were age (P = 0.02) and smoking (P = 0.02). Conclusion In this study, traditional CV risk factors and severe CAC were commonly found in patients with PM/DM. However, severe CAC was not associated with PM/DM per se, but rather with age and smoking in these patients.

Galectin-3 has been suggested as a pro-inflammatory mediator in animal arthritis and rheumatoid arthritis (RA). We aimed to study the serum level of galectin-3 in patients with newly diagnosed RA and associations with disease profile, Magnetic Resonance Imaging (MRI) findings and seromarkers of synovial matrix inflammation. One hundred and sixty DMARD naïve patients newly diagnosed with RA were included (CIMESTRA study). Clinical, serological and imaging data were recorded before treatment and at 6 weeks, 3 and 12 months. Galectin-3 and hyaluronan (HYA) were measured by ELISA (R&D and Corgenix, USA), and the N-terminal propeptide of type III collagen (PIIINP) by radioimmuno assay (Orion Diagnostica, Finland). One-hundred-and-nineteen, 87 and 60 blood donors served as controls for galectin-3, HYA and PIIINP, respectively. Baseline galectin-3 was significantly elevated in anti-CCP positive (4.2 μg/l IQR [3.6;6.1]) patients as compared with anti-CCP negatives (4.0 μg/l [2.6;4.9], p=0.05) and controls (3.8 μg/l [3.0;4.8], p

The expanding spectrum of targeted therapies for rheumatoid arthritis (RA) implies a need for development of precision tools for disease assessment reflecting pathobiologic processes. Type IV collagen is an abundant protein of basement membranes, but is also present in the intercellular matrix of the synovial lining layer. We aimed to investigate the association of type IV collagen turnover with RA disease activity, response to IL-6 inhibition and radiographic progression.C4M, a serologic marker of type IV collagen metabolism, was measured at baseline and at follow-up in serum samples of RA patients participating in the phase III studies LITHE (n=687) and RADIATE (n=217). Both were double-blinded, placebo-controlled clinical trials testing the safety and efficacy of 4 and 8 mg/kg tocilizumab (TCZ) in combination with methotrexate (MTX) vs. MTX plus placebo. Associations with disease activity, radiographic severity and ACR response were investigated.Baseline C4M correlated significantly with clinical disease parameters in both study populations, including DAS28, HAQ score and VASpain (all p0.00001). C4M at baseline correlated significantly with change in JSN (p=0.001) and Sharp score (p=0.00002) at 52 weeks. TCZ lowered C4M by 11-40% in a dose dependent manner. The likelihood of achieving an ACR20 response by week 16 was associated with C4M suppression exceeding the median decrease at week 4 (p0.0001).Type IV collagen remodelling was associated with disease activity and radiographic progression in RA and was persistently and dose-dependently suppressed by TCZ. These findings indicate that C4M may serve as a plausible biologic marker of destructive synovitis growth in RA.

Objective.The aim was to identify plasma (i.e., cell-free) microRNA (miRNA) predicting antitumor necrosis and/or methotrexate (MTX) treatment response in patients enrolled in an investigator-initiated, prospective, double-blinded, placebo-controlled trial (The OPERA study,NCT00660647).Methods.We included 180 disease-modifying antirheumatic drug–naive patients with early rheumatoid arthritis (RA) randomized to adalimumab (ADA; n = 89) or placebo (n = 91) in combination with MTX. Plasma samples before and 3 months after treatment initiation were analyzed for 91 specific miRNA by quantitative reverse transcriptase-polymerase chain reaction on microfluidic dynamic arrays. A linear mixed-effects model was used to test for associations between pretreatment miRNA and changes in miRNA expression and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean (28 joints) remission at 3 and 12 months, applying false discovery rate correction for multiple testing. Using leave-one-out cross validation, we built predictive multivariate miRNA models and estimated classification performances using receiver-operating characteristics (ROC) curves.Results.In the ADA group, a higher pretreatment level of miR-27a-3p was significantly associated with remission at 12 months. The level decreased in remitting patients between pretreatment and 3 months, and increased in nonremitting patients. No associations were found in the placebo group receiving only MTX. Two multivariate miRNA models were able to predict response to ADA treatment after 3 and 12 months, with 63% and 82% area under the ROC curves, respectively.Conclusion.We identified miR-27a-3p as a potential predictive biomarker of ACR/EULAR remission in patients with early RA treated with ADA in combination with MTX. We conclude that pretreatment plasma-miRNA profiles may be of predictive value, but the results need confirmation in independent cohorts.

Surfactant protein-D (SP-D) is a collectin, which plays an important role in airway protection and inflammation. The molecule has both pro- and anti-inflammatory capacities depending on its molecular size. Its involvement in joint diseases is largely unknown and the aim of this investigation was to study SP-D occurrence and distribution in the synovial membrane of patients with long-standing rheumatoid arthritis (RA) and osteoarthritis (OA). Six RA patients and six OA patients, who underwent total hip arthroplasty, were included in the study. Synovial tissue biopsies were obtained during surgery and subsequently prepared for immunohistochemistry. In this first, small-scale comparative study on the occurrence of SP-D in the synovial membrane of RA and OA, we report that SP-D was only present in the microvascular endothelium in subsynovial and pannus tissue and that the immunostaining was much stronger than in OA. This distribution pattern suggests that SP-D modulates RA inflammatory activities.