Characterization of DNA-protein complexes by nanoparticle tracking analysis and their association with systemic lupus erythematosus.

Nanotechnology enables investigations of single biomacromolecules, but technical challenges have limited the application in liquid biopsies, for example, blood plasma. Nonetheless, tools to characterize single molecular species in such samples represent a significant unmet need with the increasing appreciation of the physiological importance of protein structural changes at nanometer scale. Mannose-binding lectin (MBL) is an oligomeric plasma protein and part of the innate immune system through its ability to activate complement. MBL also serves a role as a scavenger for cellular debris, especially DNA. This may link functions of MBL with several inflammatory diseases in which cell-free DNA now appears to play a role, but mechanistic insight has been lacking. By making nanoparticle tracking analysis possible in human plasma, we now show that superoligomeric structures of MBL form nanoparticles with DNA. These oligomers correlate with disease activity in systemic lupus erythematosus patients. With the direct quantification of the hydrodynamic radius, calculations following the principles of Taylor dispersion in the blood stream connect the size of these complexes to endothelial inflammation, which is among the most important morbidities in lupus. Mechanistic insight from an animal model of lupus supported that DNA-stabilized superoligomers stimulate the formation of germinal center B cells and drive loss of immunological tolerance. The formation involves an inverse relationship between the concentration of MBL superoligomers and antibodies to double-stranded DNA. Our approach implicates the structure of DNA-protein nanoparticulates in the pathobiology of autoimmune diseases.

Plasma levels of multiple cardiovascular- and inflammation-related proteins analysed for associations with disease activity and anti-cyclic citrullinated peptide status in active early rheumatoid arthritis.

OBJECTIVES: To compare plasma levels of 92 cardiovascular- and inflammation-related proteins (CIRPs) and to analyse for associations with anti-cyclic citrullinated peptide (anti-CCP) status and disease activity in early and treatment-naive rheumatoid arthritis (RA). METHODS: Olink CVD-III-panel was used to measure 92 CIRP plasma levels in 180 early, treatment-naive, and highly inflamed RA patients from the OPERA trial. CIRP plasma levels as well as correlation between CIRP plasma levels and RA disease activity were compared between anti-CCP groups. CIRP level-based hierarchical cluster analysis was performed in each anti-CCP group separately. RESULTS: The study included 117 anti-CCP-positive and 63 anti-CCP-negative RA patients. Among the 92 CIRPs measured, the levels of chitotriosidase-1 (CHIT1) and tyrosine-protein-phosphatase non-receptor-type substrate-1 (SHPS-1) were increased and those of metalloproteinase inhibitor-4 (TIMP-4) decreased in the anti-CCP-negative group compared to anti-CCP-positive group. The strongest associations with RA disease activity were found for interleukin-2 receptor-subunit-alpha (IL2-RA) and E-selectin levels in the anti-CCP-negative group and for C-C-motif chemokine-16 levels (CCL16) in the anti-CCP-positive group. None of the differences passed the Hochberg sequential multiplicity test, however, the CIPRs were interacting and thus the prerequisites of the Hochberg procedure were not fulfilled. CIRP level-based cluster analysis identified two patient clusters in both anti-CCP groups. Demographic and clinical characteristics were similar in the two clusters for each anti-CCP group. CONCLUSIONS: In active and early RA, the findings regarding CHIT1, SHPS-1 TIMP-4, IL2-RA, E-selectin, and CCL16 differed between the two anti-CCP groups. In addition, we identified two patient clusters that were independent of the anti-CCP status.

Improved pregnancy outcomes in systemic lupus erythematosus: A retrospective study of pregnancies from a single centre in Denmark from 2010-2020 compared with the period 1990-2010.

OBJECTIVES: Over the past decades new international guidelines recommend that pregnant Systemic lupus erythematosus (SLE) patients are monitored closely in a multi-professional team throughout pregnancy. The importance of low disease activity before pregnancy and continued treatment during pregnancy has been established. However, there is still a high risk of adverse pregnancy outcome (APO).The APO in a Danish SLE cohort was evaluated and compared with the results in a previous study cohort from the same centre and referral area. METHODS: This retrospective cohort study used the local patient registry to identify pregnancies in SLE patients followed at the Department of Rheumatology, Aarhus University Hospital, Denmark, from January 2010 to October 2020. In total, 66 pregnancies were registered in 41 women. Data were compared with a previous retrospective study (1990-2010) from the same hospital. RESULTS: Adverse pregnancy outcome occurred in 65% of pregnancies. Forty-seven pregnancies resulted in a live birth, while 15 ended in miscarriages. Compared to the 1990-2010 cohort, a numerical reduction in preterm deliveries (7.58% vs. 17.9%) and emergent caesarean (6.1% vs. 15.5%) was observed, although not reaching statistical significance (p = .07 in both cases). Further, a higher average birth weight (3045 g vs. 2870 g) as well as a higher number of pregnancies and live births per year were observed. Gestational hypertension was significantly reduced from 23.8% to 13.6% (p = .05). Significantly more patients were treated with prednisolone (66.7% vs 35.7%, p = .0002), hydroxychloroquine (6% vs. 73.4%, p < .0001) and acetylsalicylic acid (39.3% vs. 73.1%, p = .0001) in 2010-2020 compared to the 1990-2010. CONCLUSION: We observed significant improvements in the frequency of some APOs in the recent 2010-2020 cohort compared with the previous cohort followed from 1990 to 2010. However, even though a specialized multi-professional team closely follows SLE patients through their pregnancies, pregnancy in SLE still carries a high risk of APO.

Predictors of joint damage progression and stringent remission in patients with established rheumatoid arthritis in clinical remission.

OBJECTIVES: To study if clinical, radiographic and MRI markers can predict MRI and radiographic damage progression and achievement of stringent remission in patients with established RA in clinical remission followed by a targeted treatment strategy. METHODS: RA patients (DAS28-CRP <3.2, no swollen joints) receiving conventional synthetic DMARDs were randomized to conventional or MRI-targeted treat-to-target strategies with predefined algorithmic treatment escalations. Potentially predictive baseline variables were tested in multivariate logistic regression analyses. RESULTS: In the 171 patients included, baseline MRI osteitis independently predicted progression in MRI erosion [odds ratio (OR) 1.13 (95% CI 1.06, 1.22)], joint space narrowing [OR 1.15 (95% CI 1.07, 1.24)] and combined damage [OR 1.23 (95% CI 1.13, 1.37)], while tenosynovitis independently predicted MRI erosion progression [OR 1.13 (95% CI 1.03, 1.25)]. A predictor of radiographic erosion progression was age, while gender predicted progression in joint space narrowing. Following an MRI treat-to-target strategy predicted stringent remission across all remission definitions: Clinical Disease Activity Index remission OR 2.94 (95% CI 1.25, 7.52), Simplified Disease Activity Index remission OR 2.50 (95% CI 1.01, 6.66), ACR/EULAR Boolean remission OR 5.47 (95% CI 2.33, 14.13). Similarly, low tender joint count and low patient visual analogue scale pain and global independently predicted achievement of more stringent remission. CONCLUSION: Baseline MRI osteitis and tenosynovitis were independent predictors of 2 year MRI damage progression in RA patients in clinical remission, while independent predictors of radiographic damage progression were age and gender. Following an MRI treat-to-target strategy, low scores of patient-reported outcomes and low tender joint count predicted achievement of stringent remission. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT01656278.

Similar lipid level changes in early rheumatoid arthritis patients following 1-year treat-to-target strategy with adalimumab plus methotrexate versus placebo plus methotrexate: secondary analyses from the randomised controlled OPERA trial.

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.

Methotrexate pharmacokinetic is influenced by co-administration of cyclosporin in rheumatoid arthritis patients. Results from a randomized clinical trial.

The aim was to investigate if the pharmacokinetics of methotrexate (MTX) are affected by the addition of cyclosporin (CsA). Forty patients diagnosed with early rheumatoid arthritis (RA) were included in this open prospective study: 20 patients were treated with a dose of 7.5 mg MTX and a dose of 2.5 mg/kg CsA, 20 patients were treated with a dose of 7.5 mg MTX and placebo. Baseline measurements of plasma MTX and erythrocyte MTX were made. Area under the plasma concentration versus time curve (AUC) and other pharmacokinetic variables were estimated by means of a population based software model. Clinical improvement of 20-50-70% according to the American College of Rheumatology (ACR) and adverse events were evaluated ongoing for 52 weeks. We found that mean peak plasma MTX concentration was significantly higher in the MTX + CsA combination treatment group (p = .003). No differences in AUC, erythrocyte MTX or other pharmacokinetic parameters were found between the two treatment groups. Estimated Glomerular Filtration Rate (eGFR) decreased significantly in the MTX + CsA treatment group (p < .001), but no serious adverse events occurred in either of the two groups. In conclusion, CsA added to methotrexate treatment in early RA significantly increased peak-plasma MTX concentration, but other pharmacokinetic parameters and measurements of MTX were unchanged.

A positive Helicobacter pylori test is associated with low spondylarthritis incidence in a Danish historical cohort study.

Ankylosing spondylitis (AS) and undifferentiated spondylarthritis (uSpA) are related inflammatory diseases affecting the spine and joints with infections among possible etiological factors. Helicobacter pylori (H. pylori) may affect the development of inflammatory diseases. Thus, we hypothesized that H. pylori infection affects AS and uSpA development. This cohort study was performed in Denmark with 56,000 patients from primary health care centers who were enrolled when a UBT was performed. They were followed for a median time of 8 years. From nationwide administrative registries, we extracted personal, diagnostic, and treatment information. Prevalence at time of UBT was studied on enrollment using logistic regression and incidence in the follow-up time of 8 years after UBT was studied using Cox regression, comparing H. pylori positive and H. pylori negative patients and adjusting for confounding variables. The prevalence of AS at the time of the UBT was higher among H. pylori positive individuals (OR = 2.00, CI 1.17-3.41), but likely to be linked to confounding as trends disappeared when stratifying for country of birth. The incidence of AS after UBT was lower for individuals who were previously H. pylori positive (OR = 0.23, CI 0.06-0.93). A similar phenomenon was observed for uSpA. As a novel finding, after UBT, the previously H. pylori infected individuals had lower risk of developing AS and uSpA compared to non-infected. This finding may be caused by etiological effects of previous H. pylori infection or unknown confounders. This suggests that H. pylori may somehow be positively involved in the pathogenesis of AS and uSpA.

Ficolin-3 Deficiency Is Associated with Disease and an Increased Risk of Systemic Lupus Erythematosus.

PURPOSE: Ficolin-3 deficiency is caused by a mutation (+1637delC) in the FCN3 gene. It is a rare condition and has been associated with both infection and autoimmune disease including systemic lupus erythematosus (SLE). Here we investigated if ficolin-3 deficiency is more frequent in patients than in controls and tried to identify a common phenotype among ficolin-3 deficient individuals. Since a significant part of patients identified with ficolin-3 deficiency was diagnosed with SLE, we explored whether the heterozygous state of the FCN3+1637delC variant represents a risk factor in the development of SLE. Further, we examined other possible causes of ficolin-3 deficiency when the FCN3+1637delC is not present. METHODS: A systematic literature search for studies measuring ficolin-3 was carried out. We examined 362 SLE patients and 596 controls for the presence of the variant FCN3+1637delC. We established assays for measurements of ficolin-3 and of auto-antibodies against ficolin-3. We sequenced the coding and non-coding regions of the FCN3 gene in an SLE patient with ficolin-3 deficiency not carrying the +1637delC. RESULTS: Ficolin-3 deficiency leads to an 8-time increased odds of having a disease (p < 0.05). Three out of nine patients with deficiency had SLE. The heterozygous state of the deficiency variant is not associated with increased risk of developing SLE (p = 0.18). CONCLUSION: By systematically reviewing the literature for the described cases of ficolin-3 deficiency, an autoimmune phenotype is emerging. Thirty-three percent of the ficolin-3 deficient patients had SLE. Heterozygosity for the FCN3 gene deletion causing the deficiency does not seem to be associated with the development of SLE.

Effect of Magnetic Resonance Imaging vs Conventional Treat-to-Target Strategies on Disease Activity Remission and Radiographic Progression in Rheumatoid Arthritis: The IMAGINE-RA Randomized Clinical Trial.

Importance: Whether using magnetic resonance imaging (MRI) to guide treatment in patients with rheumatoid arthritis (RA) improves disease activity and slows joint damage progression is unknown. Objective: To determine whether an MRI-guided treat-to-target strategy vs a conventional clinical treat-to-target strategy improves outcomes in patients with RA in clinical remission. Design, Setting, and Participants: Two-year, randomized, multicenter trial conducted at 9 hospitals in Denmark. Two hundred patients with RA in clinical remission (disease activity score in 28 joints-C-reactive protein [DAS28-CRP] <3.2 and no swollen joints) were enrolled between April 2012 and June 2015. The final follow-up visit was April 2017. Interventions: Patients were randomly allocated (1:1) to an MRI-guided vs a conventional treat-to-target strategy. In the MRI-guided group, the treatment goal was absence of MRI bone marrow edema combined with clinical remission, defined as DAS28-CRP of 3.2 or less and no swollen joints. In the conventional group, the treatment goal was clinical remission. Main Outcomes and Measures: Co-primary outcomes were proportions of patients achieving DAS28-CRP remission (DAS28-CRP <2.6) and with no radiographic progression (no increase in total van der Heijde-modified Sharp score) at 24 months. Significance testing for the primary outcome was based on 1-sided testing. Secondary outcomes were clinical and MRI measures of disease activity, physical function, and quality of life. Results: Of 200 patients randomized (133 women [67%]; mean [SD] age, 61.6 [10.5] years; median baseline DAS28-CRP, 1.9 [interquartile range, 1.7-2.2]; van der Heijde-modified Sharp score, 18.0 [interquartile range, 7.0-42.5]), 76 patients (76%) in the MRI-guided group and 95 (95%) in the conventional group completed the study. Of these, 64 (85%) vs 83 (88%), respectively, reached the primary clinical end point (risk difference, -4.8% [1-sided 95% CI, -13.6% to + ∞; 1-sided P = .19]) and 49 (66%) vs 58 (62%), respectively, reached the primary radiographic end point (risk difference, 4.7% [1-sided 95% CI, -7.0% to + ∞; 1-sided P = .25). Of 10 key secondary end points, 8 were null and 2 showed statistically significant benefit for the MRI treat-to-target group. Seventeen patients (17%) in the MRI-guided treat-to-target group and 6 patients (6%) in the conventional treat-to-target group experienced serious adverse events. Conclusions and Relevance: Among patients with RA in clinical remission, an MRI-guided treat-to-target strategy compared with a conventional treat-to-target strategy did not result in improved disease activity remission rates or reduce radiographic progression. These findings do not support the use of an MRI-guided strategy for treating patients with RA. Trial Registration: ClinicalTrials.gov Identifier: NCT01656278.

Immunomodulating peptides derived from different human endogenous retroviruses (HERVs) show dissimilar impact on pathogenesis of a multiple sclerosis animal disease model.

Retroviruses including Human Endogenous Retroviruses (HERVs), contain a conserved region with highly immunomodulatory functions in the transmembrane proteins in envelope gene (env) named immunosuppressive domain (ISU). In this report, we demonstrate that Env59-GP3 peptide holds therapeutic potential in a mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). The results show that this specific HERV-H derived ISU peptide, but not peptide derived from another env gene HERV-K, decreased the development of EAE in C57BL/6 mice, accompanied by reduced demyelination and inhibition of inflammatory cells. Moreover, here we tested the effect of peptides on macrophages differentiation. The treatment with Env59-GPS peptide modulate the pro-inflammatory M1 profile and anti-inflammatory M2 macrophages, being shown by inhibiting inflammatory M1 hallmark genes/cytokines expression and enhancing expression of M2 associated markers. These results demonstrate that Env59-GP3 ISU peptide has therapeutic potential in EAE possibly through inducing the polarization of M2 macrophages and inhibiting inflammatory responses.

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 naïve, early Rheumatoid Arthritis Patients.

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)2 D. 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 (25OHD2 , 25OHD3 and 1,25(OH)2 D) 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)2 D and DAS28-CRP (P = 0.004, rho = -0.23), HAQ (P = 0.005, rho = -0.22), CRP (P = 0.001, rho = -0.25), VASpatient-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)2 D 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)2 D.

Calprotectin in patients with chronic rheumatoid arthritis correlates with disease activity and responsiveness to methotrexate.

OBJECTIVE: Calprotectin (myeloid-related protein 8/14) is elevated in inflammatory diseases and a correlation of serum calprotectin and disease activity in rheumatoid arthritis (RA) has been shown. In this study, we investigated plasma calprotectin as a disease marker in patients with chronic RA treated with methotrexate (MTX) monotherapy and compared plasma calprotectin with C-reactive protein (CRP) in this matter. METHODS: Seventy-six patients with chronic RA were included in this open prospective study and of these 40 were included prior to initiation of MTX therapy. The patients were followed with laboratory and clinical parameters for 52-56 weeks. Plasma calprotectin was analyzed at the start of study and at various intervals. Radiographic evaluation was performed at baseline and after 17.2 months and progression in joint destruction was measured with Larsen score. The response to MTX was evaluated according to the American College of Rheumatology criteria. RESULTS: Patients starting MTX treatment had significantly higher levels of plasma calprotectin compared to patients well established on MTX therapy (p = .008). Among the 40 patients naive to MTX, 25 responded to MTX therapy and serum calprotectin decreased significantly in these patients (p = .0007). The radiographic damage showed no relation to calprotectin. CONCLUSIONS: Plasma calprotectin is associated with disease activity in patients with chronic RA and is more strongly correlated to MTX response compared to CRP. The role of calprotectin as a disease marker is promising and the advantages compared to CRP needs to be further investigated.

Magnetic resonance imaging assessed inflammation in the wrist is associated with patient-reported physical impairment, global assessment of disease activity and pain in early rheumatoid arthritis: longitudinal results from two randomised controlled trials.

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 (p<0.01), and similar patterns were seen for other hand-related HAQ items. Incorporating metacarpophalangeal joints in the analyses did not strengthen the associations between MRI pathology and PROs. CONCLUSIONS: 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.

Expression of soluble CD83 in plasma from early-stage rheumatoid arthritis patients is not modified by anti-TNF-α therapy.

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-α therapy hereon. Early RA patients were randomized to conventional disease modifying anti-rheumatic drugs with or without additional anti-TNF-α 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-α 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-α treatment has no effect on the sCD83 plasma level. This suggest that in RA patients sCD83 regulation is beyond control of TNF-α.

Soluble CD206 plasma levels in rheumatoid arthritis reflect decrease in disease activity.

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.

Effects of maternal health anxiety on children's health complaints, emotional symptoms, and quality of life.

Little is known about family risk factors and intergenerational transmission of psychological disturbance in the development of health anxiety (HA). This study investigated HA and related concepts in 8- to 17-year-old children who had been exposed to different maternal health status. Using a family case-control design, three family groups were included: (1) 50 case children of mothers with severe (HA); (2) 49 control children of mothers with rheumatoid arthritis (RA); and (3) 51 control children of healthy mothers. Children and mothers completed a battery of standardised questionnaires. Case children reported significantly higher level of HA symptoms than children of mothers with RA but not compared to children of healthy mothers. There was no significant difference between the children's self-reports in the three groups with regard to anxiety symptoms in general, physical complaints, or quality of life. In contrast, mothers with HA reported their children as having more emotional and physical symptoms than mothers in one or both control groups. Compared to mothers with RA but not healthy mothers, mothers with HA also reported more visits to the general practitioner with their children during the past year. The findings suggest that maternal HA only weakly affects children's own report of HA and thereby may not be a strong risk factor for the development of HA symptoms in childhood. However, mothers with severe HA seem to conceive their children as more ill and present them more often in the health care system which could, therefore, be an important target for intervention in adult patients.

A disintegrin and metalloprotease-17 and galectin-9 are important regulators of local 4-1BB activity and disease outcome in rheumatoid arthritis.

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.

A treat-to-target strategy with methotrexate and intra-articular triamcinolone with or without adalimumab effectively reduces MRI synovitis, osteitis and tenosynovitis and halts structural damage progression in early rheumatoid arthritis: results from the OPERA randomised controlled trial.

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 (p<0.0001) during the 12-months' follow-up, with mean change scores of -3.7 (median -3.0), -2.2 (-1) and -5.3 (-4.0), respectively. No overall change in MRI bone erosion and JSN scores was seen, with change scores of 0.1 (0) and 0.2 (0). The tenosynovitis score at month 6 was significantly lower in the adalimumab group, 1.3 (0), than in the placebo group, 3.9 (2), Mann-Whitney: p<0.035. Furthermore, the osteitis score decreased significantly during the 12-months' follow-up in the adalimumab group, but not in the placebo group, Wilcoxon: p=0.001-0.002 and p=0.062-0.146. DCE-MRI parameters correlated closely with conventional MRI inflammatory parameters. Clinical measures decreased highly significantly during follow-up. CONCLUSIONS: 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.

Macrophage activity assessed by soluble CD163 in early rheumatoid arthritis: association with disease activity but different response patterns to synthetic and biologic DMARDs.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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), (p<0.001). 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, p<0.05). In the DMARD+PLA group baseline sCD163 also correlated with CRP during the follow-up period. CONCLUSIONS: 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.

Back pain was less explained than leg pain: a cross-sectional study using magnetic resonance imaging in low back pain patients with and without radiculopathy.

BACKGROUND: Cross-sectional studies have shown associations between lumbar degenerative manifestations on magnetic resonance imaging (MRI) and low back pain (LBP). Disc herniations and other degenerative manifestations, however, frequently occur in asymptomatic individuals. The purpose of this cross-sectional study was to analyze for associations between pain intensity and degenerative manifestations and other pain variables in patients for whom prognostic factors have been published previously. METHODS: Included were 141 consecutive patients with and without radiculopathy, all sick-listed 1-4 months due to low back pain and subsequently examined by MRI of the lumbar spine. Using different methods of grouping the degenerative manifestations, linear regression analyses were performed with the intensity of back + leg pain, back pain and leg pain as dependent variables covering actual pain and pain the preceding 2 weeks. The clinical classification into +/- radiculopathy was established before and independently of the standardised description of MRI findings. RESULTS: Radiculopathy was present in 43 % of the patients. Pain was best explained using rank-ordered degenerative manifestations on MRI. Back pain and leg pain were differently associated, and back pain was less explained than leg pain in the multivariate analyses (15 % vs. 31 % of the variation). Back pain intensity was higher in patients with type 1 Modic changes and in some patients with nerve root touch, but was not associated with disc herniations. Leg pain intensity was well explained by disc herniations causing MRI nerve root compromise and radiculopathy. In patients with radiculopathy, nerve root touch caused as much leg pain as nerve root displacement or compression. High intensity zones and osteophytes were not associated with back pain, but only associated with leg pain in patients with radiculopathy. Tender points explained some of the back pain, and widespread pain explained leg pain in some of the patients without radiculopathy. CONCLUSIONS: Back pain was associated with type 1 Modic changes, nerve root touch and tender points, whereas leg pain was associated with osteophytes, HIZ, disc herniation, all sorts of MRI nerve root compromise, radiculopathy and widespread pain.