Saedis Saevarsdottir - Academia.edu (original) (raw)

Papers by Saedis Saevarsdottir

Annals of the Rheumatic Diseases, 2015

No Is the first author applying for a travel bursary or an award for undergraduate medical studen... more No Is the first author applying for a travel bursary or an award for undergraduate medical students?: Yes -Travel bursary Please confirm that you will apply for the travel bursary on the EULAR website www.eular.org: Yes Background: In our previous study (1) from the Swedish Farmacotherapy (SWEFOT) trial (2), we showed that a change of multi-biomarker disease activity (ΔMBDA) score (3) in methotrexate incomplete responders (MTX-IR) was predictive for subsequent response to non-biological triple therapy (TT; a combination of MTX with sulfasalazine and hydroxychloroquine) or to anti-tumour necrosis factor (anti-TNF) therapy. Objectives: To evaluate further how ΔMBDA score could be used to predict optimal choice of second-line treatment, by investigating different cut-offs and by comparing this to using the C-reactive protein (CRP) for prediction. Methods: 157 MTX-IR patients from the SWEFOT trial with complete data were grouped into those with and without big ΔMBDA (big decrease >22 and non-big decrease ≤22 respectively from baseline to Month 3) based on highest quartile. The change of CRP (ΔCRP) was studied in parallel using a cut-off based on the highest quartile (>28 & ≤28). Analysis was done by last observation carried forward. The proportion of clinical responders (DAS28 ≤3.2) across ΔMBDA groups between the two therapy arms was assessed by Breslow-Day test. Results: Among patients with ΔMBDA>22, 76% responded to TT and 47% to anti-TNF, while among the others more responded to anti-TNF (55% vs 38%; cross-comparison for all 4 groups p=0.016; figure 1). When based on ΔCRP responses were 50% and 39% versus 45% and 56% (p=0.226). Image/graph:

The Journal of Rheumatology

To determine whether low mannose binding lectin (MBL) is associated with poor prognosis in rheuma... more To determine whether low mannose binding lectin (MBL) is associated with poor prognosis in rheumatoid arthritis (RA) and whether patients with RA have increased frequency of MBL deficiency. Patients with recent onset symmetric polyarthritis (< 1 year, median 3 mo) were recruited if they had not been treated longer than 2 weeks with disease modifying drugs. They were reevaluated after 6 months and their disease activity and progression were correlated with their MBL concentration, rheumatoid factor (RF) isotypes, and C-reactive protein (CRP). Sixty-three female patients with advanced RA were also analyzed. Sixty-five patients with early arthritis fulfilled American College of Rheumatology criteria for RA and 52 were followed for 6 months or longer. Low MBL was associated with raised RF, IgA RF in particular (p = 0.02). and also with a combined elevation of IgM and IgA RF (p = 0.035). Patients with low MBL (lowest 25th percentile) showed less improvement after 6 months of treatment than patients in the highest MBL quartile. This applied to the Thompson joint score (p = 0.03) and grip strength (p = 0.004). Low MBL was also significantly associated with radiological joint erosions at recruitment and at 6 month followup (p = 0.039); and the group with advanced RA also showed a significant association between low MBL concentration and radiological damage (p = 0.036). However. neither patient group had increased frequency of MBL deficiency compared to healthy controls. Low MBL predicts poor prognosis in patients with early RA.

Arthritis Research & Therapy, 2015

Introduction: Receptor activator of nuclear factor kappa B ligand (RANKL) is a key regulator of b... more Introduction: Receptor activator of nuclear factor kappa B ligand (RANKL) is a key regulator of bone metabolism. Anti-citrullinated protein antibodies (ACPA) have been suggested to cause bone destruction by osteoclast activation. We investigated the relationship between RANKL and ACPA in patients with early untreated rheumatoid arthritis (RA). Methods: Patients with newly diagnosed untreated RA (n = 183) were analyzed at baseline and 3 months after initiating methotrexate (MTX) treatment. Serum RANKL (total RANKL), ACPA (anti-CCP2) and ACPA specificities (anti-citrullinated (cit)-vimentin, anti-cit-enolase and anti-cit-fibrinogen) were determined by enzyme-linked immunosorbent assay (ELISA). Synovial RANKL expression was evaluated by immunohistochemistry in a small group of patients (n = 15). The relationship between anti-cit-vim antibodies and bone destruction was further validated in 1116 RA patients included in the EIRA cohort. Pearson's chi-square test, Wilcoxon rank sum test, Wilcoxon signed rank test and linear regression models were used.

BMC Musculoskeletal Disorders

Arthritis & Rheumatology, 2015

Objective Rheumatoid arthritis (RA) clinical trials often exclude patients with low C-reactive pr... more Objective Rheumatoid arthritis (RA) clinical trials often exclude patients with low C-reactive protein (CRP), slowing trial enrollment. We evaluated whether RA patients with a high multi-biomarker disease activity (MBDA) score (>44) among those with low CRP (≤10 mg/L) could complement patients with CRP >10mg/L to enhance patient recruitment without affecting clinical trial outcomes. Methods We evaluated patients from the Swedish pharmacotherapy (SWEFOT) trial, which had no CRP selection criteria. Clinical outcomes were assessed after 3 months of methotrexate (MTX) monotherapy for MTX-naïve patients (N=220) and after add-on therapy from Months 3 to 12 for MTX-inadequate responder (IR) patients (N=127). Radiographic outcomes were assessed at 1 year for all patients. Within each cohort, outcomes were compared between patients with CRP ≤10 mg/L and MBDA score >44 at the start of the respective treatment interval versus those with CRP >10 mg/L. Results Patients with baseline CRP ≤10 mg/L and MBDA score >44 at baseline had comparable clinical and radiographic outcomes to those for patients with CRP>10 mg/L. This broadened definition of inclusion criteria identified an additional 24% MTX-naïve and 47% MTX-IR patients. Conclusion Patient recruitment of RA clinical trials may be substantially enhanced by using "CRP >10 mg/L and/or MBDA score >44" as an inclusion criterion, without diminishing clinical or radiographic outcomes. This article is protected by copyright. All rights reserved.

The Journal of rheumatology, 2007

Mannan-binding lectin (MBL) is present in serum and synovial fluid; its levels vary widely, and t... more Mannan-binding lectin (MBL) is present in serum and synovial fluid; its levels vary widely, and the variations are strongly associated with polymorphisms in the MBL2 gene. Studies have compared MBL in patients with rheumatoid arthritis (RA) and in unrelated controls, but the findings have been contradictory. In the first family-based study, we compared MBL levels in patients with RA to population controls and also to their nonaffected first-degree relatives, who may be regarded as optimal controls because of less genetic variation. Serum levels of MBL and rheumatoid factor were analyzed in 210 patients with RA and 406 of their first-degree relatives from 74 extended families. Population controls for MBL levels were 330 randomly selected adult Icelanders. Patients with RA had higher MBL levels in serum (median 1553 microg/l) than their first-degree relatives (1073 microg/l; p = 0.003) and the unrelated controls (938 microg/l; p < 0.0001). No association was found between MBL and r...

Annals of the Rheumatic Diseases, 2014

My abstract has been or will be presented at a scientific meeting during a 12 months period prior... more My abstract has been or will be presented at a scientific meeting during a 12 months period prior to EULAR 2014: No Is the first author applying for a travel bursary?: Yes Is the first author of this abstract an undergraduate medical student?: No Background: For patients with early RA (eRA), methotrexate (MTX) is recommended as first-line treatment and in non-responders both the addition of conventional non-biological disease modifying anti-rheumatic drug therapy (triple DMARD therapy) and of biological (anti-TNF) therapy are supported by data. Identification of patients with a higher likelihood of responding to one or the other of these options would lead to more personalised medicine and an increased effectiveness of therapy. Objectives: To evaluate the change in the multi-biomarker disease activity (MBDA) score during MTX therapy as a predictor of response to subsequent triple versus biological therapy. Methods: Patients with eRA and DAS28>3.2 entered the SWEFOT clinical trial and received MTX monotherapy for 3 months, at which time clinical non-responders (DAS28>3.2) were randomised to receive non-biological triple DMARD therapy (arm A) or anti-TNF (infliximab) therapy with MTX (arm B). For this study, 129 non-responders at month 3 (n=62 from arm A and n=67 from arm B) were analysed by MBDA score at baseline (BL) and month 3. The assessment of changes in the MBDA score (∆MBDA) from BL to month 3 as a predictor for response to triple or anti-TNF therapy at year 1 was done by defining small (≤6), moderate (7-20) and large (>20) decreases by tertiles. Small and moderate decreases were combined together (small/moderate) and compared versus large decreases for arms A and B. The proportion of patients in arm A versus arm B with response at year 1 was evaluated by the odds ratio (OR) for patients with small/moderate versus large decreases. Homogeneity of the odds ratios between the two cohorts was assessed by Breslow-Day test. Results: The mean (median) decreases in MBDA score from BL to month 3 for year 1 responders (n=66) and non-responders (n=63) were 12.9 (10) and 10.8 (9), respectively (p=0.431), and month 3 mean (median) MBDA scores were 47.1 (45) and 50.3 (47), respectively (p=0.336). Patients who had small/moderate decreases in MBDA score during MTX monotherapy, 43% responded to subsequent triple therapy and 57% responded to anti-TNF (OR=0.577). In contrast, among patients with a large decreases in MBDA score from BL to month 3, 67% responded to subsequent triple therapy and 37% to anti-TNF treatment (OR=3.33). Thus the relative treatment effect of arm A versus arm B differed according to the degree of change in the MBDA score from BL to 3 months (p=0.032). Conclusions: Among patients with eRA who did not achieve low disease activity on MTX monotherapy, those patients with the greatest decreases in MDBA score were more likely to respond to triple therapy whereas patients with lesser decreases of the MBDA score were more likely to respond to anti-TNF therapy. These findings suggest that in MTX non-responders the changes in MBDA score may help guide subsequent therapy.

Annals of the Rheumatic Diseases, 2013

My abstract has been or will be presented at a scientific meeting during a 12 months period prior... more My abstract has been or will be presented at a scientific meeting during a 12 months period prior to EULAR 2013: No Background: In early rheumatoid arthritis (eRA), predictors of clinical response and of radiographic progression would be very useful for optimal targeting of available therapies. Individual biomarkers as well as combinations of biomarkers, such as the MBDA test, can be considered for these purposes. In the SWEFOT study, patients with eRA (symptom duration < 1 year) were started on methotrexate (MTX); at 3 months, responders (DAS28 < 3.2) continued MTX monotherapy and were followed in regular care, whereas non-responders were randomized to receive either triple DMARD therapy or the addition of infliximab. Objectives: To study the MBDA score and the levels of the 12 individual biomarkers at baseline (BL) as predictors of clinical response at 3 months and radiographic progression at 1 year in eRA. Methods: Analyses were performed for patients from the SWEFOT trial who had BL and 3-month assessments of DAS28 (based on ESR), and the MBDA score and the 12 individual biomarkers at BL; and for a subset of patients who also had radiographs at BL and 1 year time-points (assessed using the Van der Heijde modified Sharp score [SvdH]). Patients with DAS28 > 3.2 at 3 months were considered clinical non-responders, and patients with a change in SvdH > 0 as radiographic progressors ("radiological non-responders"). Group comparisons of biomarkers and MBDA scores were performed by Mann-Whitney U test.

Annals of the Rheumatic Diseases, 2013

ABSTRACT Background A multi-biomarker disease activity (MBDA) score has been shown to reflect dis... more ABSTRACT Background A multi-biomarker disease activity (MBDA) score has been shown to reflect disease activity at the molecular level in patients with rheumatoid arthritis (RA). The use of MBDA or its components to predict methotrexate (MTX) response has yet to be determined. Objectives To characterize the MBDA score in RA patients treated with MTX and its ability to predict treatment response. Methods The Epidemiological Investigation of Rheumatoid Arthritis (EIRA) cohort includes patients diagnosed with RA and symptom disease duration &lt; 1 year. This study was conducted on a subgroup of 186 EIRA subjects from the Karolinska University Hospital who were naïve to disease modifying anti-rheumatic drug and were started on MTX monotherapy at study entry. Clinical disease activity and serum biomarker concentrations were measured at baseline (BL) and 3 months. Concentrations of VCAM-1, EGF, VEGF-A, IL-6, TNF-RI, YKL-40, MMP-1, MMP-3, leptin, resistin, SAA and CRP were integrated to derive a MBDA score (range 1-100) using a previously validated algorithm [1]. Anti-CCP was measured by ELISA at BL. Spearman’s rank correlation was used to determine correlations between the clinical disease activity scores and the individual biomarker concentrations or the MBDA Score. Response to treatment at 3 months was assessed using the EULAR criteria. MBDA stratification of EULAR good- and moderate- responders vs. non-responders was evaluated with area under receiver operating characteristic curves (AUROCs). No correction for multiple testing was done when analyzing the single biomarkers. Results Patient baseline characteristics (n=186) were similar to those of the original large EIRA cohort with median (IQR) age 52(42-59), 72% female, 67% anti-CCP positive. At baseline the median (IQR) DAS28-ESR was 5.7 (5.0-6.2) and MBDA score was 58 (47-66). 29% of the patients were good EULAR responders, 37% moderate and 34% non-responders. When analyzing patient baseline characteristics anti-CCP negativity and male sex were associated with EULAR response to MTX treatment at 3 months, whereas BL MBDA score and BL concentrations of individual biomarkers were not. The median changes in MBDA score from BL to 3 months were (-16) for good responders, (-12) for moderate and (+2) for non-responders. Changes in MBDA scores and in concentrations of single biomarkers differentiated responders from non-responders at 3 months (MBDA Score: AUROC = 0.79, p-value &lt;0.001). The changes in MBDA score and in concentration of biomarkers were significantly correlated with changes in DAS28-ESR (MBDA Score: r = 0.60, p &lt;0.001). A sub-analysis to compare the behavior of MBDA score in patients with different anti-CCP status showed no significant difference in the AUROC for the changes in MBDA score when discriminating responders from non-responders (AUROC=0.76 vs. 0.84 for ACPA (+) vs. (-) group; p&gt;0.05). Conclusions MBDA and its biomarker components can track and differentiate the clinical response in early RA patients treated with MTX, regardless of anti-CCP status. References Disclosure of Interest W. Li Shareholder of: Crescendo Bioscience, Employee of: Crescendo Bioscience, A. Hensvold : None Declared, S. Saevarsdottir: None Declared, N. Defranoux Shareholder of: Crescendo Bioscience, Employee of: Crescendo Bioscience, L. Klareskog: None Declared, A. Catrina : None Declared

Annals of the rheumatic diseases, Jan 8, 2014

Prediction of radiographic progression (RP) in early rheumatoid arthritis (eRA) would be very use... more Prediction of radiographic progression (RP) in early rheumatoid arthritis (eRA) would be very useful for optimal choice among available therapies. We evaluated a multi-biomarker disease activity (MBDA) score, based on 12 serum biomarkers as a baseline predictor for 1-year RP in eRA. Baseline disease activity score based on erythrocyte sedimentation rate (DAS28-ESR), disease activity score based on C-reactive protein (DAS28-CRP), CRP, MBDA scores and DAS28-ESR at 3 months were analysed for 235 patients with eRA from the Swedish Farmacotherapy (SWEFOT) clinical trial. RP was defined as an increase in the Van der Heijde-modified Sharp score by more than five points over 1 year. Associations between baseline disease activity measures, the MBDA score, and 1-year RP were evaluated using univariate and multivariate logistic regression, adjusted for potential confounders. Among 235 patients with eRA, 5 had low and 29 moderate MBDA scores at baseline. None of the former and only one of the l...

Annals of the rheumatic diseases, Jan 30, 2014

To determine the relationship between changes in antibody levels towards citrullinated peptides d... more To determine the relationship between changes in antibody levels towards citrullinated peptides derived from different candidate autoantigens and therapeutic outcome in early rheumatoid arthritis (RA). Baseline and 3-month serum samples from 316 patients with early RA enrolled in the Swedish Farmacotherapy (SWEFOT) trial were analysed for antibodies against cyclic citrullinated peptides (CCP) and citrullinated peptides derived from vimentin (cVim), fibrinogen (cFib) and α-enolase (CEP-1). At 3-month follow-up, methotrexate monotherapy-inadequate responders were randomised to add-on therapy with sulfasalazine and hydroxychloroquine or infliximab. In these patients, anticitrullinated peptide antibodies (ACPA) were also assessed at 12 and 24 months. The proportion of antibody-positive patients and relative changes in antibody levels were compared across ACPA specificities and related to therapeutic response and radiographic progression. During the 2-year follow-up, the proportion of pa...

Annals of the rheumatic diseases, Jan 4, 2014

To study clinical predictors for radiographic progression after 1 year in an early rheumatoid art... more To study clinical predictors for radiographic progression after 1 year in an early rheumatoid arthritis (RA) trial. In the SWEFOT trial population, disease modifying antirheumatic drug (DMARD) naïve RA patients started methotrexate; 3-month responders (DAS28 <3.2) continued (n=147), while non-responders were randomised to addition of sulfasalazine+hydroxychloroquine (n=130) or infliximab (n=128). X-rays were scored by the Sharp-van der Hejde score (SHS) method and radiographic progression was defined as a ≥5 increase after 1 year. Potential baseline predictors of radiographic progression were tested using multivariable logistic regression, adjusted for potential confounders. 79 of 311 patients with available radiographs at baseline and follow-up had radiographic progression. The following baseline parameters were independent predictors of radiographic progression at 1 year: baseline erosions (adjusted OR=2.29, 95% CI 1.24 to 4.24), erythrocyte sedimentation rate (adjusted OR per ...

Plos Genetics, 2013

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheum... more Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (DDAS) in the etanercept subset of patients (P = 8610 28 ), but not in the infliximab or adalimumab subsets (P.0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 39 UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1610 211 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better DDAS in a subset of RA patients with gene expression data (n = 31, etanercepttreated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA Abstract patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8).

PLoS ONE, 2014

Translational medicine is becoming increasingly dependent upon data generated from health care, c... more Translational medicine is becoming increasingly dependent upon data generated from health care, clinical research, and molecular investigations. This increasing rate of production and diversity in data has brought about several challenges, including the need to integrate fragmented databases, enable secondary use of patient clinical data from health care in clinical research, and to create information systems that clinicians and biomedical researchers can readily use. Our case study effectively integrates requirements from the clinical and biomedical researcher perspectives in a translational medicine setting. Our three principal achievements are (a) a design of a user-friendly web-based system for management and integration of clinical and molecular databases, while adhering to proper de-identification and security measures; (b) providing a real-world test of the system functionalities using clinical cohorts; and (c) system integration with a clinical decision support system to demonstrate system interoperability. We engaged two active clinical cohorts, 747 psoriasis patients and 2001 rheumatoid arthritis patients, to demonstrate efficient query possibilities across the data sources, enable cohort stratification, extract variation in antibody patterns, study biomarker predictors of treatment response in RA patients, and to explore metabolic profiles of psoriasis patients. Finally, we demonstrated system interoperability by enabling integration with an established clinical decision support system in health care. To assure the usefulness and usability of the system, we followed two approaches. First, we created a graphical user interface supporting all user interactions. Secondly we carried out a system performance evaluation study where we measured the average response time in seconds for active users, http errors, and kilobits per second received and sent. The maximum response time was found to be 0.12 seconds; no server or client errors of any kind were detected. In conclusion, the system can readily be used by clinicians and biomedical researchers in a translational medicine setting.

Scandinavian Journal of Immunology, 2004

Mannan-binding lectin (MBL) is a pattern recognition receptor in the innate immune system. It rec... more Mannan-binding lectin (MBL) is a pattern recognition receptor in the innate immune system. It recognizes certain sugar residues arranged in a pattern that enables MBL to bind with sufficient strength. Such sugar patterns are common on the surface of many microorganisms, and MBL has therefore been considered to be an agent that can discriminate between self and nonself. There is, however, increasing evidence supporting that MBL, like many membrane-bound C-type lectin-like receptors, also helps to dispose of various outworn or abnormal body components. Most self-components are protected with sialic acid or galactose that disrupt the pattern of the sugars that MBL can bind, but MBL may be significantly involved in the elimination of self-components that have lost these protective terminal residues. The role of MBL in the clearance of invading pathogens has previously been thoroughly reviewed. Here, we review some findings that support the notion that MBL may contribute to noninflammatory removal of immune complexes and abnormal cells by the reticuloendothelial system. Defects in this clearance mechanism may cause an accumulation of potentially dangerous self-components, thereby increasing the likelihood of chronic inflammation and autoimmunity.

Scandinavian Journal of Immunology, 2004

Mannose-binding lectin (MBL) is an important component of innate immunity that can bind to certai... more Mannose-binding lectin (MBL) is an important component of innate immunity that can bind to certain sugar residues on the surface of many types of pathogenic micro-organisms. On binding, MBL generates opsonic activity mainly through activation of the complement system. Genetically determined MBL deficiency is very common and can be associated with increased susceptibility to a variety of infections, especially in children and immunosuppressed individuals. The potential benefits of MBL reconstitution therapy therefore need to be evaluated. We have carried out a phase I safety and pharmacokinetic study on 20 MBL-deficient healthy adult volunteers. The MBL was prepared from plasma of nonremunerated, voluntary Danish donors tested and found negative for hepatitis B surface antigen, antibodies to human immunodeficiency virus (HIV) and hepatitis C virus. Each volunteer received a total of 18 mg of MBL in three 6 mg doses given intravenously, once weekly over a period of 3 weeks.

Journal of Experimental Medicine, 2005

Inflammation can predispose to myocardial infarction (MI), and mannan binding lectin (MBL) promot... more Inflammation can predispose to myocardial infarction (MI), and mannan binding lectin (MBL) promotes phagocytic clearance of inflammatory agents, but the predictive value of MBL levels for MI is not known. MBL was analyzed in subgroups of the population-based Reykjavik study, a cohort of 19,381 participants recruited from 1967. MBL levels were very stable over time (self correlation: 0.86). In a cross-sectional group from the original cohort ( n ϭ 987), high MBL ( Ͼ 1,000 g/L) was associated with a greatly lowered odds ratio for MI (0.64, P Ͻ 0.001). To verify this finding, a nested case control sample ( n ϭ 1,309) was randomly selected from the cohort. High MBL at recruitment was also associated with decreased MI risk in this follow-up group, but to a lesser extent and not significant for the whole group, smokers, or hypertensive individuals. However, high MBL was as in the crosssectional group, associated with greatly decreased MI risk in diabetic (P ϭ 0.02) or hypercholesterolemic individuals (P ϭ 0.004). This also applied to raised erythrocyte sedimentation rate (P ϭ 0.007). Diabetic patients with high MBL did not have a higher MI risk than nondiabetic individuals. Our findings indicate that high MBL may predict decreased likelihood of MI, particularly in diabetics, and are consistent with the possibility that MBL may promote clearance of atherogenic agents.

Clinical Infectious Diseases, 2008

Previous studies have shown associations between low mannose-binding lectin (MBL) level or varian... more Previous studies have shown associations between low mannose-binding lectin (MBL) level or variant MBL2 genotype and sepsis susceptibility. However, MBL deficiency has not been rigorously defined, and associations with sepsis outcomes have not been subjected to multivariable analysis. We reanalyzed MBL results in a large cohort with use of individual data from 4 studies involving a total of 1642 healthy control subjects and systematically defined a reliable deficiency cutoff. Subsequently, data were reassessed to extend previous MBL and sepsis associations, with adjustment for known outcome predictors. We reanalyzed individual data from 675 patients from 5 adult studies and 1 pediatric study of MBL and severe bacterial infection. XA/O and O/O MBL2 genotypes had the lowest median MBL concentrations. Receiver operating characteristic analysis revealed that an MBL cutoff value of 0.5 microg/mL was a reliable predictor of low-producing MBL2 genotypes (sensitivity, 82%; specificity, 82%; negative predictive value, 98%). MBL deficiency was associated with increased likelihood of death among patients with severe bacterial infection (odds ratio, 2.11; 95% confidence interval, 1.30-3.43). In intensive care unit-based studies, there was a trend toward increased risk of death among MBL-deficient patients (odds ratio, 1.58; 95% confidence interval, 0.90-2.77) after adjustment for Acute Physiology and Chronic Health Enquiry II score. The risk of death was increased among MBL-deficient patients with Streptococcus pneumoniae infection (odds ratio, 5.62; 95% confidence interval, 1.27-24.92) after adjustment for bacteremia, comorbidities, and age. We defined a serum level for MBL deficiency that can be used with confidence in future studies of MBL disease associations. The risk of death was increased among MBL-deficient patients with severe pneumococcal infection, highlighting the pathogenic significance of this innate immune defence protein.

Clinical & Experimental Immunology, 2007

Deficiency of both mannan-binding lectin (MBL) and complement components C4 and C2 has been assoc... more Deficiency of both mannan-binding lectin (MBL) and complement components C4 and C2 has been associated with increased risk of systemic lupus erythematosus (SLE). MBL can activate the complement system either through C4 and C2 or directly through C3. Circulating immune complexes (CICs) are believed to play a pathogenic role in SLE and MBL has been shown to bind certain forms of immunoglobulins, including IgM, IgG and IgA. Thus, MBL might promote CIC clearance. In order to evaluate this, six individuals with non-functional classical pathway due to the rare homozygous C2 deficiency were chosen, as the classical pathway is known to have a fundamental role in CIC clearance. Four of the six C2-deficient individuals had SLE, two of whom also had MBL deficiency. MBL serum levels and genotypes were compared with the serum levels of CICs, as measured by their content of kappa, lambda, IgM, IgA, IgG and C3 opsonization. The C2-deficient individuals had higher serum levels of CICs than 16 healthy controls (P < 0·0001). Furthermore, an inverse association was observed between MBL and CIC levels in the C2-deficient individuals, which was strongest for IgM-CICs (r = -0·84, P = 0·037). Moreover, C3 opsonization of the CICs correlated positively with MBL levels in the C2-deficient individuals (r = 0·89, P = 0·017). In conclusion, individuals with C2 deficiency have increased levels of CICs and MBL may facilitate their clearance. Defective CIC clearance might partly explain the increased risk of SLE associated with low MBL.

BMC Musculoskeletal Disorders, 2013

Background: To investigate hand bone loss (HBL) measured by digital X-ray radiogrammetry (DXR) in... more Background: To investigate hand bone loss (HBL) measured by digital X-ray radiogrammetry (DXR) in patients with early rheumatoid arthritis (RA) receiving different treatment regimens, and to evaluate if DXR change rates during the first 12 months correlate with radiological damage after 24 months.

Annals of the Rheumatic Diseases, 2015

No Is the first author applying for a travel bursary or an award for undergraduate medical studen... more No Is the first author applying for a travel bursary or an award for undergraduate medical students?: Yes -Travel bursary Please confirm that you will apply for the travel bursary on the EULAR website www.eular.org: Yes Background: In our previous study (1) from the Swedish Farmacotherapy (SWEFOT) trial (2), we showed that a change of multi-biomarker disease activity (ΔMBDA) score (3) in methotrexate incomplete responders (MTX-IR) was predictive for subsequent response to non-biological triple therapy (TT; a combination of MTX with sulfasalazine and hydroxychloroquine) or to anti-tumour necrosis factor (anti-TNF) therapy. Objectives: To evaluate further how ΔMBDA score could be used to predict optimal choice of second-line treatment, by investigating different cut-offs and by comparing this to using the C-reactive protein (CRP) for prediction. Methods: 157 MTX-IR patients from the SWEFOT trial with complete data were grouped into those with and without big ΔMBDA (big decrease >22 and non-big decrease ≤22 respectively from baseline to Month 3) based on highest quartile. The change of CRP (ΔCRP) was studied in parallel using a cut-off based on the highest quartile (>28 & ≤28). Analysis was done by last observation carried forward. The proportion of clinical responders (DAS28 ≤3.2) across ΔMBDA groups between the two therapy arms was assessed by Breslow-Day test. Results: Among patients with ΔMBDA>22, 76% responded to TT and 47% to anti-TNF, while among the others more responded to anti-TNF (55% vs 38%; cross-comparison for all 4 groups p=0.016; figure 1). When based on ΔCRP responses were 50% and 39% versus 45% and 56% (p=0.226). Image/graph:

The Journal of Rheumatology

To determine whether low mannose binding lectin (MBL) is associated with poor prognosis in rheuma... more To determine whether low mannose binding lectin (MBL) is associated with poor prognosis in rheumatoid arthritis (RA) and whether patients with RA have increased frequency of MBL deficiency. Patients with recent onset symmetric polyarthritis (&lt; 1 year, median 3 mo) were recruited if they had not been treated longer than 2 weeks with disease modifying drugs. They were reevaluated after 6 months and their disease activity and progression were correlated with their MBL concentration, rheumatoid factor (RF) isotypes, and C-reactive protein (CRP). Sixty-three female patients with advanced RA were also analyzed. Sixty-five patients with early arthritis fulfilled American College of Rheumatology criteria for RA and 52 were followed for 6 months or longer. Low MBL was associated with raised RF, IgA RF in particular (p = 0.02). and also with a combined elevation of IgM and IgA RF (p = 0.035). Patients with low MBL (lowest 25th percentile) showed less improvement after 6 months of treatment than patients in the highest MBL quartile. This applied to the Thompson joint score (p = 0.03) and grip strength (p = 0.004). Low MBL was also significantly associated with radiological joint erosions at recruitment and at 6 month followup (p = 0.039); and the group with advanced RA also showed a significant association between low MBL concentration and radiological damage (p = 0.036). However. neither patient group had increased frequency of MBL deficiency compared to healthy controls. Low MBL predicts poor prognosis in patients with early RA.

Arthritis Research & Therapy, 2015

Introduction: Receptor activator of nuclear factor kappa B ligand (RANKL) is a key regulator of b... more Introduction: Receptor activator of nuclear factor kappa B ligand (RANKL) is a key regulator of bone metabolism. Anti-citrullinated protein antibodies (ACPA) have been suggested to cause bone destruction by osteoclast activation. We investigated the relationship between RANKL and ACPA in patients with early untreated rheumatoid arthritis (RA). Methods: Patients with newly diagnosed untreated RA (n = 183) were analyzed at baseline and 3 months after initiating methotrexate (MTX) treatment. Serum RANKL (total RANKL), ACPA (anti-CCP2) and ACPA specificities (anti-citrullinated (cit)-vimentin, anti-cit-enolase and anti-cit-fibrinogen) were determined by enzyme-linked immunosorbent assay (ELISA). Synovial RANKL expression was evaluated by immunohistochemistry in a small group of patients (n = 15). The relationship between anti-cit-vim antibodies and bone destruction was further validated in 1116 RA patients included in the EIRA cohort. Pearson's chi-square test, Wilcoxon rank sum test, Wilcoxon signed rank test and linear regression models were used.

BMC Musculoskeletal Disorders

Arthritis & Rheumatology, 2015

Objective Rheumatoid arthritis (RA) clinical trials often exclude patients with low C-reactive pr... more Objective Rheumatoid arthritis (RA) clinical trials often exclude patients with low C-reactive protein (CRP), slowing trial enrollment. We evaluated whether RA patients with a high multi-biomarker disease activity (MBDA) score (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;44) among those with low CRP (≤10 mg/L) could complement patients with CRP &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;10mg/L to enhance patient recruitment without affecting clinical trial outcomes. Methods We evaluated patients from the Swedish pharmacotherapy (SWEFOT) trial, which had no CRP selection criteria. Clinical outcomes were assessed after 3 months of methotrexate (MTX) monotherapy for MTX-naïve patients (N=220) and after add-on therapy from Months 3 to 12 for MTX-inadequate responder (IR) patients (N=127). Radiographic outcomes were assessed at 1 year for all patients. Within each cohort, outcomes were compared between patients with CRP ≤10 mg/L and MBDA score &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;44 at the start of the respective treatment interval versus those with CRP &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;10 mg/L. Results Patients with baseline CRP ≤10 mg/L and MBDA score &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;44 at baseline had comparable clinical and radiographic outcomes to those for patients with CRP&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;10 mg/L. This broadened definition of inclusion criteria identified an additional 24% MTX-naïve and 47% MTX-IR patients. Conclusion Patient recruitment of RA clinical trials may be substantially enhanced by using &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;CRP &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;10 mg/L and/or MBDA score &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;44&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; as an inclusion criterion, without diminishing clinical or radiographic outcomes. This article is protected by copyright. All rights reserved.

The Journal of rheumatology, 2007

Mannan-binding lectin (MBL) is present in serum and synovial fluid; its levels vary widely, and t... more Mannan-binding lectin (MBL) is present in serum and synovial fluid; its levels vary widely, and the variations are strongly associated with polymorphisms in the MBL2 gene. Studies have compared MBL in patients with rheumatoid arthritis (RA) and in unrelated controls, but the findings have been contradictory. In the first family-based study, we compared MBL levels in patients with RA to population controls and also to their nonaffected first-degree relatives, who may be regarded as optimal controls because of less genetic variation. Serum levels of MBL and rheumatoid factor were analyzed in 210 patients with RA and 406 of their first-degree relatives from 74 extended families. Population controls for MBL levels were 330 randomly selected adult Icelanders. Patients with RA had higher MBL levels in serum (median 1553 microg/l) than their first-degree relatives (1073 microg/l; p = 0.003) and the unrelated controls (938 microg/l; p < 0.0001). No association was found between MBL and r...

Annals of the Rheumatic Diseases, 2014

My abstract has been or will be presented at a scientific meeting during a 12 months period prior... more My abstract has been or will be presented at a scientific meeting during a 12 months period prior to EULAR 2014: No Is the first author applying for a travel bursary?: Yes Is the first author of this abstract an undergraduate medical student?: No Background: For patients with early RA (eRA), methotrexate (MTX) is recommended as first-line treatment and in non-responders both the addition of conventional non-biological disease modifying anti-rheumatic drug therapy (triple DMARD therapy) and of biological (anti-TNF) therapy are supported by data. Identification of patients with a higher likelihood of responding to one or the other of these options would lead to more personalised medicine and an increased effectiveness of therapy. Objectives: To evaluate the change in the multi-biomarker disease activity (MBDA) score during MTX therapy as a predictor of response to subsequent triple versus biological therapy. Methods: Patients with eRA and DAS28>3.2 entered the SWEFOT clinical trial and received MTX monotherapy for 3 months, at which time clinical non-responders (DAS28>3.2) were randomised to receive non-biological triple DMARD therapy (arm A) or anti-TNF (infliximab) therapy with MTX (arm B). For this study, 129 non-responders at month 3 (n=62 from arm A and n=67 from arm B) were analysed by MBDA score at baseline (BL) and month 3. The assessment of changes in the MBDA score (∆MBDA) from BL to month 3 as a predictor for response to triple or anti-TNF therapy at year 1 was done by defining small (≤6), moderate (7-20) and large (>20) decreases by tertiles. Small and moderate decreases were combined together (small/moderate) and compared versus large decreases for arms A and B. The proportion of patients in arm A versus arm B with response at year 1 was evaluated by the odds ratio (OR) for patients with small/moderate versus large decreases. Homogeneity of the odds ratios between the two cohorts was assessed by Breslow-Day test. Results: The mean (median) decreases in MBDA score from BL to month 3 for year 1 responders (n=66) and non-responders (n=63) were 12.9 (10) and 10.8 (9), respectively (p=0.431), and month 3 mean (median) MBDA scores were 47.1 (45) and 50.3 (47), respectively (p=0.336). Patients who had small/moderate decreases in MBDA score during MTX monotherapy, 43% responded to subsequent triple therapy and 57% responded to anti-TNF (OR=0.577). In contrast, among patients with a large decreases in MBDA score from BL to month 3, 67% responded to subsequent triple therapy and 37% to anti-TNF treatment (OR=3.33). Thus the relative treatment effect of arm A versus arm B differed according to the degree of change in the MBDA score from BL to 3 months (p=0.032). Conclusions: Among patients with eRA who did not achieve low disease activity on MTX monotherapy, those patients with the greatest decreases in MDBA score were more likely to respond to triple therapy whereas patients with lesser decreases of the MBDA score were more likely to respond to anti-TNF therapy. These findings suggest that in MTX non-responders the changes in MBDA score may help guide subsequent therapy.

Annals of the Rheumatic Diseases, 2013

My abstract has been or will be presented at a scientific meeting during a 12 months period prior... more My abstract has been or will be presented at a scientific meeting during a 12 months period prior to EULAR 2013: No Background: In early rheumatoid arthritis (eRA), predictors of clinical response and of radiographic progression would be very useful for optimal targeting of available therapies. Individual biomarkers as well as combinations of biomarkers, such as the MBDA test, can be considered for these purposes. In the SWEFOT study, patients with eRA (symptom duration < 1 year) were started on methotrexate (MTX); at 3 months, responders (DAS28 < 3.2) continued MTX monotherapy and were followed in regular care, whereas non-responders were randomized to receive either triple DMARD therapy or the addition of infliximab. Objectives: To study the MBDA score and the levels of the 12 individual biomarkers at baseline (BL) as predictors of clinical response at 3 months and radiographic progression at 1 year in eRA. Methods: Analyses were performed for patients from the SWEFOT trial who had BL and 3-month assessments of DAS28 (based on ESR), and the MBDA score and the 12 individual biomarkers at BL; and for a subset of patients who also had radiographs at BL and 1 year time-points (assessed using the Van der Heijde modified Sharp score [SvdH]). Patients with DAS28 > 3.2 at 3 months were considered clinical non-responders, and patients with a change in SvdH > 0 as radiographic progressors ("radiological non-responders"). Group comparisons of biomarkers and MBDA scores were performed by Mann-Whitney U test.

Annals of the Rheumatic Diseases, 2013

ABSTRACT Background A multi-biomarker disease activity (MBDA) score has been shown to reflect dis... more ABSTRACT Background A multi-biomarker disease activity (MBDA) score has been shown to reflect disease activity at the molecular level in patients with rheumatoid arthritis (RA). The use of MBDA or its components to predict methotrexate (MTX) response has yet to be determined. Objectives To characterize the MBDA score in RA patients treated with MTX and its ability to predict treatment response. Methods The Epidemiological Investigation of Rheumatoid Arthritis (EIRA) cohort includes patients diagnosed with RA and symptom disease duration &lt; 1 year. This study was conducted on a subgroup of 186 EIRA subjects from the Karolinska University Hospital who were naïve to disease modifying anti-rheumatic drug and were started on MTX monotherapy at study entry. Clinical disease activity and serum biomarker concentrations were measured at baseline (BL) and 3 months. Concentrations of VCAM-1, EGF, VEGF-A, IL-6, TNF-RI, YKL-40, MMP-1, MMP-3, leptin, resistin, SAA and CRP were integrated to derive a MBDA score (range 1-100) using a previously validated algorithm [1]. Anti-CCP was measured by ELISA at BL. Spearman’s rank correlation was used to determine correlations between the clinical disease activity scores and the individual biomarker concentrations or the MBDA Score. Response to treatment at 3 months was assessed using the EULAR criteria. MBDA stratification of EULAR good- and moderate- responders vs. non-responders was evaluated with area under receiver operating characteristic curves (AUROCs). No correction for multiple testing was done when analyzing the single biomarkers. Results Patient baseline characteristics (n=186) were similar to those of the original large EIRA cohort with median (IQR) age 52(42-59), 72% female, 67% anti-CCP positive. At baseline the median (IQR) DAS28-ESR was 5.7 (5.0-6.2) and MBDA score was 58 (47-66). 29% of the patients were good EULAR responders, 37% moderate and 34% non-responders. When analyzing patient baseline characteristics anti-CCP negativity and male sex were associated with EULAR response to MTX treatment at 3 months, whereas BL MBDA score and BL concentrations of individual biomarkers were not. The median changes in MBDA score from BL to 3 months were (-16) for good responders, (-12) for moderate and (+2) for non-responders. Changes in MBDA scores and in concentrations of single biomarkers differentiated responders from non-responders at 3 months (MBDA Score: AUROC = 0.79, p-value &lt;0.001). The changes in MBDA score and in concentration of biomarkers were significantly correlated with changes in DAS28-ESR (MBDA Score: r = 0.60, p &lt;0.001). A sub-analysis to compare the behavior of MBDA score in patients with different anti-CCP status showed no significant difference in the AUROC for the changes in MBDA score when discriminating responders from non-responders (AUROC=0.76 vs. 0.84 for ACPA (+) vs. (-) group; p&gt;0.05). Conclusions MBDA and its biomarker components can track and differentiate the clinical response in early RA patients treated with MTX, regardless of anti-CCP status. References Disclosure of Interest W. Li Shareholder of: Crescendo Bioscience, Employee of: Crescendo Bioscience, A. Hensvold : None Declared, S. Saevarsdottir: None Declared, N. Defranoux Shareholder of: Crescendo Bioscience, Employee of: Crescendo Bioscience, L. Klareskog: None Declared, A. Catrina : None Declared

Annals of the rheumatic diseases, Jan 8, 2014

Prediction of radiographic progression (RP) in early rheumatoid arthritis (eRA) would be very use... more Prediction of radiographic progression (RP) in early rheumatoid arthritis (eRA) would be very useful for optimal choice among available therapies. We evaluated a multi-biomarker disease activity (MBDA) score, based on 12 serum biomarkers as a baseline predictor for 1-year RP in eRA. Baseline disease activity score based on erythrocyte sedimentation rate (DAS28-ESR), disease activity score based on C-reactive protein (DAS28-CRP), CRP, MBDA scores and DAS28-ESR at 3 months were analysed for 235 patients with eRA from the Swedish Farmacotherapy (SWEFOT) clinical trial. RP was defined as an increase in the Van der Heijde-modified Sharp score by more than five points over 1 year. Associations between baseline disease activity measures, the MBDA score, and 1-year RP were evaluated using univariate and multivariate logistic regression, adjusted for potential confounders. Among 235 patients with eRA, 5 had low and 29 moderate MBDA scores at baseline. None of the former and only one of the l...

Annals of the rheumatic diseases, Jan 30, 2014

To determine the relationship between changes in antibody levels towards citrullinated peptides d... more To determine the relationship between changes in antibody levels towards citrullinated peptides derived from different candidate autoantigens and therapeutic outcome in early rheumatoid arthritis (RA). Baseline and 3-month serum samples from 316 patients with early RA enrolled in the Swedish Farmacotherapy (SWEFOT) trial were analysed for antibodies against cyclic citrullinated peptides (CCP) and citrullinated peptides derived from vimentin (cVim), fibrinogen (cFib) and α-enolase (CEP-1). At 3-month follow-up, methotrexate monotherapy-inadequate responders were randomised to add-on therapy with sulfasalazine and hydroxychloroquine or infliximab. In these patients, anticitrullinated peptide antibodies (ACPA) were also assessed at 12 and 24 months. The proportion of antibody-positive patients and relative changes in antibody levels were compared across ACPA specificities and related to therapeutic response and radiographic progression. During the 2-year follow-up, the proportion of pa...

Annals of the rheumatic diseases, Jan 4, 2014

To study clinical predictors for radiographic progression after 1 year in an early rheumatoid art... more To study clinical predictors for radiographic progression after 1 year in an early rheumatoid arthritis (RA) trial. In the SWEFOT trial population, disease modifying antirheumatic drug (DMARD) naïve RA patients started methotrexate; 3-month responders (DAS28 <3.2) continued (n=147), while non-responders were randomised to addition of sulfasalazine+hydroxychloroquine (n=130) or infliximab (n=128). X-rays were scored by the Sharp-van der Hejde score (SHS) method and radiographic progression was defined as a ≥5 increase after 1 year. Potential baseline predictors of radiographic progression were tested using multivariable logistic regression, adjusted for potential confounders. 79 of 311 patients with available radiographs at baseline and follow-up had radiographic progression. The following baseline parameters were independent predictors of radiographic progression at 1 year: baseline erosions (adjusted OR=2.29, 95% CI 1.24 to 4.24), erythrocyte sedimentation rate (adjusted OR per ...

Plos Genetics, 2013

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheum... more Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (DDAS) in the etanercept subset of patients (P = 8610 28 ), but not in the infliximab or adalimumab subsets (P.0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 39 UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1610 211 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better DDAS in a subset of RA patients with gene expression data (n = 31, etanercepttreated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA Abstract patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8).

PLoS ONE, 2014

Translational medicine is becoming increasingly dependent upon data generated from health care, c... more Translational medicine is becoming increasingly dependent upon data generated from health care, clinical research, and molecular investigations. This increasing rate of production and diversity in data has brought about several challenges, including the need to integrate fragmented databases, enable secondary use of patient clinical data from health care in clinical research, and to create information systems that clinicians and biomedical researchers can readily use. Our case study effectively integrates requirements from the clinical and biomedical researcher perspectives in a translational medicine setting. Our three principal achievements are (a) a design of a user-friendly web-based system for management and integration of clinical and molecular databases, while adhering to proper de-identification and security measures; (b) providing a real-world test of the system functionalities using clinical cohorts; and (c) system integration with a clinical decision support system to demonstrate system interoperability. We engaged two active clinical cohorts, 747 psoriasis patients and 2001 rheumatoid arthritis patients, to demonstrate efficient query possibilities across the data sources, enable cohort stratification, extract variation in antibody patterns, study biomarker predictors of treatment response in RA patients, and to explore metabolic profiles of psoriasis patients. Finally, we demonstrated system interoperability by enabling integration with an established clinical decision support system in health care. To assure the usefulness and usability of the system, we followed two approaches. First, we created a graphical user interface supporting all user interactions. Secondly we carried out a system performance evaluation study where we measured the average response time in seconds for active users, http errors, and kilobits per second received and sent. The maximum response time was found to be 0.12 seconds; no server or client errors of any kind were detected. In conclusion, the system can readily be used by clinicians and biomedical researchers in a translational medicine setting.

Scandinavian Journal of Immunology, 2004

Mannan-binding lectin (MBL) is a pattern recognition receptor in the innate immune system. It rec... more Mannan-binding lectin (MBL) is a pattern recognition receptor in the innate immune system. It recognizes certain sugar residues arranged in a pattern that enables MBL to bind with sufficient strength. Such sugar patterns are common on the surface of many microorganisms, and MBL has therefore been considered to be an agent that can discriminate between self and nonself. There is, however, increasing evidence supporting that MBL, like many membrane-bound C-type lectin-like receptors, also helps to dispose of various outworn or abnormal body components. Most self-components are protected with sialic acid or galactose that disrupt the pattern of the sugars that MBL can bind, but MBL may be significantly involved in the elimination of self-components that have lost these protective terminal residues. The role of MBL in the clearance of invading pathogens has previously been thoroughly reviewed. Here, we review some findings that support the notion that MBL may contribute to noninflammatory removal of immune complexes and abnormal cells by the reticuloendothelial system. Defects in this clearance mechanism may cause an accumulation of potentially dangerous self-components, thereby increasing the likelihood of chronic inflammation and autoimmunity.

Scandinavian Journal of Immunology, 2004

Mannose-binding lectin (MBL) is an important component of innate immunity that can bind to certai... more Mannose-binding lectin (MBL) is an important component of innate immunity that can bind to certain sugar residues on the surface of many types of pathogenic micro-organisms. On binding, MBL generates opsonic activity mainly through activation of the complement system. Genetically determined MBL deficiency is very common and can be associated with increased susceptibility to a variety of infections, especially in children and immunosuppressed individuals. The potential benefits of MBL reconstitution therapy therefore need to be evaluated. We have carried out a phase I safety and pharmacokinetic study on 20 MBL-deficient healthy adult volunteers. The MBL was prepared from plasma of nonremunerated, voluntary Danish donors tested and found negative for hepatitis B surface antigen, antibodies to human immunodeficiency virus (HIV) and hepatitis C virus. Each volunteer received a total of 18 mg of MBL in three 6 mg doses given intravenously, once weekly over a period of 3 weeks.

Journal of Experimental Medicine, 2005

Inflammation can predispose to myocardial infarction (MI), and mannan binding lectin (MBL) promot... more Inflammation can predispose to myocardial infarction (MI), and mannan binding lectin (MBL) promotes phagocytic clearance of inflammatory agents, but the predictive value of MBL levels for MI is not known. MBL was analyzed in subgroups of the population-based Reykjavik study, a cohort of 19,381 participants recruited from 1967. MBL levels were very stable over time (self correlation: 0.86). In a cross-sectional group from the original cohort ( n ϭ 987), high MBL ( Ͼ 1,000 g/L) was associated with a greatly lowered odds ratio for MI (0.64, P Ͻ 0.001). To verify this finding, a nested case control sample ( n ϭ 1,309) was randomly selected from the cohort. High MBL at recruitment was also associated with decreased MI risk in this follow-up group, but to a lesser extent and not significant for the whole group, smokers, or hypertensive individuals. However, high MBL was as in the crosssectional group, associated with greatly decreased MI risk in diabetic (P ϭ 0.02) or hypercholesterolemic individuals (P ϭ 0.004). This also applied to raised erythrocyte sedimentation rate (P ϭ 0.007). Diabetic patients with high MBL did not have a higher MI risk than nondiabetic individuals. Our findings indicate that high MBL may predict decreased likelihood of MI, particularly in diabetics, and are consistent with the possibility that MBL may promote clearance of atherogenic agents.

Clinical Infectious Diseases, 2008

Previous studies have shown associations between low mannose-binding lectin (MBL) level or varian... more Previous studies have shown associations between low mannose-binding lectin (MBL) level or variant MBL2 genotype and sepsis susceptibility. However, MBL deficiency has not been rigorously defined, and associations with sepsis outcomes have not been subjected to multivariable analysis. We reanalyzed MBL results in a large cohort with use of individual data from 4 studies involving a total of 1642 healthy control subjects and systematically defined a reliable deficiency cutoff. Subsequently, data were reassessed to extend previous MBL and sepsis associations, with adjustment for known outcome predictors. We reanalyzed individual data from 675 patients from 5 adult studies and 1 pediatric study of MBL and severe bacterial infection. XA/O and O/O MBL2 genotypes had the lowest median MBL concentrations. Receiver operating characteristic analysis revealed that an MBL cutoff value of 0.5 microg/mL was a reliable predictor of low-producing MBL2 genotypes (sensitivity, 82%; specificity, 82%; negative predictive value, 98%). MBL deficiency was associated with increased likelihood of death among patients with severe bacterial infection (odds ratio, 2.11; 95% confidence interval, 1.30-3.43). In intensive care unit-based studies, there was a trend toward increased risk of death among MBL-deficient patients (odds ratio, 1.58; 95% confidence interval, 0.90-2.77) after adjustment for Acute Physiology and Chronic Health Enquiry II score. The risk of death was increased among MBL-deficient patients with Streptococcus pneumoniae infection (odds ratio, 5.62; 95% confidence interval, 1.27-24.92) after adjustment for bacteremia, comorbidities, and age. We defined a serum level for MBL deficiency that can be used with confidence in future studies of MBL disease associations. The risk of death was increased among MBL-deficient patients with severe pneumococcal infection, highlighting the pathogenic significance of this innate immune defence protein.

Clinical & Experimental Immunology, 2007

Deficiency of both mannan-binding lectin (MBL) and complement components C4 and C2 has been assoc... more Deficiency of both mannan-binding lectin (MBL) and complement components C4 and C2 has been associated with increased risk of systemic lupus erythematosus (SLE). MBL can activate the complement system either through C4 and C2 or directly through C3. Circulating immune complexes (CICs) are believed to play a pathogenic role in SLE and MBL has been shown to bind certain forms of immunoglobulins, including IgM, IgG and IgA. Thus, MBL might promote CIC clearance. In order to evaluate this, six individuals with non-functional classical pathway due to the rare homozygous C2 deficiency were chosen, as the classical pathway is known to have a fundamental role in CIC clearance. Four of the six C2-deficient individuals had SLE, two of whom also had MBL deficiency. MBL serum levels and genotypes were compared with the serum levels of CICs, as measured by their content of kappa, lambda, IgM, IgA, IgG and C3 opsonization. The C2-deficient individuals had higher serum levels of CICs than 16 healthy controls (P < 0·0001). Furthermore, an inverse association was observed between MBL and CIC levels in the C2-deficient individuals, which was strongest for IgM-CICs (r = -0·84, P = 0·037). Moreover, C3 opsonization of the CICs correlated positively with MBL levels in the C2-deficient individuals (r = 0·89, P = 0·017). In conclusion, individuals with C2 deficiency have increased levels of CICs and MBL may facilitate their clearance. Defective CIC clearance might partly explain the increased risk of SLE associated with low MBL.

BMC Musculoskeletal Disorders, 2013

Background: To investigate hand bone loss (HBL) measured by digital X-ray radiogrammetry (DXR) in... more Background: To investigate hand bone loss (HBL) measured by digital X-ray radiogrammetry (DXR) in patients with early rheumatoid arthritis (RA) receiving different treatment regimens, and to evaluate if DXR change rates during the first 12 months correlate with radiological damage after 24 months.