Maria Bokarewa

University of Gothenburg, Goeteborg, Västra Götaland, Sweden

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Publications (116)523.66 Total impact

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    ABSTRACT: Background: The identification of biomarkers that predict optimal and individual choices of treatment for patients with rheumatoid arthritis gains increasing attention. The purpose of this study was to investigate if the proto-oncogene survivin might aid in treatment decisions in early rheumatoid arthritis. Methods: Serum survivin levels were measured in 302 patients who completed the Swedish pharmacotherapy (SWEFOT) trial at baseline, 3, 12, and 24 months. Survivin levels > 0.45 ng/mL were considered positive. Based on the survivin status, core set outcomes measuring disease activity, functional disability, as well as global health and pain were evaluated after methotrexate (MTX) monotherapy at 3 months, and at 12 and 24 months of follow-up. Treatment of non-responders was randomly intensified with either a combination of disease-modifying antirheumatic drugs (triple therapy: MTX, sulfasalazine, and hydroxychloroquine) or by adding antibodies against tumor necrosis factor (anti-TNF). Results: Antirheumatic treatment resulted in an overall decrease of serum survivin levels. Survivin-positive patients at baseline who initially responded to MTX had a higher risk of disease re-activation (OR 3.21 (95 % CI 1.12–9.24), P = 0.032) and failed to improve in their functional disability (P = 0.018) if having continued on MTX monotherapy compared to survivin-negative patients. Ever-smokers who were survivin-positive were less likely to respond to MTX than those who were survivin-negative (OR 1.91 (1.01–3.62), P = 0.045). In survivin-positive patients, triple therapy led to better improvements in disease activity than did MTX + anti-TNF. At 24 months, survivin-positive patients randomized to anti-TNF had a higher risk of active disease than those randomized to triple therapy (OR 3.15 (1.09–9.10), P = 0.037). Discussion: We demonstrate for the first time that survivin is a valuable serologic marker that can distinguish drug-specific clinical responses in early rheumatoid arthritis through the pragmatic clinical setting of the care-based SWEFOT trial. Although treatment response cannot solely be attributable to survivin status, per protocol sensitivity analyses confirmed the superior effect of triple therapy on survivin-positive patients. Conclusions: Survivin-positive patients have poor outcomes if treated with MTX monotherapy. A decrease of survivin levels during treatment is associated with better clinical responses. For survivin-positive patients who fail MTX, triple therapy is associated with better outcomes than anti-TNF therapy.
    BMC Medicine 09/2015; 13(1):247. DOI:10.1186/s12916-015-0485-2 · 7.25 Impact Factor
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    ABSTRACT: Osteoclasts are bone-resorbing cells that accumulate in the joints of patients with rheumatoid arthritis causing severe bone damage. Fms-like tyrosine kinase 3 ligand is enriched in the synovial fluid of patients with rheumatoid arthritis, and local exposure to Fms-like tyrosine kinase 3 ligand aggravates arthritis in mice. Because Fms-like tyrosine kinase 3 ligand has been suggested to facilitate osteoclast differentiation, we asked whether Fms-like tyrosine kinase 3 ligand affects bone remodeling in arthritis. The effect of Fms-like tyrosine kinase 3 signaling on osteoclast development was studied by immunohistochemistry in methylated bovine serum albumin-induced arthritis using mice that lack the gene for Flt3l (Flt3L(-/-)) and by an in vitro assay. Bone and joint changes were studied morphologically and by microcomputer tomography. We found that Flt3L(-/-) mice had increased accumulations of osteoclasts in the periarticular area of the arthritic joint. This triggered bone destruction and trabecular bone loss. The increased number of osteoclasts in Flt3L(-/-) mice may be a consequence of insufficient expression of interferon regulatory factor 8. Treatment of Flt3L(-/-) mice with Fms-like tyrosine kinase 3 ligand increased expression of interferon regulatory factor 8, reduced the number of osteoclasts in arthritic mice, and promoted trabecular bone formation. Finally, the reduced number of regulatory T cells in the bone marrow of Flt3L(-/-) mice could further contribute to the increased osteoclastogenesis by reducing the ratio of regulatory T cells to T helper 17 cells. This study shows that Fms-like tyrosine kinase 3 ligand may serve as a negative regulator of osteoclast development by promoting transcription of interferon regulatory factor 8 and sustaining a balance between protective regulatory T cells and pathogenic T helper 17 cells in the pathogenesis of arthritis.
    Journal of leukocyte biology 09/2015; DOI:10.1189/jlb.3HI1114-572RR · 4.29 Impact Factor
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    ABSTRACT: Follicular T helper (Tfh) cells are recognized by the expression of CXCR5 and the transcriptional regulator Bcl-6. Tfh cells control B cell maturation and antibody production, and if deregulated, may lead to autoimmunity. Here, we study the role of the proto-oncogene survivin in the formation of Tfh cells. We show that blood Tfh cells of patients with the autoimmune condition rheumatoid arthritis, have intracellular expression of survivin. Survivin was co-localized with Bcl-6 in the nuclei of CXCR5+CD4 lymphocytes and was immunoprecipitated with the Bcl-6 responsive element of the target genes. Inhibition of survivin in arthritic mice led to the reduction of CXCR5+ Tfh cells and to low production of autoantibodies. Exposure to survivin activated STAT3 and induced enrichment of PD-1+Bcl-6+ subset within Tfh cells. Collectively, our study demonstrates that survivin belongs to the Tfh cell phenotype and ensures their optimal function by regulating transcriptional activity of Bcl-6.
    Oncotarget 09/2015; 6(24):20043-20057. DOI:10.18632/oncotarget.4994 · 6.36 Impact Factor
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    ABSTRACT: Alternative splicing distinguishes normal and pathologic cells. High levels of oncoprotein survivin recognise patients with severe rheumatoid arthritis (RA). Here, we assess clinical relevance of alternative splicing of survivin in leukocytes of peripheral blood (PBMC) and bone marrow (BM) in RA patients. Transcription of survivin wild-type (survivin-WT), survivin-2B and survivin-ΔEx3 was measured in 67 randomly selected RA patients and in 23 patients before and after B cell depletion with rituximab. Analysis was done in relation to disease activity, anti-rheumatic treatment and serum levels of rheumatoid factor (RF) and survivin. Survivin-WT was the dominant splice variant equally expressed in T and B cells, while survivin-2B and survivin-ΔEx3 were higher in B cells. High disease activity (DAS28>5.1) was associated with an excess of survivin-WT and low ratios between survivin-2B/WT (p=0.035) and survivin-ΔEx3/WT in PBMC. Depletion of B cells by rituximab caused a decrease in survivin-WT (p=0.005) in PBMC, increasing the ratio between survivin-2B/WT (p=0.009) and survivin-ΔEx3/WT (p=0.001) in BM. This increase in survivin-2B/WT was associated with reduction in CD19+ BM cells (r=0.929, p=0.007), RF (IgM, r=0.857, p=0.024; IgA, r=0.739, p=0.021), and DAS28 (0.636, p=0.054). The increase in survivin-ΔEx3 in BM was associated with a reduction of CD19+ BM cells (r=0.714, p=0.058) and DAS28 (r=0.648, p=0.049), while survivin-ΔEx3/WT was associated with RF (IgG, r=0.882, p=0.016). This study demonstrates that the suppressed diversity of survivin splicing in leukocytes may attribute to adverse self-recognition in RA. Depletion of autoantibody producing B cells improves the balance of survivin splicing.
    Arthritis research & therapy 07/2015; 17(1):175. DOI:10.1186/s13075-015-0689-z · 3.75 Impact Factor
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    ABSTRACT: T helper cells producing IL-17A and IL-17F cytokines (Th17 cells) are considered the source of autoimmunity in rheumatoid arthritis (RA). In this study we characterized specific pathogenic features of Th17 cells in RA.Using nano-string technology we analyzed transcription of 419 genes in the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of 14 RA patients and 6 healthy controls and identified 109 genes discriminating Th17 cells of RA patients from the controls. Th17 cells of RA patients had aggressive pathogenic profile and in addition to signature cytokines IL-17, IL-23, and IL-21, and transcriptional regulators RORγt and JAK2, they produced high levels of IL-23R, CCL20, GM-CSF and transcription factor Tbet required for synovial homing. We showed that Th17 cells are enriched with Helios producing, Foxp3 and IL2RA deficient cells indicating altered regulatory profile. The follicular T-helper (Tfh) cells presented functional profile of adaptor molecules, transcriptional regulator Bcl-6 and B-cell activating cytokines IL-21, IL-31 and LIF. We observed that anti-TNF treatment had limited effect on the transcription signature of Th17 cells. Patients in remission retained the machinery of receptors (IL-23R and IL-1R1), pro-inflammatory cytokines (IL-17F, IL-23, IL-21 and TNF) and adaptor molecules (CXCR5 and CTLA-4), essential for efficient trans-differentiation and accumulation of Th17 cells.This study convincingly shows that the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of RA patients harbor pathogenic subsets of Th17 and Tfh cells, which may trans-differentiate from Tregs and contribute to perpetuation of the disease.
    Molecular Medicine 06/2015; DOI:10.2119/molmed.2015.00057 · 4.51 Impact Factor
  • Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):252.1-252. DOI:10.1136/annrheumdis-2015-eular.5864 · 10.38 Impact Factor
  • Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):427.2-427. DOI:10.1136/annrheumdis-2015-eular.3421 · 10.38 Impact Factor
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    ABSTRACT: Background Survivin is an oncological biomarker. In rheumatoid arthritis (RA), elevated serum survivin is common and has been used to predict disease onset and progressive joint damage. Objectives We investigated the predictive capacity of survivin in clinical disease activity and/or response to various antirheumatic treatments in patients with early RA. Methods Survivin levels from serum were measured using ELISA at baseline in 302 patients enrolled in the Swedish pharmacotherapy (SWEFOT) trial with follow-up at 3, 12 and 24 months. After methotrexate (MTX) monotherapy for 3 months, responders (DAS28≤3.2) remained on MTX, while non-responders were randomized to triple therapy (MTX+sulfasalazine+hydroxychloroquine) or anti-TNF (MTX+infliximab). Survivin levels >0.45 ng/mL were considered positive. Based on survivin status over 24 months, core-set outcomes (i.e. DAS28, HAQ, pain & global VAS) were evaluated at 3, 12, and 24 months. Results Over one-third of all patients (n=114) were survivin-positive at baseline. Survivin-positive ever-smokers (51/71 vs. 64/112, OR 1.91 [95% CI 1.01-3.62], p=0.045) and survivin-negative patients who converted to positive over 24 months (13/161 vs. 2/100, OR 4.39 [0.97, 19.88], p=0.037) responded seldom to MTX. At 3 months, survivin-positive patients who converted negative (n=11) had greater reductions in DAS28 (p=0.002), HAQ (p=0.011) and global VAS (p=0.025) vs. those who remained positive (n=28), which were maintained over 24 months. At 12 months, survivin-positive MTX-responders who continued monotherapy had a higher risk of disease re-activation on MTX compared to the survivin-negative patients (12/36 vs. 7/52, OR 3.21 [1.12-9.24], p=0.032) and showed no improvement in HAQ over 24 months. Survivin-positive MTX non-responders who converted to negative (n=32) or remained negative (n=83) had greater improvements from 3 to 12 months than those who converted to positive (n=13) (ΔDAS28>1.2, 63% & 60% vs. 31%, p=0.053, p=0.046, respectively). Among survivin-positive patients on triple therapy, converting to negative (n=19) yielded a lower DAS28 at 12 months (2.34 vs. 4.12, p=0.046) and a high frequency of DAS≤3.2 (86% vs. 37%, p=0.056) at 24 months vs. converting to positive (n=7). They also had lower pain (p=0.048) and global VAS (p=0.015) at 24 months compared to the same subgroup, which was not observed among anti-TNF – where no differences in core-set outcomes were observed between the survivin groups. Survivin-positive patients on anti-TNF had a higher risk to have active disease at 24 months compared to those on triple therapy (16/29 vs. 9/32, OR 3.15 [1.09-9.10], p=0.037). Conclusions Survivin-positive patients have worse 24-month outcomes than survivin-negative patients if treated with MTX monotherapy, but conversion to survivin-negative is associated with a good and stable response to MTX monotherapy. For survivin-positive patients with early RA who fail MTX, triple therapy is associated with a better likelihood for response than anti-TNF therapy. Disclosure of Interest A. Levitsky: None declared, M. Erlandsson: None declared, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, UCB, Consultant for: AbbVie, Biotest, BMS, Crescendo, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB, Vertex, M. Bokarewa: None declared
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):224.2-224. DOI:10.1136/annrheumdis-2015-eular.3151 · 10.38 Impact Factor
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    ABSTRACT: Survivin is a biomarker of cancer known for its anti-apoptotic and cell-cycle regulating properties. In the context of non-cancer pathology, high levels of survivin may be measured in blood and synovial fluid of patients with rheumatoid arthritis (RA) and associate with early joint damage and poor therapy response.The aim of the study was to investigate the value of survivin measurements in blood for diagnosis of RA in the frame of the Malaysian epidemiological investigation of rheumatoid arthritis (MyEIRA) study. The study enrolled RA patients from eight rheumatology centres in Peninsular Malaysia. The healthy controls matched by age, gender and ethnicity were recruited on the community basis from the residential area of the patients. Levels of survivin were measured in blood of RA patients (n = 1233) and controls (n = 1566) by an enzyme-linked immuno-sorbent assay (ELISA). The risk for RA was calculated as odds ratio (OR) and 95% confidence intervals in the individuals with high levels of survivin. The risk was calculated in relation to antibodies against cyclic citrullinated peptides (ACPA), detected by ELISA and HLA-DRB1 shared epitope (SE) alleles, identified by the polymerase chain reaction using sequence specific oligonucleotide method.High levels of survivin were detected in 625 of 1233 (50.7%) RA cases and in 85 of 1566 (5.4%) controls, indicating its high specificity for RA. Survivin was association with an increase in RA risk in the patients having neither SE-alleles nor ACPA (OR = 5.40, 95% CI 3.81-7.66). For the patients combining survivin, SE, and ACPA, the estimated risk for RA was 16-folds higher compared to the survivin negative patients with SE and ACPA(OR = 16.21, 95% CI 5.70-46.18).To conclude, detection of survivin in blood provides a simple test to improve diagnostic and to increase predictability for RA.
    Medicine 01/2015; 94(4):e468. DOI:10.1097/MD.0000000000000468 · 5.72 Impact Factor
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    ABSTRACT: Specific serum antibodies mediating humoral immunity and autoimmunity are provided by mature plasma cells (PC) residing in the bone marrow (BM), yet their dynamics and composition are largely unclear. We here characterize distinct subsets of human PC differing by CD19 expression. Unlike CD19(+) PC, CD19(-) PC were restricted to BM, expressed predominantly IgG and carried a pro-survival, distinctly mature phenotype, i.e. HLA-DR(low)Ki-67(-)CD95(low)CD28(+)CD56(+/-), with increased BCL2 and resisted their mobilization from the BM after systemic vaccination. Fewer mutations within immunoglobulin VH rearrangements of CD19(-) BMPC may indicate their differentiation in early life. Their resistance to in vivo B cell depletion, i.e. their independency from supply with new plasmablasts is consistent with long-term stability of this PC subset in the BM. Moreover, CD19(-) PC were detectable in chronically inflamed tissues and secreted autoantibodies. We propose a multi-layer model of PC memory in which CD19(+) and CD19(-) PC represent dynamic and static components, respectively, permitting both adaptation and stability of humoral immune protection. Copyright © 2015 American Society of Hematology.
    Blood 01/2015; 125(11). DOI:10.1182/blood-2014-02-555169 · 10.45 Impact Factor
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    ABSTRACT: Survivin is a proto-oncogene that regulates cell division and apoptosis. It is a molecular marker of cancer. Recently, survivin has emerged as a feature of RA, associated with severe joint damage and poor treatment response. The present study examined if inhibition of survivin affects experimental arthritis, which was induced in mBSA-immunized mice by an injection of mBSA in the knee joint or developed spontaneously in collagen type II-immunized mice. The inhibition of survivin transcription by a lentivirus shRNA construct alleviated joint inflammation and reduced bone damage. The inhibition of survivin reduced the levels of metalloproteinases, β-catenin, and vimentin, limiting the invasive capacity of synovia, while no inhibition of osteoclastogenesis could be found. The inhibition of survivin led to a p53-independent reduction of T cell proliferation and favored the transcription and activity of Blimp-1, which limited IL-2 production and facilitated formation of regulatory Foxp3(+)CD4(+) and effector CD8(+) T cells. The study shows that the inhibition of survivin is sufficient to reduce joint inflammation and bone damage in preclinical models of arthritis. Antiarthritic effects of survivin inhibition are related to p53-independent control of lymphocyte proliferation.
    Journal of Leukocyte Biology 11/2014; 97(1). DOI:10.1189/jlb.3A0714-317R · 4.29 Impact Factor
  • Jan L Bjersing · Maria I Bokarewa · Kaisa Mannerkorpi
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    ABSTRACT: Fibromyalgia (FM) is characterized by generalized chronic pain and reduced pain thresholds. Disturbed neuroendocrine function and impairment of growth hormone/insulin-like growth factor-1 is common. However, the pathophysiology of FM is not clear. MicroRNAs are important regulatory factors reflecting interface of genes and environment. Our aim was to identify characteristic microRNAs in FM and relations of specific microRNAs with characteristic symptoms. A total of 374 circulating microRNAs were measured in women with FM (n = 20; median 52.5 years) and healthy women (n = 20; 52.5 years) by quantitative PCR. Pain thresholds were examined by algometry. Pain [fibromyalgia impact questionnaire (FIQ) pain] levels were rated (0-100 mm) using FIQ. Fatigue (FIQ fatigue) was rated (0-100 mm) using FIQ and multidimensional fatigue inventory general fatigue. Sleep quantity and quality (1-4) rated from satisfactory to nonsatisfactory. Higher scores indicate more severe symptoms. Eight microRNAs differed significantly between FM and healthy women. Seven microRNAs, miR-103a-3p, miR-107, let-7a-5p, miR-30b-5p, miR-151a-5p, miR-142-3p and miR-374b-5p, were lower in FM. However, levels of miR-320a were higher in FM. MiR-103a-3p correlated with pain (r = 0.530, p = 0.016) and sleep quantity (r = 0.593, p = 0.006) in FM. MiR-320a correlated inversely with pain (r = -0.468, p = 0.037). MiR-374b-5p correlated inversely with pain threshold (r = -0.612, p = 0.004). MiR-30b-5p correlated with sleep quantity (r = 0.509, p = 0.022), and let-7a-5p was associated with sleep symptoms. When adjusted for body mass index, the correlation of sleep quantity with miR-103a and miR-30b was no longer significant. To our knowledge, this is the first study of circulating microRNAs in FM. Levels of several microRNAs differed significantly in FM compared to healthy women. Three microRNAs were associated with pain or pain threshold in FM.
    Rheumatology International 09/2014; 35(4). DOI:10.1007/s00296-014-3139-3 · 1.52 Impact Factor
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    ABSTRACT: Smoking deregulates neuroendocrine responses to pain supporting production of neuropeptide Y (NpY) by direct stimulation of nicotinic receptors or by inhibiting adipokine leptin. Present study addressed the effect of cigarette smoking on adipokines and pain parameters, in 62 women with fibromyalgia (FM) pain syndrome with unknown etiology. Pain was characterized by a visual analogue scale, tender point (TP) counts, pressure pain threshold, and neuroendocrine markers NpY and substance P (sP). Levels of IGF-1, leptin, resistin, visfatin, and adiponectin were measured in blood and cerebrospinal fluid. Current smokers (n = 18) had lower levels of leptin compared to ex-smokers (n = 25, P = 0.002), while the expected NpY increase was absent in FM patients. In smokers, this was transcribed in higher VAS-pain (P = 0.04) and TP count (P = 0.03), lower pain threshold (P = 0.01), since NpY levels were directly related to the pain threshold (rho = 0.414) and inversely related to TP counts (rho = −0.375). This study shows that patients with FM have no increase of NpY levels in response to smoking despite the low levels of leptin. Deregulation of the balance between leptin and neuropeptide Y may be one of the essential mechanisms of chronic pain in FM.
    Mediators of Inflammation 08/2014; 2014:627041. DOI:10.1155/2014/627041 · 3.24 Impact Factor
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    ABSTRACT: Background A calcium-binding protein S100A4 regulates non-muscle myosin assembly and activity and plays important part in cell motility and differentiation. The binding of S100A4 to calcium drives conformation changes and permits S100A4 to regulate the activity of its multiple intracellular protein partners placing S100A4 at the crossroad of several intracellular transduction mechanisms. In RA, S100A4 is abundantly expressed in synovial fibroblasts, macrophages and vascular endothelial cells of the inflamed joints and may be measured in synovial fluid and in blood. The clinical consequences of the high levels of S100A4 in RA patients are associated with resistant joint inflammation and high skeletal damage. Objectives In the present study we evaluated the role of intracellular functions of S100A4 for T-cell responses in rheumatoid arthritis. Methods A preclinical model of the methylated BSA induced arthritis was induced in S100A4-deficent mice lacking the entire S100A4 protein (S100A4KO) and in wild-type (WT) counterparts where the S100A4 gene was inhibited with a specific shRNA-lentiviral constructs (S100A4-shRNA). The subsets of Th-cell in synovial infiltrates were analysed by immunohistology and in spleens by flow cytometry and qPCR. Phosphorylation of STAT3 (pTy5705), CD5 (pTyr453), Fyn (pTyr530) and ZA70 (pTyr319/Syk, pTyr352) were analysed by flow cytometry in spleen cell cultures. Kinase activity of Fyn and Lck was analysed by phosphorylation of CD5 peptide. Results Histological analysis of the inflamed joints demonstrated that S100A4-deficient mice had significantly alleviated joint inflammation and damage. Leukocyte infiltrates in the arthritic joints of S100A4-deficient mice presented accumulation of Foxp3+ Treg, while the effector T-cell population and the number of RORγt+ and pSTAT3+ cells were reduced. T-cells of S100A4-deficient mice were characterized by a limited formation of Th17-cells, which was a result of low mRNA levels of RORγt and STAT3 (pTyr705) activity in spleen and low production of IL17 and IFNg. In vitro experiments provide evidence that S100A4 directly binds Lck and Fyn and reciprocally regulates their kinase activity towards TCR inhibitor CD5. Nuclear magnetic resonance analysis demonstrated an interaction between CD5 cytoplasmic domain and EF2-binding sites of S100A4. This suggests that S100A4 is able to disrupt intracellular interactions of CD5 and could modify its inhibition of TCR. Consequently, S100A4-deficiency was translated in low expression of CD5, and increased lymphocyte proliferation and phosphorylation of ZAP-70. Conclusions Here we provide experimental evidence that S100A4 directly binds the Src-kinases Lck and Fyn and reciprocally regulates their kinase activity. S100A4-deficiency results in reduced activity of STAT3 suppressing transcription of RORgt and lineage differentiation of Th17-cells. The immunological events controlled by S100A4 are functionally important for the pathogenesis of arthritis, since the deficiency in S100A4 alleviates experimental arthritis. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5414
    Annals of the Rheumatic Diseases 07/2014; 1842(11). DOI:10.1016/j.bbadis.2014.07.003 · 10.38 Impact Factor
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    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 07/2014; 1842(11):2049-2059. DOI:10.1016/j.bbadis.2014.07.003. · 4.88 Impact Factor
  • Annals of the Rheumatic Diseases 06/2014; 73(Suppl 2):814-815. DOI:10.1136/annrheumdis-2014-eular.5490 · 10.38 Impact Factor
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    ABSTRACT: Antibodies against citrullinated peptides (anti-CCP) and increased levels of cytokines precede the development of rheumatoid arthritis (RA) by several years. Recently, the proteins survivin and Fms-like tyrosine kinase 3 ligand (Flt3L) have been identified as biomarkers of RA associated with joint destruction. Our objective was to investigate the potential of survivin and Flt3L as predictors of RA in samples from patients prior to onset of symptoms. This study included 47 individuals sampled before onset of RA (median 2.5 years (IQR 4.5) and 155 matched controls, all were donors to the Medical Biobank of Northern Sweden, and 36 RA patients. Levels of anti-CCP, survivin and Flt3L were measured using ELISAs and 29 cytokines/chemokines by multiplex detection. Levels of survivin were increased in pre-symptomatic individuals compared with controls (P = 0.003), whilst the levels of Flt3L were similar. The frequency of survivin positivity in the pre-symptomatic individuals was increased compared with the controls (36.2 vs.14.2%, P = 0.001) and predicted disease development (odds ratio (OR) =3.4 (95% confidence interval (CI) 1.6-7.2)). The frequency of survivin and Flt3L in RA patients was increased compared with the controls (both, P <0.0001, OR = 12.1 (95% CI, 5.3-27.6) and OR = 11.0 (95% CI, 3.9-30.9), respectively). Anti-CCP positive pre-symptomatic individuals and patients had significantly higher levels of survivin compared with anti-CCP2 negative individuals. In pre-symptomatic individuals, survivin correlated with IL-12, IL-1beta and IL-9 whereas Flt3L correlated to a significantly broader spectrum of cytokines in RA patients. Proto-oncogene survivin was increased in individuals prior to onset of symptoms of RA and was correlated to cytokines suggesting its role at pre-clinical stages of the disease.
    Arthritis research & therapy 02/2014; 16(1):R45. DOI:10.1186/ar4474 · 3.75 Impact Factor
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    ABSTRACT: Background Presence of antibodies against citrullinated peptides (anti-CCP2) and increased levels of cytokines and chemokines precedes the development of rheumatoid arthritis (RA) by several years [1, 2]. Recently, the proteins survivin and Fms-like tyrosine kinase 3 ligand (Flt3L) have been associated with RA and RA associated joint damage [3, 4]. Objectives To investigate the potential of survivin and Flt3L as predictors of RA and their relationships to cytokines and anti-CCP antibodies in blood samples from individuals before onset of symptoms of RA. Methods This study includes 47 individuals sampled before onset of symptoms of RA (median 2.5 years (IQR 1.1-5.6) and 155 population controls matched for sex and age, all donors to the Medical Biobank of Northern Sweden. 36 of the pre-symptomatic individuals were also sampled at the time of RA diagnose (ACR criteria 1987). Levels of survivin and Flt3L were measured using sandwich ELISAs (both, R&D Systems, Minneapolis, MN). Anti-CCP antibodies was analyzed using ELISA (Euro-Diagnostica AB, Malmö, Sweden) and 29 cytokines, and chemokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, eotaxin, IL-1Ra, bFGF, G-CSF, GM-CSF, IFNγ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGFBB, TNFα, VEGF, Mig, MIF and IL-2Rα by multiplex detection (Bio-Rad, Hercules, CA). The cut-off levels were for survivin 450 pg/mL, and for Flt3L 130 pg/mL. Results The levels of survivin were increased in the pre-symptomatic individuals compared with the controls (p=0.003) whilst the levels of Flt3-ligand (p=0.21) were similar. The frequency of survivin in the pre-symptomatic individuals was increased compared with controls (36.2 vs. 14.2% p=0.001). The odds ratio (OR) for predicting disease development in individuals with survivin levels above cut-off was 3.4 (95%CI 1.6-7.2). The frequencies of survivin and Flt3L were increased in RA patients compared with controls (both, p<0.0001. OR12.1 [95%CI, 5.3-27.6] and OR11.0 [3.9-30.9], respectively). Anti-CCP positive pre-diseased individuals and RA-patients had significantly higher concentrations of survivin compared with those being negative. After correction for the number of comparisons, IL-1β, GM-CSF in pre-symptomatic individuals was correlated with survivin and IL-1α, IL-10, eotaxin and TNF-α was correlated with Flt3L, while IL-2, IL-9 and IL12 was correlated with both survivin and Flt3L in the pre-symptomatic individuals. Conclusions The proto-oncogene survivin was increased in individuals before onset of symptoms of RA and it was related to cytokines suggesting its role in the events preceding development of the disease. References Disclosure of Interest None Declared
    Annals of the Rheumatic Diseases 01/2014; 72(Suppl 3):A193-A193. DOI:10.1136/annrheumdis-2013-eular.618 · 10.38 Impact Factor
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    ABSTRACT: Background Fibromyalgia (FM) is a chronic condition characterized by widespread musle pain and tenderness. Chronic pain is the major symptom that affects patients physically, mentally and socially. Mechanisms of pain in FM are not completely understood. Relation between smoking and pain is contradictive. In epidemiologic studies smoking is associated to chronic pain, while in acute experiment stimulation of nicotine receptors alleviates pain. Objectives The present study evaluates the possible relation between pain, cigarette smoking, and levels of IGF-1 in patients with FM. Methods Pain was characterised in 63 patients with FM (all women, age 52 years) by Fibromialgia Impact Questionnaire (FIQ), tender points count, and pain threshold was assessed by algometer. All patients participated in the structured telephone interview regarding their smoking habits. Levels of IGF-1, leptin, resistin, and adiponectin were measured in blood. The statistical analysis was performed regarding smoking habits, IGF-1 levels and intensity of pain. Patients were categorized by pain (FIQ and threshold) quartiles, and relative risk (95%CI) was calculated. Results Eighteen patients (28.6%) reported to be current smokers, and 45 were non-smokers. Among the non-smokers, 25 patients smoked previously and ceased before the study (median 13 years, range 1-30). Smokers had higher pain experience compared to non-smokers, characterised by higher FIQ (p=0.036), and lower pain threshold (p=0.014). The difference in pain was largest between the current smokers and patients who had ceased smoking (dFIQ 12%, p=0.005). The RR of pain in the upper quartile in smokers was 6.3 (95%CI: 1.41-36.18) compared to previous smokers. Furthermore, previous smokers have lower pain, fewer tender points and a higher pain threshold compared to smokers. Smokers had significantly lower levels of IGF-1 (ng/ml, median: 2.72 vs 4.82, p=0.027) compared to never-smokers and lower levels of leptin (ng/ml, median: 16.9 vs 34.8, p=0.013) compared to non-smokers. Current and previous smokers had frequently low levels of IGF-1 compared to non-smokers (88% vs 12%, p=0.018). Conclusions Smoking in FM patients was associated with high pain experience. Pain experience improved in the patients who had ceased smoking. Current and previous smoking was associated with low levels of IGF-1 suggesting long-term effects of smoking on regulation of IGF-1 levels in FM patients. Disclosure of Interest None Declared
    Annals of the Rheumatic Diseases 01/2014; 71(Suppl 3):274-274. DOI:10.1136/annrheumdis-2012-eular.2315 · 10.38 Impact Factor
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    ABSTRACT: High levels of the oncoprotein survivin may be detected in the majority of patients with early rheumatoid arthritis (RA). Survivin is a sensitive predictor of joint damage and persistent disease activity. Survivin-positive patients are often poor responders to anti-rheumatic and biological treatment. The aim of this study was to investigate the reproducibility of survivin status and its significance for clinical and immunological assessment of RA patients. Survivin levels were measured in 339 patients from the Better Anti-Rheumatic FarmacOTherapy (BARFOT) cohort of early RA at baseline and after 24 months. The association of survivin status with joint damage (total Sharp-van der Heijde score), disease activity (disease activity score based on evaluation of 28 joints (DAS28)), functional disability (health assessment questionnaire (HAQ)), and pain perception (visual analogue scale (VAS)) was calculated in the groups positive and negative for survivin on both occasions, and for the positive-negative and negative-positive groups. In 268 patients (79%) the levels of survivin were similar at baseline and after 24 months, 15% converted from survivin-positive to being negative, and 5% from survivin-negative to being positive. A combination of smoking and antibodies against cyclic citrullinated peptides (aCCP) predicted persistently (baseline and 24 months) high levels of survivin (odds ratio 4.36 (95% confidence interval: 2.64 to 7.20), P <0.001), positive predictive value 0.66 and specificity 0.83). The independent nature of survivin and aCCP was demonstrated by statistical and laboratory analysis. Survivin positivity on both test occasions was associated with the progression of joint damage, significantly higher DAS28 and lower rate of remission at 24 and 60 months compared to negative-negative patients. Survivin status was less associated with changes in HAQ and VAS. Survivin is a relevant and reproducible marker of severe RA. Persistently high levels of survivin were associated with smoking and the presence of aCCP and/or RF antibodies and predicted persistent disease activity and joint damage.
    Arthritis research & therapy 01/2014; 16(1):R12. DOI:10.1186/ar4438 · 3.75 Impact Factor

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  • 2005–2015
    • University of Gothenburg
      • • Department of Rheumatology and Inflammation Research (DRIR)
      • • Institute of Medicine
      Goeteborg, Västra Götaland, Sweden
  • 2001–2012
    • Sahlgrenska University Hospital
      • Department of Cardiology
      Goeteborg, Västra Götaland, Sweden
  • 2010
    • Lund University
      • Department of Rheumatology
      Lund, Skåne, Sweden
  • 2008
    • Hospital General de Niños Pedro de Elizalde
      Buenos Aires, Buenos Aires F.D., Argentina