Maria Bokarewa

University of Gothenburg, Goeteborg, Västra Götaland, Sweden

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Publications (94)381.74 Total impact

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    ABSTRACT: Objectives: To evaluate the role of S100A4, a calcium-binding regulator of nonmuscle myosin assembly, for T-cell responses in rheumatoid arthritis. Methods: Arthritis was induced in the methylated bovine serum albumin (mBSA)-immunized mice lacking the entire S100A4 protein (S100A4KO) and in wild-type counterparts treated with short hairpin ribonucleic acid (shRNA)-lentiviral constructs targeting S100A4 (S100A4-shRNA). The severity of arthritis was evaluated morphologically. T-cell subsets were characterized by the expression of master transcription factors, and functionally by proliferation activity and cytokine production. The activity of the Scr-kinases Fyn and Lck was assessed by the autophosphorylation of C-terminal thyrosine and by the phosphorylation of the CD5 cytodomain. The interaction between S100A4 and the CD5 cytodomain was analysed by nuclear magnetic resonance spectrophotometry. Results: S100A4-deficient mice (S100A4KO and S100A4-shRNA) had significantly alleviated morphological signs of arthritis and joint damage. Leukocyte infiltrates in the arthritic joints of S100A4-deficient mice accumulated Foxp3(+) Treg cells, while the number of RORγt(+) and (pTyr705)STAT3(+) cells was reduced. S100A4-deficient mice had a limited formation of Th17-cells with low retinoic acid orphan receptor gamma t (RORγt) mRNA and IL17 production in T-cell cultures. S100A4-deficient mice had a low expression and activity of T-cell receptor (TCR) inhibitor CD5 and low (pTyr705)STAT3 (signal transducer and activator of transcription 3), which led to increased (pTyr352)ZAP-70 (theta-chain associated protein kinase of 70kDa), lymphocyte proliferation and production of IL2. In vitro experiments showed that S100A4 directly binds Lck and Fyn and reciprocally regulates their kinase activity towards the CD5 cytodomain. Spectrometry demonstrates an interaction between the CD5 cytodomain and EF2-binding sites of S100A4. Conclusion: The present study demonstrates that S100A4 plays an important part in the pathogenesis of arthritis. It controls CD5-dependent differentiation of Th17 cells by regulating the activity of the Src-family kinases Lck and Fyn.
    Biochimica et biophysica acta. 07/2014;
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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. · 4.27 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. · 4.27 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 01/2014; 2014:627041. · 3.88 Impact Factor
  • Mikael Brisslert, Maria Rehnberg, Maria I Bokarewa
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    ABSTRACT: Epstein-Barr virus (EBV) infection may initiate production of autoantibodies and development of cancer and autoimmune diseases. Here we outline phenotypic and functional changes in B cells of RA patients related to EBV infection. The B cell phenotype was analysed in blood and bone marrow (BM) of RA patients who had EBV transcripts in BM (EBV(+) , n=13) and in EBV- (n=22). The functional effect of EBV was studied in the sorted CD25(+) and CD25(-) peripheral B cells of RA patients (n=18) and healthy controls (n=9). RTX-treatment results in enrichment of CD25(+) B cells in PB of EBV(+) RA patients. The CD25(+) B cell subset displayed a more mature phenotype accumulating IgG-expressing cells. It was also enriched with CD27(+) and CD95(+) cells in PB and BM. EBV stimulation of the sorted CD25+ B cells in vitro induced a polyclonal IgG and IgM secretion in RA patients, while CD25(+) B cells of healthy subjects did not respond to EBV stimulation. CD25(+) B cells were enriched in PB and synovial fluid of RA patients. EBV infection affects B cell phenotype in RA patients by increasing the CD25(+) subset and by imposing their Ig-production. These findings clearly link CD25(+) B cells to the EBV-dependent sequence of reaction in the pathogenesis of RA. This article is protected by copyright. All rights reserved.
    Immunology 07/2013; · 3.71 Impact Factor
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    ABSTRACT: Objectives: Primary Sjögren's syndrome (pSS) is an autoimmune disease affecting the exocrine glands and internal organs including the central nervous system (CNS). The fms-related tyrosine kinase 3 ligand (Flt3L) is a maturation factor essential for brain homeostasis. Blood levels of Flt3L are increased in inflammatory diseases including the inflamed salivary glands in pSS. The present study evaluated the role of Flt3L in the CNS of patients with pSS and in two non-autoimmune conditions, fibromyalgia (FM) and Alzheimer's disease (AD). Method: Levels of Flt3L were measured in cerebrospinal fluid (CSF) and serum of patients with pSS (n = 15), FM (n = 29), and AD (n = 39) and related to CNS symptoms and to markers of inflammation and degeneration. Results: Levels of CSF Flt3L in pSS and AD were significantly lower than in FM (p = 0.005 and p = 0.0003, respectively). Flt3L in pSS correlated to tau proteins [total tau (T-tau), r = 0.679; phosphorylated tau (P-tau), r = 0.646] and to a marker for microglia activation, monocyte chemoattractant protein 1 (MCP-1). Similar correlations were present in FM and AD patients. One-third of pSS patients had low levels of CSF Flt3L. This group had decreased levels of amyloid precursor protein metabolites (Aβ40 and Aβ42) in CSF, which was not seen in FM patients. Conclusions: This study shows a strong correlation between CSF Flt3L and tau proteins in pSS patients suggesting ongoing degradation/remodelling in the CNS. In pSS patients, low levels of Flt3L were linked to changes in amyloid turnover and may represent processes similar to those in AD.
    Scandinavian journal of rheumatology 07/2013; · 2.51 Impact Factor
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    ABSTRACT: S100A4 is a Ca-binding protein that regulates cell growth, survival, and motility. The abundant expression of S100A4 in rheumatiod arthritis contributes to the invasive growth of joint tissue and to bone damage. In the present study, we analyzed the role of S100A4 in bone homeostasis. Peripheral quantitative computed tomography and histomorphometric analysis were performed in mice lacking the entire S100A4 protein (S100A4KO) and in wild-type (WT) counterparts treated with shRNA-lentiviral constructs targeting S100A4 (S100A4-shRNA). Control groups consisted of sex-matched WT counterparts and WT mice treated with a non-targeting RNA construct. S100A4 deficiency was associated with higher trabecular and cortical bone mass, increased number and thickness of trabeculi combined with larger periosteal circumference and higher predicted bone strength. S100A4 inhibition by shRNA led to an increase in cortical bone in WT mice. S100A4-deficieny was associated with a reduced number of functional osteoclasts. S100A4KO and S100A4-shRNA-treated bone marrow progenitors gave rise to a large number of small TRAP+ cells with few nuclei and few pseudopodial processes. Poor osteoclastogenesis and the low resorptive capacity in S100A4Ko mice may be linked to low levels of surface integrins, impaired adhesion capacity, and poor multinucleation in S100A4-deficient osteoclasts, as well as a low content of proteolytic enzymes cathepsin K and MMP3 and MMP9 to break down the organic matrix. S100A4 emerges as a negative regulator of bone metabolism potentially responsible for the excessive bone turnover in conditions marked by high levels of S100A4 protein, such as inflammation and rheumatoid arthritis.
    Biochimica et Biophysica Acta 07/2013; · 4.66 Impact Factor
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    ABSTRACT: Objectives.S100A4 is a Ca-binding protein participating in regulation of cell growth, survival, and motility. Here, we studied, the role of S100A4 protein in sex hormone regulated bone formation.Material and methods.Bone mineral density in the trabecular and cortical compartments was evaluated in female S100A4KO, in matched WT counterparts, and in WT mice treated with lentiviral shRNA construct inhibiting the S100A4 gene transcription or with a non-targeting construct, by pQCT. The effect of sex hormones on bone was measured 5 weeks after ovariectomy (OVX) and/or dehydroepiadrosterone (DHEA) treatment.Results.S100A4KO had an excessive trabecular and cortical bone formation compared to the age and sex matched WT mice. S100A4KO had an increased periosteal circumference (p=0.001), cortical thickness (p=0.056) and cortical area (p=0.003), which predicted 20% higher bone strength in S100A4KO (p=0.013). WT mice treated with shRNA-S100A4 showed an increase of the cortical bone parameters in a fashion identical to S100A4KO mice, indicating the key role of S100A4 in the changed bone formation. S100A4KO mice had higher serum levels of osteocalcin and higher number of osteocalcin-positive osteoblasts under the periosteum. OVX-S100A4 resulted in the loss of the cortical bone supported by high CTX-I levels, while no such changes were observed in OVX-WT mice. S100A4KO mice resisted the DHEA-induced bone formation observed in the WT counterparts.Conclusions.Our study indicates that S100A4 is a regulator of bone formation, which inhibits bone excess in the estrogen-sufficient mice, and prevents the cortical bone loss in the estrogen-deprived mice.
    Molecular Endocrinology 06/2013; · 4.75 Impact Factor
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    ABSTRACT: INTRODUCTION: Severe fatigue is a major health problem in fibromyalgia (FM). Obesity is common in FM, but the influence of adipokines and growth factors is not clear. The aim was to examine effects of exercise on fatigue, in lean, overweight and obese FM patients. METHODS: In a longitudinal study, 48 FM patients (median 52 years) exercised for 15 weeks. Nine patients were lean (body mass index, BMI 18.5-24.9), 26 overweight (BMI 25-29.9) and 13 obese. Fatigue was rated on a 0-100 mm scale (fibromyalgia impact questionnaire [FIQ] fatigue) and multidimensional fatigue inventory (MFI-20) general fatigue (MFIGF). Higher levels in FIQ fatigue and MFIGF indicate greater degree of fatigue. Free and total IGF-1, neuropeptides, adipokines were determined in serum and cerebrospinal fluid (CSF). RESULTS: Baseline FIQ fatigue correlated negatively with serum leptin (r=-0.345; p=0.016) and nerve growth factor (NGF; r=-0.412; p=0.037). In lean patients, baseline MFIGF associated negatively with serum resistin (r=-0.694; p=0.038). FIQ Fatigue associated negatively with CSF resistin (r=-0.365; p=0.073). Similarly, FIQ fatigue (r=-0.444; p=0.026) and MFIGF correlated negatively with CSF adiponectin (r=-0.508; p=0.01). In lean patients, FIQ fatigue (p=0.046) decreased after 15 weeks. After 30 weeks, MFIGF decreased significantly in lean (MFIGF: p=0.017), overweight (MFIGF: p=0.001), and obese patients (MFIGF: p=0.016). After 15 weeks, total IGF-1 increased in lean (p=0.043) patients. [increment]Total IGF-1 differed significantly between lean and obese patients (p=0.010). [increment]Total IGF-1 related negatively with [increment]MFIGF after 15 weeks (r=-0.329; p=0.050). After 30 weeks, [increment]FIQ fatigue negatively correlated with [increment]NGF (r=-0.463; p=0.034) and positively with [increment]neuropeptide Y (NPY) (r=0.469; p=0.032). Resistin increased after 30 weeks (p=0.034). [increment]MFIGF correlated negatively with [increment]resistin (r=-0.346; p=0.031), being strongest in obese patients (r=-0.815; p=0.007). In obese patients, [increment]FIQ fatigue after 30 weeks correlated negatively with [increment]Free IGF-1 (r=-0.711; p=0.032). CONCLUSIONS: Exercise reduced fatigue in all FM patients, this effect was achieved earlier in lean patients. Baseline levels of resistin in both serum and CSF associated negatively with fatigue. Resistin was increased after the exercise period which correlated with decreased fatigue. Changes in IGF-1 indicate similar long-term effects in obese patients. This study shows reduced fatigue after moderate exercise in FM and indicates the involvement of IGF-1 and resistin in these beneficial effects. Trial registration: ClinicalTrials.gov NCT00643006.
    Arthritis research & therapy 02/2013; 15(1):R34. · 4.27 Impact Factor
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    ABSTRACT: Fms-like tyrosine kinase 3 ligand (Flt3L) is known as the primary differentiation and survival factor for dendritic cells (DCs). Furthermore, Flt3L is involved in the homeostatic feedback loop between DCs and regulatory T cell (Treg). We have previously shown that Flt3L accumulates in the synovial fluid in rheumatoid arthritis (RA) and that local exposure to Flt3L aggravates arthritis in mice, suggesting a possible involvement in RA pathogenesis. In the present study we investigated the role of Flt3L on DC populations, Tregs as well as inflammatory responses in experimental antigen-induced arthritis. Arthritis was induced in mBSA-immunized mice by local knee injection of mBSA and Flt3L was provided by daily intraperitoneal injections. Flow cytometry analysis of spleen and lymph nodes revealed an increased formation of DCs and subsequently Tregs in mice treated with Flt3L. Flt3L-treatment was also associated with a reduced production of mBSA specific antibodies and reduced levels of the pro-inflammatory cytokines IL-6 and TNF-α. Morphological evaluation of mBSA injected joints revealed reduced joint destruction in Flt3L treated mice. The role of DCs in mBSA arthritis was further challenged in an adoptive transfer experiment. Transfer of DCs in combination with T-cells from mBSA immunized mice, predisposed naïve recipients for arthritis and production of mBSA specific antibodies. We provide experimental evidence that Flt3L has potent immunoregulatory properties. Flt3L facilitates formation of Treg cells and by this mechanism reduces severity of antigen-induced arthritis in mice. We suggest that high systemic levels of Flt3L have potential to modulate autoreactivity and autoimmunity.
    PLoS ONE 01/2013; 8(1):e54884. · 3.53 Impact Factor
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    ABSTRACT: Fibromyalgia (FM) is characterized by chronic pain and reduced pain threshold. The pathophysiology involves disturbed neuroendocrine function, including impaired function of the growth hormone/insulin-like growth factor-1 axis. Recently, microRNAs have been shown to be important regulatory factors in a number of diseases. The aim of this study was to try to identify cerebrospinal microRNAs with expression specific for FM and to determine their correlation to pain and fatigue. The genome-wide profile of microRNAs in cerebrospinal fluid was assessed in ten women with FM and eight healthy controls using real-time quantitative PCR. Pain thresholds were examined by algometry. Levels of pain (FIQ pain) were rated on a 0-100 mm scale (fibromyalgia impact questionnaire, FIQ). Levels of fatigue (FIQ fatigue) were rated on a 0-100 mm scale using FIQ and by multidimensional fatigue inventory (MFI-20) general fatigue (MFIGF). Expression levels of nine microRNAs were significantly lower in patients with FM patients compared to healthy controls. The microRNAs identified were miR-21-5p, miR-145-5p, miR-29a-3p, miR-99b-5p, miR-125b-5p, miR-23a-3p, 23b-3p, miR-195-5p, miR-223-3p. The identified microRNAs with significantly lower expression in FM were assessed with regard to pain and fatigue. miR-145-5p correlated positively with FIQ pain (r=0.709, p=0.022, n=10) and with FIQ fatigue (r=0.687, p=0.028, n=10). To our knowledge, this is the first study to show a disease-specific pattern of cerebrospinal microRNAs in FM. We have identified nine microRNAs in cerebrospinal fluid that differed between FM patients and healthy controls. One of the identified microRNAs, miR-145 was associated with the cardinal symptoms of FM, pain and fatigue.
    PLoS ONE 01/2013; 8(10):e78762. · 3.53 Impact Factor
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    ABSTRACT: Lubricin (or proteoglycan 4 (PRG4)) is an abundant mucin-like glycoprotein in synovial fluid (SF) and a major component responsible for joint lubrication. In this study, it was shown that O-linked core 2 oligosaccharides (Galβ1-3(GlcNAcβ1-6)GalNAcα1-Thr/Ser) on lubricin isolated from rheumatoid arthritis SF contained both sulfate and fucose residues, and SF lubricin was capable of binding to recombinant L-selectin in a glycosylation-dependent manner. Using resting human polymorphonuclear granulocytes (PMN) from peripheral blood, confocal microscopy showed that lubricin coated circulating PMN and that it partly co-localized with L-selectin expressed by these cells. In agreement with this, activation-induced shedding of L-selectin also mediated decreased lubricin binding to PMN. It was also found that PMN recruited to inflamed synovial area and fluid in rheumatoid arthritis patients kept a coat of lubricin. These observations suggest that lubricin is able to bind to PMN via an L-selectin-dependent and -independent manner and may play a role in PMN-mediated inflammation.
    Journal of Biological Chemistry 08/2012; 287(43):35922-33. · 4.65 Impact Factor
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    ABSTRACT: INTRODUCTION: Complement activation is involved in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and atypical hemolytic uremic syndrome (aHUS). Autoantibodies to complement inhibitor factor H (FH), particularly in association with deletions of the gene coding for FH-related protein 1 (CFHR1), are associated with aHUS. METHODS: Autoantibodies against FH, factor I (FI) and C4b-binding protein (C4BP) were measured by ELISA, while CFHR1 homozygous deletion was determined with Western blotting of sera. Epitopes for FH autoantibodies were mapped using recombinant fragments of FH. RESULTS: FH autoantibodies were detected in SLE (6.7%, n = 60, RA patients (16.5%, n = 97 in the Swedish cohort and 9.2%, n = 217 in the Dutch cohort) and thrombosis patients positive for the lupus anticoagulants (LA+) test (9.4%, n = 64) compared with aHUS patients (11.7%, n = 103). In the control groups (n = 354), an average of 4% of individuals were positive for FH autoantibodies. The frequencies observed in both RA cohorts and LA+ patients were statistically significantly higher than in controls. We also found that an average of 15.2% of the FH-autoantibody positive individuals in all studied disease groups had homozygous deficiency of CFHR1 compared with 3.8% of the FH autoantibody negative patients. The levels of FH autoantibodies varied in individual patients over time. FH autoantibodies found in LA+, SLE and RA were directed against several epitopes across FH in contrast to those found in aHUS, which bound mainly to the C-terminus. Autoantibodies against FI and C4BP were detected in some patients and controls but they were not associated with any of the diseases analyzed in this study. CONCLUSIONS: Autoantibodies against FH are not specific for aHUS but are present at a significant frequency in rheumatic diseases where they could be involved in pathophysiological mechanisms.
    Arthritis research & therapy 08/2012; 14(4):R185. · 4.27 Impact Factor
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    ABSTRACT: The aim of the study was to evaluate long-term clinical and immunological effects of anti-B cell treatment in patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis refractory to conventional immunosuppressive treatment. Rituximab (RTX) was added to the ongoing immunosuppressive treatment in 29 patients with refractory ANCA-associated vasculitis. The disease activity was measured using Birmingham Vasculitis Activity Score/Wegener's granulomatosis (BVAS/WG score), and clinical laboratory variables were recorded. The median BVAS/WG score before treatment was 6 (IQR 3-8), and 28 patients (97%) had disease flare classified either severe (62%) or limited (34%). Six of 29 patients (21%) achieved a complete remission, and 12 (41%) had a treatment response with ≥50% decrease in BVAS/WG score at 6 months. Fourteen patients (64%) with kidney involvement achieved remission, and in seven patients (50%), no flare was seen during the follow-up period. Three patients had renal flare and were successfully re-treated with RTX. Seventeen patients had disease symptoms from airways and eyes at RTX initiation, whereas only 29% displayed ≥50% treatment response. Limited clinical improvement was seen in patients with endobronchial lesions and trachea-subglottic granulomatous disease. RTX is a potent therapeutic option for ANCA-associated vasculitis refractory to conventional treatment. Best response may be expected in patients with vasculitic manifestations.
    Scandinavian Journal of Immunology 07/2012; 76(4):411-20. · 2.20 Impact Factor
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    ABSTRACT: INTRODUCTION: Fibromyalgia (FM) is characterized by chronic pain. Impaired growth hormone responses and reduced serum insulin-like growth factor 1 (IGF-1) are common in FM. The aim was to examine changes in serum IGF-1, cerebrospinal fluid (CSF), neuropeptides, and cytokines during aerobic exercise in FM patients. METHODS: In total, 49 patients (median age, 52 years) with FM were included in the study. They were randomized to either the moderate- to high-intensity Nordic Walking (NW) program (n = 26) or the supervised low-intensity walking (LIW) program (n = 23). Patients participated in blood tests before and after 15 weeks of aerobic exercise. Changes in serum levels of free IGF-1, pain rating on a 0- to 100-mm scale, pain threshold, and 6-minute walk test (6MWT) were examined. CSF, neuropeptides, matrix metalloproteinase 3 (MMP-3), and inflammatory cytokines were determined. Nonparametric tests were used for group comparisons and correlation analyses. RESULTS: Serum free IGF-1 levels did not change during 15 weeks of exercise between the two groups, although the 6MWT significantly improved in the NW group (p = 0.033) when compared with LIW. Pain did not significantly change in any of the groups, but tended to decrease (p = 0.052) over time in the total group. A tendency toward a correlation was noted between baseline IGF-1 and a decrease of pain in response to exercise (r = 0.278; p = 0.059). When adjusted for age, this tendency disappeared. The change in serum free IGF-1 correlated positively with an alteration in CSF substance P (SP) levels (rs = 0.495; p = 0.072), neuropeptide Y (NPY) (rs = 0.802; p = 0.001), and pain threshold (rs = 0.276; p = 0.058). Differing CSF SP levels correlated positively to a change in pain threshold (rs = 0.600; p = 0.023), whereas the shift in CSF MMP-3 inversely correlated with an altered pain threshold (rs = -0.569; p = 0.034). CONCLUSIONS: The baseline level of serum free IGF-1 did not change during high or low intensity of aerobic exercise. Changes in IGF-1 correlated positively with a variation in CSF SP, NPY, and pain threshold. These data indicate a beneficial role of IGF-1 during exercise in FM.Trial registration: ClinicalTrials.gov NCT00643006.
    Arthritis research & therapy 07/2012; 14(4):R162. · 4.27 Impact Factor
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    ABSTRACT: The presence of autoantibodies against C-reactive protein (anti-CRP) has been reported in association with autoimmunity and histopathology in chronic hepatitis C virus (HCV) infection. Resistin could play a role in the pathogenesis of hepatitis, although results on HCV infection are ambiguous. Here we retrospectively analyzed anti-CRP and resistin levels in the sera of 38 untreated and well-characterized HCV patients at the time of their first liver biopsy. HCV activity and general health were assessed by a physician at least yearly until follow-up ended. Anti-CRP and resistin were also measured in patients with autoimmune hepatitis (AIH) and nonalcoholic fatty liver disease (NAFLD). Anti-CRP antibodies were registered in all HCV patients, whereas only a few AIH (11%) and NAFLD (12%) sera were positive. Anti-CRP levels were related to histopathological severity and were highest in patients with cirrhosis at baseline. Resistin levels were similar in HCV, AIH, and NAFLD patients, but high levels of resistin were associated with early mortality in HCV patients. Neither anti-CRP nor resistin predicted a response to interferon-based therapy or cirrhosis development or was associated with liver-related mortality. We conclude that anti-CRP antibodies are frequently observed in chronic HCV infection and could be a useful marker of advanced fibrosis and portal inflammation.
    Human immunology 02/2012; 73(4):382-8. · 2.55 Impact Factor
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    ABSTRACT: To assess the potential of metastasin S100A4 as a biological marker in patients with RA. A total of 87 unselected patients with established RA (disease duration 2-44 years) and treated with MTX and infliximab at a single rheumatology centre were included in a cross-sectional study. Radiographs of hands and feet were taken prior to infliximab treatment and at inclusion (time interval 48 ± 27 months) and scored for the radiographic damage. S100A4 levels were analysed in relation to radiographic damage, clinical disease activity (DAS-28), inflammation (IL-6, CRP, ESR), bone and cartilage markers [MMP-3, COMP, C-telopeptide of type I collagen (CTX-I)] and proto-oncogenes [survivin, insulin-like growth factor 1 (IGF-1), Flt3 ligand]. High levels of S100A4 were associated with severe radiographic damage (OR = 3.40, P = 0.025), non-response to infliximab (OR = 4.63, P = 0.003), presence of antibodies to infliximab (OR = 6.24, P = 0.003) and high levels of Flt3 ligand (OR = 2.73, P = 0.04). Regression analysis showed that high S100A4 was predictive for radiographic progression during infliximab treatment [positive predictive value (PPV) 0.68, P = 0.05]. Low levels of S100A4 were associated with response to infliximab (OR = 2.67, P = 0.049), clinical remission (OR = 4.01, P = 0.0047) and negative RF (OR = 9.22, P = 0.0047). S100A4 correlated with survivin (r = 0.71, P > 0.0001). S100A4 levels are increased in proportion to radiographic damage and its further progression in RA patients. High S100A4 levels were associated with a poor clinical response to infliximab and high rate of anti-infliximab antibodies. The finding of a correlation between S100A4 and survivin and Flt3 ligand suggests that these proteins may represent a new cluster of biomarkers predicting radiographic progression and poor treatment response in RA patients.
    Rheumatology (Oxford, England) 01/2012; 51(5):932-40. · 4.24 Impact Factor
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    ABSTRACT: Survivin is known as an inhibitor of apoptosis and a positive regulator of cell division. We have recently identified survivin as a predictor of joint destruction in patients with rheumatoid arthritis (RA). Flt3 ligand (Flt3L) is expressed in the inflamed joints and has adjuvant properties in arthritis. Studies on 90 RA patients (median age 60.5 years [range, 24-87], disease duration 10.5 years [range, 0-35]) show a strong positive association between the levels of survivin and Flt3L in blood. Here, we present experimental evidence connecting survivin and Flt3L signaling. Treatment of BALB/c mice with Flt3L led to an increase of survivin in the bone marrow and in splenic dendritic cells. Flt3L changed the profile of survivin splice variants, increasing transcription of the short survivin40 in the bone marrow. Treatment with an Flt3 inhibitor reduced total survivin expression in bone marrow and in the dendritic cell population in spleen. Inhibition of survivin transcription in mice, by shRNA lentiviral constructs, reduced the gene expression of Flt3L. We conclude that expression of survivin is a downstream event of Flt3 signaling, which serves as an essential mechanism supporting survival of leukocytes during their differentiation, and maturation of dendritic cells, in RA.
    PLoS ONE 01/2012; 7(10):e47668. · 3.53 Impact Factor
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    ABSTRACT: The neuroendocrine impact on rheumatoid arthritis is not yet fully described although numerous neurotransmitters are shown to act as inflammatory modulators. One of these is the excitatory transmitter glutamate (Glu). In this study, the influence of the Glu receptor (GluR)-mediated effects on collagen-induced arthritis (CIA) was investigated. CIA was induced in DBA/1 mice by immunization with chicken collagen type II (CII). Mice were exposed to the following GluR antagonists: group 1, the N-methyl-D-aspartic acid (NMDA) receptor channel blocker memantine; group 2, the metabotropic GluR antagonist AIDA, and group 3, the excitatory amino acid receptor antagonist kynurenic acid (KA). Arthritis was evaluated clinically and histologically and compared to PBS-treated controls. The effects of treatment on T cell populations and the levels of anti-CII and anti-citrullinated peptide antibodies were evaluated. Memantine treatment significantly improved the course of CIA, reducing synovitis (p = 0.007) and the frequency of erosions (p = 0.007). Memantine treatment up-regulated the expression of Foxp3 in spleen CD4+ T cells followed by an increase in CD4+CD25+ regulatory T cells. The other GluR antagonists, AIDA and KA, had no effect on CIA. These results demonstrate that blockade of the NMDA receptor channel with memantine delays and attenuates the development of arthritis, probably by promoting the development of regulatory T lymphocytes.
    Neurosignals 12/2011; 20(2):61-71. · 2.56 Impact Factor
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    ABSTRACT: Objective: To evaluate if the measurement of survivin in the blood of patients with rheumatoid arthritis (RA) undergoing infliximab treatment has predictive value for treatment response. Methods: The study included 87 consecutive RA patients (age 24-89 years, disease duration 18-526 months) treated with regular infusions of influximab. Survivin levels were measured by enzyme-linked immunosorbent assay and evaluated in relation to the total dose of infliximab, disease activity (DAS28), response to infliximab treatment (change in DAS28 1.2), and radio-graphic damage (vdH-Sharp score). Results: Thirty-seven percent of patients were survivin-positive (survivin 0.9 ng/mL) and showed severe radiographic damage at the start of infliximab treatment compared with survivin-negative (P 0.027). Patients with high survivin levels were unlikely to respond to infliximab treatment (OR 4.02 [1.22-14.61], P 0.022) and achieve remission (OR 4.32[1.01-30.11], P 0.048) compared with patients with low survivin levels. Conclusions: High survivin levels are associated with severe radiographic damage at the start of treatment and a poor response to infliximab. Survivin measurement should be considered an additional tool for aiding the selection and follow-up of antirheumatic treatment. R heumatoid arthritis (RA) is an inflammatory joint disease that affects 1% of the world's population. If untreated, it leads to progressive joint destruc-tion, functional disability, and increased mortality. Treat-ment with drugs that inhibit tumor necrosis factor-(TNF-) dramatically changes the development of RA, improves functional capacity, and reduces joint destruc-tion and mortality, all of which are associated with signif-icant socioeconomic benefits (1-4). Randomized controlled clinical trials show that TNF inhibitors are effective in 28% to 56% of RA patients; however, studies of large observational cohorts outside clinical trials show that the long-term response rates to TNF inhibitors may be considerably lower (5,6). There-fore, there is a need for biological markers that can predict the response to TNF inhibitors. A number of candidate markers, including genetic and protein markers, are cur-rently under investigation (7-9). A multistep proteomic approach using RA antigens and cytokine profiles in se-rum (7-9) and synovial tissues (10,11) has recently been proposed to select patients that are likely to respond TNF-inhibitors. We have recently shown that levels of the proto-onco-gene survivin can be measured in blood and synovial fluid samples from RA patients and that higher levels are asso-ciated with severe joint destruction (12). Survivin is a multifunctional protein known for its association with tumorigenesis (13,14). Expression of survivin is generally connected to cell proliferation and invasive tissue growth. The observation of a high level of circulating survivin in
    Seminars in Arthritis and Rheumatism 10/2011; 41(5):652-7. · 3.81 Impact Factor

Publication Stats

2k Citations
381.74 Total Impact Points

Institutions

  • 2004–2013
    • University of Gothenburg
      • Department of Rheumatology and Inflammation Research (DRIR)
      Goeteborg, Västra Götaland, Sweden
  • 2001–2012
    • Sahlgrenska University Hospital
      Goeteborg, Västra Götaland, Sweden
  • 2010
    • Lund University
      Lund, Skåne, Sweden
  • 2009
    • Jagiellonian University
      • Department of Microbiology
      Kraków, Lesser Poland Voivodeship, Poland
  • 2008
    • Hospital General de Niños Pedro de Elizalde
      Buenos Aires, Buenos Aires F.D., Argentina
    • Skaraborgs Sjukhus
      Falkøping, Västra Götaland, Sweden