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  • 1.
    Berglin, Ewa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Mohammad, Aladdin J.
    Department of Clinical Sciences/Rheumatology, Lund University, Lund, Sweden; Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
    Dahlqvist, Johanna
    Department of Medical Biochemistry and Microbiology, and Medical Sciences, Uppsala University, Uppsala, Sweden.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Eriksson, Catharina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk immunologi.
    Sjöwall, Johanna
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Clinic of Infectious Diseases Linköping University Hospital, Linköping, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Anti-neutrophil cytoplasmic antibodies predate symptom onset of ANCA-associated vasculitis: a case-control study2021Ingår i: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 117, artikel-id 102579Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: Anti-neutrophil cytoplasmic autoantibodies [ANCA) are important for diagnosis of ANCA-associated vasculitides (AAV). The timing of antibody development is not well established. To investigate the development of proteinase 3 (PR3)- and myeloperoxidase (MPO)-ANCA, blood samples collected before onset of symptoms of AAV were analysed.

    Methods: To identify AAV patients with blood samples predating symptoms, the National Patient Register and Cause of Death register were scrutinized for ICD codes for AAV and linked to the registers of five biobanks. Diagnoses of AAV and time point for symptom onset were confirmed by reviewing 504 case-record. Eighty-five AAV cases (34 males, 51 females) with samples >1 month < 10 years from AAV symptom onset and two controls matched for sex, age, and sampling time for each case were included. Samples were screened using ELISAs for ANCA and further analysed for PR3-or MPO- specificities.

    Results: In ANCA-screen 35.7% of the pre-symptomatic cases and 3.5% of controls tested positive (p < 0.01). 26.2% of the cases were PR3-ANCA+ and 10.7% MPO-ANCA+. Median (Q1-Q3) predating time for PR3-ANCA+ was 2.7 (0.3–7.7) years and MPO-ANCA+ 2.0 (0.9–3.5) years. PR3-ANCA was demonstrated in samples up to nine years before symptom onset. At symptom onset predating PR3-ANCA+ cases were younger than PR3-ANCA- (P < 0.01), and MPO-ANCA+ were older than MPO-ANCA- (p < 0.05). Predating MPO-ANCA+ cases vs. MPO-ANCA- and vs. PR3-ANCA+ cases had more often at symptoms onset manifestations from lungs, kidneys or peripheral nervous system (p < 0.01 and p < 0.05, respectively).

    Conclusion: The PR3-and MPO-ANCAs are present years before AAV symptom onset and represent distinct diseases.

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  • 2.
    Brink, Mikael
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Nygren, E.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Ärlestig, Lisbeth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Hultdin, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Vitamin D in individuals before onset of rheumatoid arthritis: relation to vitamin D binding protein and its associated genetic variants2018Ingår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, s. 23-24Artikel i tidskrift (Övrigt vetenskapligt)
  • 3.
    Esberg, Anders
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Berglin, Ewa
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Mohammad, Aladdin J.
    Department of Clinical Sciences/Rheumatology, Lund University, Lund, Sweden; Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
    Jonsson, Andreas P.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Dahlqvist, Johanna
    Department of Medical Sciences/Rheumatology, Uppsala University, Uppsala, Sweden; Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Stegmayr, Bernd
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Oral Microbiota Profile in Patients with Anti-Neutrophil Cytoplasmic Antibody–Associated Vasculitis2022Ingår i: Microorganisms, E-ISSN 2076-2607, Vol. 10, nr 8, artikel-id 1572Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Microbiota has been associated with autoimmune diseases, with nasal Staphylococcus aureus being implicated in the pathogenesis of anti-neutrophil cytoplasmic antibody–associated vasculitis (AAV). Little is known about the role of oral microbiota in AAV. In this study, levels of IgG antibodies to 53 oral bacterial species/subspecies were screened using immunoblotting in plasma/serum in pre-symptomatic AAV-individuals (n = 85), matched controls, and established AAV-patients (n = 78). Saliva microbiota from acute-AAV and controls was sequenced from 16s rDNA amplicons. Information on dental status was extracted from a national register. IgG levels against oral bacteria were lower in established AAV versus pre-AAV and controls. Specifically, pre-AAV samples had, compared to controls, a higher abundance of periodontitis-associated species paralleling more signs of periodontitis in established AAV-patients than controls. Saliva microbiota in acute-AAV showed higher within-sample diversity but fewer detectable amplicon-sequence variants and taxa in their core microbiota than controls. Acute-AAV was not associated with increased abundance of periodontal bacteria but species in, e.g., Arthrospira, Staphylococcus, Lactobacillus, and Scardovia. In conclusion, the IgG profiles against oral bacteria differed between pre-AAV, established AAV, and controls, and microbiota profiles between acute AAV and controls. The IgG shift from a pre-symptomatic stage to established disease cooccurred with treatment of immunosuppression and/or antibiotics.

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  • 4.
    Esberg, Anders
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Oral microbiota identifies patients in early onset rheumatoid arthritis2021Ingår i: Microorganisms, E-ISSN 2076-2607, Vol. 9, nr 8, artikel-id 1657Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Rheumatoid arthritis (RA) is the most common autoimmune inflammatory disease, and single periodontitis-associated bacteria have been suggested in disease manifestation. Here, the oral microbiota was characterized in relation to the early onset of RA (eRA) taking periodontal status into consideration. 16S rRNA gene amplicon sequencing of saliva bacterial DNA from 61 eRA patients without disease-modifying anti-rheumatic drugs and 59 matched controls was performed. Taxonomic classification at 98.5% was conducted against the Human Oral Microbiome Database, microbiota functions were predicted using PICRUSt, and periodontal status linked from the Swedish quality register for clinically assessed caries and periodontitis. The participants were classified into three distinct microbiota-based cluster groups with cluster allocation differences by eRA status. Independently of periodontal status, eRA patients had enriched levels of Prevotella pleuritidis, Treponema denticola, Porphyromonas endodontalis and Filifactor alocis species and in the Porphyromonas and Fusobacterium genera and functions linked to ornithine metabolism, glucosylceramidase, beta-lactamase resistance, biphenyl degradation, fatty acid metabolism and 17-beta-estradiol-17-dehydrogenase metabolism. The results support a deviating oral microbiota composition already in eRA patients compared with healthy controls and highlight a panel of oral bacteria that may be useful in eRA risk assessment in both periodontally healthy and diseased persons.

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  • 5.
    Gomez-Bañuelos, Eduardo
    et al.
    John Hopkins University, Baltimore United states.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Konig, Maximilian F.
    John Hopkins University, Baltimore, United States.
    Lundquist, Anders
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Paz, Merlin
    John Hopkins University, Baltimore, United States.
    Buhlin, Kåre
    Karolinska institutet, Stockholm, Sweden.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Andrade, Felipe
    John Hopkins University, Baltimore, United States.
    Exposure to Aggregatibacter Actinomycetemcomitans before Symptom Onset and the Risk of Evolving to Rheumatoid Arthritis2020Ingår i: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 9, nr 6, artikel-id 1906Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Periodontal disease has been implicated in the pathogenesis of rheumatoid arthritis (RA), an autoimmune disease characterized by immune-mediated synovial damage, and antibodies to citrullinated antigens. Here, we investigate the association between exposure to the periodontal pathogen Aggregatibacter actinomycetemcomitans (Aa) and the development of RA. IgM, IgG and IgA antibodies to Aa leukotoxin A (LtxA) were detected by ELISA in plasma from a cohort of Swedish adults at different stages of RA development, from before onset of symptoms to established disease. Patients with early and established RA had increased levels of anti-LtxA IgM compared with matched non-RA controls and periodontally healthy individuals. Logistic regression revealed that anti-LtxA IgM levels were associated with RA during early disease (OR 1.012, 95%CI 1.007, 1.017), which was maintained after adjustment for smoking, anti-CCP antibodies, rheumatoid factor, HLA-DRB1 shared epitope alleles and sex. We found no association between anti-LtxA IgG/IgA antibodies and RA at any stage of disease development. The data support a temporal association between anti-LtxA IgM antibodies and the development of RA, suggesting that a subset of RA patients may have been exposed to Aa around the time of transition from being asymptomatic to become a patient with RA.

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  • 6.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Insights into the processes preceding the onset of rheumatoid arthritis2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by the production of anti-citrullinated protein antibodies (ACPA) in the majority of all patients and a persistent inflammation in the synovial tissue leading to joint destruction. The aetiology of RA remains to a large extent unknown but is believed to be a complex interplay between genetic, environmental and stochastic factors. Recently, several infectious agents have been shown to have the capacity to induce citrullination of both endogenous and exogenous antigens e.g., Epstein-Barr virus (EBV) and Porphyromonas gingivalis (P.gingivalis). Disease progression in patients with RA is suggested to be a longstanding process that begins several years before symptom onset of RA. This hypothesis is supported by studies showing increased antibody levels against ACPA and disease related cytokines/chemokines several years before symptom onset of RA. The presence of ACPA is highly specific for RA and is already used as an indicator of progression and prognosis of the disease. This thesis is aimed to further investigate the origin and role of ACPA and the processes preceding the development of RA. New insights into these processes are of importance in order to be able to prevent the disease onset, achieve better diagnostic methods and treatments in the future.

    All of the individuals included in these papers, had attended to the Department of Rheumatology at Umeå University to receive their diagnosis of RA. The register of the patients were thereafter co-analysed with the register of the Medical Biobank of Northern Sweden. Plasma/sera samples were analysed for antibodies and receptor activator of nuclear factor kappa-B ligand (RANKL) using different ELISA techniques from individuals before symptom onset (pre-symptomatic individuals) and at disease onset (patients). Cytokines/chemokines were analysed using Meso Scale Discovery methods. Levels of marginal jawbone loss were measured using dental radiographs from premolar/molar regions. The Larsen score at disease onset was used to grade radiographs of hands and feet.

    In Paper I antibodies against Epstein-Barr virus nuclear antigen (EBNA) 1 and 2 (VCP1 and VCP2) and histone 4 (H4) derived citrullinated peptides (HCP1 and HCP2) were found to predate symptom onset of RA. In Paper II, antibodies against anti-P.gingivalis (anti-CPP3 and -RgpB IgG) were significantly increased in pre-symptomatic individuals and were detectable several years before symptom onset of RA. In Paper III the concentration of RANKL was shown to be increased several years before symptom onset of RA, especially in ACPA/rheumatoid factor (RF)/anti-carbamylated (CarP) antibody positive individuals. Positivity for RANKL was found to appear later in time than both positivity for ACPA, RF and anti-CarP antibodies. The highest Larsen score at disease onset was yielded when combining positivity for RANKL and anti-CarPivantibodies. In Paper IV periodontitis, defined as marginal jawbone loss was significantly higher in pre-symptomatic individuals who never smoked, compared with matched controls. RANKL positive individuals particularly those that were also ACPA positive, had a significantly greater extent of jawbone loss in comparison to those individuals who were RANKL negative.

    Antibodies against citrullinated exogenous and endogenous peptides were found to be associated with the symptom onset of RA. No hierarchy among the citrullinated epitopes could be identified. RANKL levels were particular increased in ACPA-positive individuals, and RANKL positivity appeared later in time than the general ACPA response. Periodontitis, defined as marginal jawbone loss was significantly higher in pre-symptomatic individuals, who never smoked.

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  • 7.
    Johansson, Linda
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Berglin, Ewa
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Eriksson, O.
    Department of Immunology, Genetics & Pathology, Uppsala University, Uppsala, Sweden.
    Mohammad, A.J.
    Department of Clinical Sciences/Rheumatology, Lund University, Lund, Sweden; Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
    Dahlqvist, J.
    Department of Medical Sciences, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Complement activation prior to symptom onset in myeloperoxidase ANCA-associated vasculitis but not proteinase 3 ANCA associated vasculitis: a Swedish biobank study2022Ingår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 51, nr 3, s. 214-219Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Increased soluble levels of complement effectors have been demonstrated in active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but the timing of complement activation in the autoimmune inflammation remains elusive. This study investigated whether the complement system is activated before onset of symptoms in AAV.

    Method: The Swedish National Patient Register and Cause of Death register were linked to registers of five biobanks to identify individuals sampled before AAV symptom onset. Diagnosis of AAV and time-point for symptom onset were confirmed by reviewing medical records. We identified 64 presymptomatic individuals with serum samples > 1 month < 10 years from AAV symptom onset and 122 matched controls. Complement factors (C2, C5) and activation markers (C5a, C4b) were measured using Luminex technology.

    Results: Presymptomatic individuals had higher levels of C5 up to 6.5 years before symptom onset, compared with controls [median (IQR) 80.7 (131.9) vs 46.6 (63.4) µg/mL, p = 0.05]. Levels of C5a increased significantly during the pre-dating time (p = 0.033) until symptom onset. The complement levels were significantly higher in presymptomatic myeloperoxidase (MPO)-ANCA+ individuals versus MPO-ANCAand proteinase-3-ANCA+ individuals. C5 was significantly increased in cases with renal involvement at diagnosis versus controls (p = 0.022), whereas levels of both C5 and C5a were significantly increased in presymptomatic individuals diagnosed with microscopic polyangiitis after onset compared with controls (C5: p = 0.027; C5a: p = 0.027).

    Conclusion: Activation of the complement system is an early event in the pathogenesis of AAV and is mainly associated with MPO-ANCA+ AAV and with microscopic polyangiitis.

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  • 8.
    Johansson, Linda
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Pratesi, Federico
    Brink, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Ärlestig, Lisbeth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    D'Amato, Claudia
    Bartaloni, Debora
    Migliorini, Paola
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Antibodies directed against endogenous and exogenous citrullinated antigens pre-date the onset of rheumatoid arthritis2016Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, artikel-id 127Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Anti-citrullinated-peptide antibodies (ACPA) have been detected in individuals with developing rheumatoid arthritis (RA) before the onset of symptom, with an initially limited spectrum of reactivities that gradually broadens. The aim was to analyze the evolution of ACPA response pre-dating symptom onset, using four selected citrullinated exogenous and endogenous antigens. Methods: A cohort of 521 individuals sampled before symptoms of RA appeared and 272 population controls were identified from the Biobank of Northern Sweden; 241 samples from patients with early RA were also collected. ACPA were detected by ELISA on viral citrullinated peptides (VCP) derived from Epstein-Barr-virus nuclear antigen (EBNA) 1 and EBNA2 (VCP1 and VCP2) and histone-4-derived citrullinated peptides (HCP1 and HCP2). Results: In pre-symptomatic individuals vs. patients with early RA, anti-VCP1 antibodies were detected in 10.4 % vs. 36.1 %, anti-VCP2 in 17.1 % vs. 52.3 %, anti-HCP1 in 10.2 % vs. 37.3 %, and anti-HCP2 in 16.3 % vs. 48.5 %, respectively. Anti-VCP and anti-HCP concentrations were significantly increased in pre-symptomatic individuals vs. controls (p < 0.001) and were increased approaching symptom onset. Anti-VCP and anti-HCP appeared simultaneously (median (IQR) 5.3 (6) years before symptom onset) and in combination yielded a high-risk ratio for disease development (OR = 8.0-18.9). Anti-VCP2 and anti-HCP2 antibodies were associated with HLA-DRB1*0401 in pre-symptomatic individuals. Three peptidylarginine deiminase (PAD)I3/PADI4 single nucleotide polymorphisms (SNPs) were significantly associated with anti-HCP1. Conclusions: Anti-VCP and anti-HCP antibodies pre-date symptom onset and predict disease development, but no hierarchy of citrullinated epitopes can be identified. These results suggest that no inciting citrullinated antigen so far described is common to all patients with RA. The association between PADI3/PADI4 polymorphism and anti-HCP1 antibodies suggests a novel link between deimination and production of ACPA.

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  • 9.
    Johansson, Linda
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Sherina, Natalia
    Kharlamova, Nastya
    Larsson, Barbro
    Israelsson, Lena
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Lundberg, Karin
    Plasma Concentrations of Antibodies to Porphyromonas Gingivalis Are Increased before Onset of Symptom of Rheumatoid Arthritis2015Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, artikel-id 524Artikel i tidskrift (Övrigt vetenskapligt)
  • 10.
    Johansson, Linda
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Sherina, Natalia
    Kharlamova, Nastya
    Potempa, Barbara
    Larsson, Barbro
    Israelsson, Lena
    Potempa, Jan
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Lundberg, Karin
    Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis2016Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, artikel-id 201Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The periodontal pathogen Porphyromonas gingivalis is hypothesized to be important in rheumatoid arthritis (RA) aetiology by inducing production of anti-citrullinated protein antibodies (ACPA). We have shown that ACPA precede RA onset by years, and that anti-P. gingivalis antibody levels are elevated in RA patients. The aim of this study was to investigate whether anti-P. gingivalis antibodies pre-date symptom onset and ACPA production. Methods: A case-control study (251 cases, 198 controls) was performed within the Biobank of Northern Sweden. Cases had donated blood samples (n = 422) before the onset of RA symptoms by 5.2 (6.2) years (median (interquartile range)). Blood was also collected from 192 RA patients following diagnosis. Antibodies against P. gingivalis virulence factor arginine gingipainB (RgpB), and a citrullinated peptide (CPP3) derived from the P. gingivalis peptidylarginine deiminase enzyme, were analysed by ELISA. Results: Anti-RgpB IgG levels were significantly increased in pre-symptomatic individuals (mean +/- SEM; 152.7 +/- 14.8 AU/ml) and in RA patients (114.4 +/- 16.9 AU/ml), compared with controls (p < 0.001). Anti-CPP3 antibodies were detected in 5 % of pre-symptomatic individuals and in 8 % of RA patients, with elevated levels in both subsets (4.33 +/- 0.59 and 9.29 +/- 1.81 AU/ml, respectively) compared with controls (p < 0.001). Anti-CPP3 antibodies followed the ACPA response, with increasing concentrations over time, whilst anti-RgpB antibodies were elevated and stable in the pre-symptomatic individuals with a trend towards lower levels after RA diagnosis. Conclusions: Anti-P. gingivalis antibody concentrations were significantly increased in RA patients compared with controls, and were detectable years before onset of symptoms of RA, supporting an aetiological role for P. gingivalis in the development of RA.

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  • 11.
    Johansson, Linda
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Ärlestig, Lisbeth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Kokkonen, Heidi
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Brink, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    An increased concentration of receptor activator of nuclear factor kappa-B ligand pre-dates the onset of rheumatoid arthritis2017Ingår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 56, nr 12, s. 2190-2196Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: RANK ligand (RANKL) is involved in destruction and osteoporosis in RA. In this study, the relationships between RANKL and ACPA, anti-carbamylated protein antibodies (anti-CarP), cytokines and chemokines were analysed in individuals before the onset of RA symptoms, and their associations with radiological findings at disease onset were assessed.

    Methods: This was a case-control study performed within the Medical Biobank of Northern Sweden that included 470 pre-symptomatic individuals [334 women and 136 men; mean (S.D.) age 52.3 (9.4) years] using blood samples donated before symptom onset (pre-dating time; 5.0 years) and 96 controls (60 women and 36 men). Plasma was analysed for RANKL (BioVendor, Karasek, Brno, Czech Republic), anti-CCP2 antibodies (Eurodiagnostics, Malmo, Sweden), anti-CarP antibodies (in-house ELISA), ACPA specificities (ISAC-platform, Phadia AB, Uppsala, Sweden) and cytokines/chemokines (Meso Scale Discovery methods, Rockville, MD, USA). Radiographs of hands and feet were graded using the Larsen score.

    Results: The concentration of RANKL was higher in the pre-symptomatic individuals compared with controls; mean (S.E.M.): 0.50 (0.03) vs 0.22 (0.02) nmol/l (P < 0.001). The concentration increased gradually over time until symptom onset but appeared later than ACPA/RF/anti-CarP antibodies. Positivity for these antibodies yielded higher levels of RANKL compared with seronegativity (P < 0.001). RANKL concentrations were significantly associated with IL-6 and IL-10 concentrations. The combination of positivity for RANKL and anti-CarP antibodies resulted in a higher Larsen score at diagnosis beta = 6.18 (95% CI: 0.93, 11.43; P = 0.022).

    Conclusion: RANKL concentrations were increased several years before symptom onset for RA, particularly in ACPA/RF/anti-CarP-positive individuals, all detectable earlier than RANKL. Positivity for RANKL and anti-CarP antibodies yielded the highest Larsen score at disease onset.

  • 12.
    Juneblad, Kristina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Alenius, Gerd-Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Association between inflammasome-related polymorphisms and psoriatic arthritisManuskript (preprint) (Övrigt vetenskapligt)
  • 13.
    Juneblad, Kristina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Kastbom, A.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Söderkvist, P.
    Alenius, Gerd-Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Association between inflammasome-related polymorphisms and psoriatic arthritis2021Ingår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 50, nr 3, s. 206-212Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Psoriatic arthritis (PsA) is a heterogeneous inflammatory disease associated with psoriasis. Underlying genetic factors are considered important for disease expression and prognosis of PsA. Interleukin-1 beta-regulating protein complexes called inflammasomes are associated with several inflammatory diseases, e.g. rheumatoid arthritis and psoriasis. The aim was to determine whether inflammasome-related genetic variation is associated with PsA susceptibility or different disease phenotypes.

    Method: DNA from 724 patients with PsA and 587 population-based controls from northern Sweden was analysed for single-nucleotide polymorphisms in NLRP3-Q750K (rs35829419), NLRP3 (rs10733113), CARD8-C10X (rs2043211), NLRP1 (rs8079034), and NLRP1 (rs878329).

    Results: Significant associations were found with the genotype AA (vs AT+TT) of rs2043211 for PsA patients compared with controls [odds ratio (OR), 95% confidence interval (CI) 1.32 (1.05-1.65), p = 0.016]; and between the C-allele of rs878329 and axial involvement of PsA [OR (95% CI) 1.37 (1.02-1.84), p = 0.035], the T-allele of rs8079034 with prescription of conventional synthetic disease-modifying anti-rheumatic drugs [OR (95% CI) 1.76 (1.23-2.53), p = 0.0020], the G-allele of rs10733113 and patients with a skin disease with early onset [OR (95% CI) 1.58 (1.13-2.21), p = 0.007], and the C-allele of rs35829419 and a destructive/deforming disease [OR (95% CI) 1.63 (1.04-2.55), p = 0.030].

    Conclusions: This study is the first to show an association with a genetic polymorphism in an inflammasome-related gene, CARD8-C10X (rs2043211), in patients with PsA. Associations between different phenotypes of PsA and different polymorphisms of the inflammasome genes were also found. Our results indicate the involvement of inflammasome genes in the pathogenesis and disease expression of PsA.

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  • 14.
    Kindstedt, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Palmqvist, Py
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Koskinen Holm, Cecilia
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Kokkonen, Heidi
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Association between marginal jawbone loss and the onset of rheumatoid arhtritis and relationship to plasma levels of RANKL2018Ingår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 70, nr 4, s. 508-515Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: To investigate whether periodontitis, characterized by marginal jawbone loss, precedes the onset of symptoms of rheumatoid arthritis (RA), and to analyze plasma levels of RANKL (a cytokine that is crucial for bone resorption) and anti–citrullinated peptide antibodies (ACPAs) in presymptomatic individuals compared with matched referent controls.

    Methods: Marginal jawbone loss was measured on dental radiographs of the premolar/molar regions in the jaws in 176 subjects, 93 of whom subsequently developed RA. Among these participating subjects, 46 had documented radiographs predating symptom onset, and 45 cases could be matched to controls, according to sex, age, and smoking status. Plasma RANKL concentrations were analyzed using enzyme‐linked immunosorbent assay. A receiver operating characteristic curve was used to define the cutoff value for RANKL positivity.

    Results: Bone loss was significantly greater in presymptomatic subjects classified as never smokers compared with that in controls, and increasing levels of bone loss were associated with a higher risk of the subsequent development of RA (hazard ratio 1.03, 95% confidence interval 1.01–1.05). No association between jawbone loss and RA was observed in smokers. A significantly greater extent of marginal jawbone loss was detected in RANKL‐positive presymptomatic subjects, and even more pronounced jawbone loss was observed in those who were positive for both RANKL and ACPA.

    Conclusion: Marginal jawbone loss preceded the clinical onset of RA symptoms, but this was observed only in nonsmokers. Moreover, marginal jawbone loss was significantly greater in RANKL‐positive presymptomatic subjects compared with RANKL‐negative presymptomatic subjects and was highest in presymptomatic subjects positive for both ACPA and RANKL.

  • 15.
    Kindstedt, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Palmqvist, Py
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Koskinen Holm, Cecilia
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Kokkonen, Heidi
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Lundberg, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) and Marginal Jawbone Loss Predates the Onset of Rheumatoid Arthritis2017Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Background/Purpose: Previous studies have shown a higher incidence of alveolar bone loss in patients with rheumatoid arthritis (RA) and that patients with periodontitis are at a greater risk for developing RA. Periodontitis, displayed as marginal jawbone loss was analysed in individuals prior to symptom onset of RA and related to plasma levels of receptor activator of nuclear factor kappa-B (RANKL), a cytokine crucial for bone resorption. Methods: A case-control study performed within the Medical Biobank of Northern Sweden included 232 pre-symptomatic individuals with blood samples donated before symptom onset and 194 controls. A questionnaire on self-assed dental status and smoking status was retrieved. Dental radiographs to evaluate marginal jawbone levels were available from 93 pre-symptomatic individuals (mean age; 56.8 95%CI55.9, 57.7 years and pre-dating time; -5.3 95%CI -12.2, -0.2, 74.2% females) and 83 controls (mean age; 55.5 95%CI54.6, 56.5, 73.5% females) . Of these individuals 45 had radiograph documentations prior to development of RA symptoms and to whom sex, age and smoking status could be matched among the controls. Plasma were analysed for RANKL (BioVendor, Karasek, Czech Republic), and anti-citrullinated peptide antibodies (ACPA) (anti-CCP2 test, Eurodiagnostics, Sweden) from similar time points. Results: Compared to matched controls, total bone loss was significantly higher in never-smokers who developed RA but not in smokers and increasing levels on total jawbone loss was associated with a significantly higher odds to be diagnosed with RA later (OR=1.06, 95%CI 1.01, 1.11). Regardless of smoking status, the number of unaffected teeth did not differ significantly between those who were subsequently diagnosed with RA and their matched controls. In the pre-symptomatic individuals RANKL positive individuals had significantly higher extent of marginal jawbone loss, which was further increased in ACPA positive individuals. Previously documented association between smoking and ageing and marginal jawbone loss was verified. Conclusion: Marginal jawbone loss preceded onset of symptoms of RA but the difference was only manifested in non-smokers. Moreover, marginal jawbone loss and plasma RANKL levels were related in the pre-symptomatic individuals particularly in ACPA positive individuals.

  • 16.
    Kindstedt, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Palmqvist, Py
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Koskinen Holm, Cecilia
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Kokkonen, Heidi
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Lundberg, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Association between marginal jawbone loss and the onset of rheumatoid arhtritis and relationship to plasma levels of RANKL2018Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 70, nr 4, s. 508-515Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: To investigate whether periodontitis, characterized by marginal jawbone loss, precedes the onset of symptoms of rheumatoid arthritis (RA), and to analyze plasma levels of RANKL (a cytokine that is crucial for bone resorption) and anti–citrullinated peptide antibodies (ACPAs) in presymptomatic individuals compared with matched referent controls.

    Methods: Marginal jawbone loss was measured on dental radiographs of the premolar/molar regions in the jaws in 176 subjects, 93 of whom subsequently developed RA. Among these participating subjects, 46 had documented radiographs predating symptom onset, and 45 cases could be matched to controls, according to sex, age, and smoking status. Plasma RANKL concentrations were analyzed using enzyme‐linked immunosorbent assay. A receiver operating characteristic curve was used to define the cutoff value for RANKL positivity.

    Results: Bone loss was significantly greater in presymptomatic subjects classified as never smokers compared with that in controls, and increasing levels of bone loss were associated with a higher risk of the subsequent development of RA (hazard ratio 1.03, 95% confidence interval 1.01–1.05). No association between jawbone loss and RA was observed in smokers. A significantly greater extent of marginal jawbone loss was detected in RANKL‐positive presymptomatic subjects, and even more pronounced jawbone loss was observed in those who were positive for both RANKL and ACPA.

    Conclusion: Marginal jawbone loss preceded the clinical onset of RA symptoms, but this was observed only in nonsmokers. Moreover, marginal jawbone loss was significantly greater in RANKL‐positive presymptomatic subjects compared with RANKL‐negative presymptomatic subjects and was highest in presymptomatic subjects positive for both ACPA and RANKL.

  • 17.
    Kokkonen, Heidi
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Stenlund, Hans
    Umeå universitet, Medicinska fakulteten, Institutionen för epidemiologi och global hälsa. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Cardiovascular risk factors before onset of rheumatoid arthritis are associated with cardiovascular events after disease onset: a case–control study2022Ingår i: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 11, nr 21, artikel-id 6535Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The increased comorbidity and mortality in rheumatoid arthritis (RA) patients are largely due to cardiovascular disease (CVD). Previously, we demonstrated increased frequencies of risk factors for CVD (elevated body mass index (BMI), elevated apoliprotein (Apo) B:ApoA1 ratio, and smoking) in pre-RA individuals compared with matched controls. Objectives: Assess the impact of traditional CV risk factors present before the onset of RA on the risk of CV events (CVE) after diagnosis in comparison with matched controls. Methods: A case–control study including 521 pre-symptomatic individuals and 1566 controls identified within the Health Surveys of the Medical Biobank was performed. CVD risk factors were hypertension, elevated ApoB:A1 ratio, BMI, diabetes, and smoking. Information on comorbidities was requested from the Swedish National Patient Register and Cause of Death Register. Results: Pre-RA individuals had a higher risk of future CVE compared with matched controls (HR [95% CI] 1.70 [1.31–2.21]), which remained after adjustments for risk factors for CVD (HR [95% CI] 1.73 [1.27–2.35]). Most risk factors were associated with CVE after diagnosis, and a combination resulted in a higher risk in RA compared with controls; two risk factors, HR [95% CI] 2.70 [1.19–6.13] vs. 1.26 [0.75–2.13]; and three to four risk factors, HR [95% CI] 6.32 [2.92–13.68] vs. 3.77 [2.34–6.00]. Conclusions: Risk factors for CVD present in pre-RA individuals were associated with future CVE, and even after adjustments for these risk factors and treatments after RA onset, pre-RA individuals had a higher risk of CVE compared with controls. These findings further highlight the importance of the early assessment of risk for CVD.

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  • 18.
    Kokkonen, Heidi
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Stenlund, Hans
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Inflammatory Markers in Relation to Risk Factors for Cardiovascular Disease in the Pre-Symptomatic Phase of Rheumatoid Arthritis2017Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Background/Purpose: Individuals who later developed rheumatoid arthritis (RA) have increased levels and frequencies of risk factors for cardiovascular disease (CVD), years before onset of RA. The relationships between CVD risk factors and inflammatory markers, i.e., cytokines and chemokines, were analysed in individuals prior to onset of symptoms and compared with controls. Methods: A case-control study was based on population surveys from The Västerbotten Intervention Programme (VIP) and the WHO Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) with data collected on socioeconomic and lifestyle factors, BMI, waist, blood pressure, and blood samples by a nurse. The register of patients with RA (ARA criteria) was co-analysed with the registers from the Medical Biobank and 469 pre-symptomatic individuals (median age 50.2 years; 67.8% women, median predating time 5.0 (IQR; 2.0-8.0) years), and 234 controls (median age 50.3 years; 67.1% women) were identified. CVD risk factors were defined as: hypertension (treatment or systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg), elevated ApoB/ApoA1 ratio (women ≥0.7, men ≥0.8, including lipid lowering treatment), BMI ≥25kg/m2, diabetes, and ever being smoker. Concentrations of eotaxin, interferon gamma-induced protein (IP-10), monocyt-chemoattractant protein 1 (MCP1), macrophage derived chemokine (MDC), interleukin (IL) 2, IL-4, IL-6, IL-8, and IL-10, were analysed in plasma using R&D systems' assays (Minneapolis, MN) according to the manufacturer's instructions. Results: Pre-symptomatic individuals had significantly higher levels of IL-6 compared with controls, both in women and men. IL-10 was significantly higher in pre-symptomatic men compared with controls. Cytokines/chemokines were significantly associated with the CVD risk factors in the cases e.g. IL-6 with each of the risk factors, eotaxin with smoking, IP-10 with increased BMI, being diabetes or having hypertension, whilst MDC was associated significantly with smoking and BMI≥25 kg/m2. After adjustments for sex and age only eotaxin concentrations were significantly associated with being ever smoker. In women, MDC was significantly associated with smoking, BMI≥25 kg/m2 and diabetes. Having the combination of several CVD risk factors was associated with significantly higher concentrations of MCP-1, MDC, and IL-6 in pre-symptomatic women. IL-6 increased further the relative risk in combinations with all CVD risk factors for the pre-symptomatic cases compared with controls. Conclusion: Increased concentrations of cytokines/chemokines were associated with CVD risk factors to a higher extent among the pre-symptomatic RA cases compared with controls. The pattern of association varied between the risk factors and the sex of the cases.

  • 19.
    Li, Taotao
    et al.
    Section of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Ge, Changrong
    Section of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Krämer, Alexander
    Section of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Sareila, Outi
    Section of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Department of Rheumatology and Inflammation Research, University of Gothenburg, Sahlgrenska Academy, Göteborg, Sweden.
    Leu Agelii, Monica
    Department of Rheumatology and Inflammation Research, University of Gothenburg, Sahlgrenska Academy, Göteborg, Sweden.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Forslind, Kristina
    Department of Clinical Sciences, Section of Rheumatology, Faculty of Medicine, Lund University, Lund, Sweden; Spenshult Research and Development Center, Halmstad, Sweden.
    Lönnblom, Erik
    Section of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Yang, Min
    Section of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Xu, Bingze
    Section of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Li, Qixing
    Center for Medical Immunopharmacology Research, Southern Medical University, Guangzhou, China.
    Cheng, Lei
    Section of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Bergström, Göran
    Department of Clinical Physiology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Fernandez, Gonzalo
    Section of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Kastbom, Alf
    Department of Rheumatology, Linköping University, Linköping, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Gjertsson, Inger
    Department of Rheumatology and Inflammation Research, University of Gothenburg, Sahlgrenska Academy, Göteborg, Sweden; Rheumatology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Holmdahl, Rikard
    Section of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Pathogenic antibody response to glucose-6-phosphate isomerase targets a modified epitope uniquely exposed on joint cartilage2023Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 82, nr 6, s. 799-808Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: To identify the arthritogenic B cell epitopes of glucose-6-phosphate isomerase (GPI) and their association with rheumatoid arthritis (RA).

    Methods: IgG response towards a library of GPI peptides in patients with early RA, pre-symptomatic individuals and population controls, as well as in mice, were tested by bead-based multiplex immunoassays and ELISA. Monoclonal IgG were generated, and the binding specificity and affinity were determined by ELISA, gel size exclusion chromatography, surface plasma resonance and X-ray crystallography. Arthritogenicity was investigated by passive transfer experiments. Antigen-specific B cells were identified by peptide tetramer staining.

    Results: Peptide GPI293-307 was the dominant B cell epitope in K/BxN and GPI-immunised mice. We could detect B cells and low levels of IgM antibodies binding the GPI293-307 epitopes, and high affinity anti-GPI293-307 IgG antibodies already 7 days after GPI immunisation, immediately before arthritis onset. Transfer of anti-GPI293-307 IgG antibodies induced arthritis in mice. Moreover, anti-GPI293-307 IgG antibodies were more frequent in individuals prior to RA onset (19%) than in controls (7.5%). GPI293-307-specific antibodies were associated with radiographic joint damage. Crystal structures of the Fab-peptide complex revealed that this epitope is not exposed in native GPI but requires conformational change of the protein in inflamed joint for effective recognition by anti-GPI293-307 antibodies.

    Conclusions: We have identified the major pathogenic B cell epitope of the RA-associated autoantigen GPI, at position 293-307, exposed only on structurally modified GPI on the cartilage surface. B cells to this neo-epitope escape tolerance and could potentially play a role in the pathogenesis of RA.

  • 20.
    Michailidou, Despina
    et al.
    Division of Rheumatology, Department of Medicine, University of Washington, WA, Seattle, United States.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Kuley, Runa
    Division of Rheumatology, Department of Medicine, University of Washington, WA, Seattle, United States; Center of Life Sciences, Mahindra University, Hyderabad, India.
    Wang, Ting
    Division of Rheumatology, Department of Medicine, University of Washington, WA, Seattle, United States.
    Hermanson, Payton
    Division of Rheumatology, Department of Medicine, University of Washington, WA, Seattle, United States.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Lood, Christian
    Division of Rheumatology, Department of Medicine, University of Washington, WA, Seattle, United States.
    Immune complex-mediated neutrophil activation in patients with polymyalgia rheumatica2023Ingår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 62, nr 8, s. 2880-2886Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Neutrophils are important in host defence. However, neutrophils are also linked to inflammation and organ damage. The purpose of this study was to assess whether markers of neutrophil activation are increased in PMR.

    METHODS: Levels of immune complexes (IC), calprotectin and neutrophil extracellular traps (NETs) were measured in plasma of healthy individuals (n = 30) and patients with PMR (n = 60), at flare and upon treatment with glucocorticoids using ELISA. Plasma-mediated neutrophil activation was assessed in presence of an FcγRIIA inhibitory antibody (IV.3).

    RESULTS: Plasma levels of calprotectin and NETs were elevated in PMR (P < 0.001). Mechanistically, neutrophil activation was driven by ICs, present in plasma, able to up-regulate neutrophil activation markers CD66b and CD11b (P < 0.0001) in an FcγRIIA-dependent manner (P < 0.01). Of note, circulating levels of IC correlated with plasma induced CD66b and CD11b (r = 0.51, P = 0.004, and r = 0.46, P = 0.01, respectively) and decreased after glucocorticoid therapy. In contrast to NETs, calprotectin significantly decreased after glucocorticoid therapy (P < 0.001) and was higher in PMR without overlapping GCA compared with patients with overlapping disease (P = 0.014). Interestingly, musculoskeletal involvement was associated with elevated levels of calprotectin before initiation of glucocorticoid therapy (P = 0.036).

    CONCLUSIONS: Neutrophil activation, including NET formation, is increased in PMR, through IC-mediated engagement of FcγRIIA. Clinically, neutrophil activation is associated with musculoskeletal involvement, with calprotectin, but not NETs, being a biomarker of treatment response in PMR patients. In all, IC-mediated neutrophil activation is a central process in PMR pathogenesis identifying potential novel therapeutic targets (FcγRIIA), as well as soluble markers for disease monitoring (calprotectin).

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  • 21. Zhang, Yuan
    et al.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Andersson-Assarsson, Johanna
    Taube, Magdalena
    Peltonen, Markku
    Svensson, Per-Arne
    Herder, Christian
    Rudin, Anna
    Carlsson, Lena
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Maglio, Cristina
    Adiponectin Associates with Rheumatoid Arthritis Risk in Overweight and Obesity Independently of Other Adipokines2021Ingår i: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 10, nr 13, artikel-id 2791Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We recently reported that increased serum adiponectin was associated with rheumatoid arthritis (RA) risk in subjects with obesity. We hereby aim to determine if other adipokines associate with RA risk and if the association between adiponectin and RA is independent of other adipokines. Two nested-case control studies were performed in two different cohorts: 82 participants of the Swedish Obese Subjects (SOS) study who developed RA during follow-up matched with 410 controls, and 88 matched pairs from the Medical Biobank of Northern Sweden. Baseline levels of circulating adipokines were measured using ELISA. In a multivariable analysis in the SOS cohort, higher adiponectin was associated with an increased risk of RA independently of other adipokines (OR for RA risk: 1.06, 95% CI: 1.01-1.12, p = 0.02). No association between leptin, resistin, and visfatin levels and the risk of RA was detected. In the cohort from the Medical Biobank of Northern Sweden, higher adiponectin was associated with an increased risk of RA only in participants with overweight/obesity (OR: 1.17, 95% CI: 1.01-1.36, p = 0.03), independently of other adipokines. Our results show that in individuals with overweight/obesity, higher circulating levels of adiponectin, but not leptin, resistin, or visfatin, were associated with an increased RA risk.

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  • 22. Zhang, Yuan
    et al.
    Johansson, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Rudin, Anna
    Carlsson, Lena
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Maglio, Cristina
    In overweight subjects, serum adiponectin predicts the development of rheumatoid arthritis independently of other adipokines2019Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, s. 298-298Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Background: Adipokines, such as adiponectin, leptin, resistin and visfatin, are cytokines produced by the adipose tissue and involved in metabolism and inflammation1 . Adiponectin is elevated in both serum and synovial fluid of subjects with rheumatoid arthritis (RA), suggesting a possible role of this adipokine in the pathogenesis of RA 2,3. Circulating levels of leptin, resistin, and visfatin are also higher in subjects with RA compared to controls 2,4.

    Objectives: Aim of this study was to determine if adiponectin, leptin, resistin, and visfatin predict the development of RA.

    Methods: Two nested-case control studies were performed including presymptomatic participants of two cohorts from Sweden: the Swedish Obese Subjects (SOS) study and a cohort of individuals identified within the Medical Biobank of northern Sweden. The SOS is a clinical trial including 4047 subjects with obesity6 . During a follow-up for up to 29 years, 92 subjects developed RA. Among those 92 subjects, 82 subjects with available serum at baseline were matched 1:5 with 410 subjects who did not develop RA during follow-up. Matching was based on baseline age, sex, body-mass index (BMI), bariatric surgery yes/no, year of inclusion, and smoking. A nested case-control study of 88 sex- and age-matched pairs was performed within the Medical Biobank of Northern Sweden using blood samples donated before the onset of the first RA symptoms. The pre-dating time before onset of symptoms of RA was 8.5±5.0 years7 . Baseline serum levels of adiponectin, leptin, resistin, and visfatin were measured using the Quantikine ELISA kit from R&D Systems (Wiesbaden, Germany). Visfatin could not be measured in the Biobank cohort, due to lack of serum. Both binary logistic as well as conditional logistic regression analyses were used to determine if adipokines were elevated years before the onset of RA.

    Results: In a multivariable analysis including adiponectin, leptin, resistin, visfatin performed in the SOS cohort, serum adiponectin was associated with a higher risk for RA independently of other adipokines (Odds ratio, OR, 1.1, 95% confidence interval, CI, 1.0-1.1, p value=0.01). Leptin, resistin and visfatin levels were not associated with the risk of RA. In the Biobank cohort, no association between adipokines and risk for RA was detected. However, when stratifying the population according to BMI, in the subgroup having BMI>25 (n=109), adiponectin levels were associated with higher risk for RA (OR 1.2, 95% CI 1.0-1.36, p=0.03), independently of leptin and resistin levels. Virtually the same results were obtained in both the SOS and the Biobank cohorts when conditional logistic regression analysis was used.

    Conclusion: Our results suggest that higher serum adiponectin levels predict the development of RA in subjects with overweight/obesity.

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