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Insights into the processes preceding the onset of rheumatoid arthritis
Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi. (Solbritt Rantapää Dahlqvist)
2018 (Engelska)Doktorsavhandling, 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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University , 2018. , s. 62
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1954
Nyckelord [en]
rheumatoid arthritis, pre-symptomatic individuals, autoantibodies, anti-citrullinated protein/peptides antibodies, Epstein-barr virus, neutrophil extracellular traps, periodontitis, Porphyromonas gingivalis, receptor activator of nuclear factor kappa-B ligand
Nationell ämneskategori
Reumatologi och inflammation
Forskningsämne
medicin, reumatologi
Identifikatorer
URN: urn:nbn:se:umu:diva-146293ISBN: 978-91-7601-863-7 (tryckt)OAI: oai:DiVA.org:umu-146293DiVA, id: diva2:1194903
Disputation
2018-04-27, Sal D, Målpunkt T, våning 9, Norrlands Universitetsjukhus, Umeå, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-04-06 Skapad: 2018-04-04 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Delarbeten
1. Antibodies directed against endogenous and exogenous citrullinated antigens pre-date the onset of rheumatoid arthritis
Öppna denna publikation i ny flik eller fönster >>Antibodies directed against endogenous and exogenous citrullinated antigens pre-date the onset of rheumatoid arthritis
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2016 (Engelska)Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, artikel-id 127Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
BioMed Central, 2016
Nationell ämneskategori
Reumatologi och inflammation
Identifikatorer
urn:nbn:se:umu:diva-123978 (URN)10.1186/s13075-016-1031-0 (DOI)000377976100001 ()27255888 (PubMedID)
Tillgänglig från: 2016-09-06 Skapad: 2016-07-07 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
2. Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis
Öppna denna publikation i ny flik eller fönster >>Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis
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2016 (Engelska)Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, artikel-id 201Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
BioMed Central, 2016
Nationell ämneskategori
Reumatologi och inflammation
Identifikatorer
urn:nbn:se:umu:diva-126496 (URN)10.1186/s13075-016-1100-4 (DOI)000383162300002 ()27605245 (PubMedID)
Tillgänglig från: 2016-10-27 Skapad: 2016-10-10 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
3. Association between marginal jawbone loss and the onset of rheumatoid arhtritis and relationship to plasma levels of RANKL
Öppna denna publikation i ny flik eller fönster >>Association between marginal jawbone loss and the onset of rheumatoid arhtritis and relationship to plasma levels of RANKL
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2018 (Engelska)Ingår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 70, nr 4, s. 508-515Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
Oxford University Press, 2018
Nationell ämneskategori
Reumatologi och inflammation
Identifikatorer
urn:nbn:se:umu:diva-143006 (URN)10.1002/art.40394 (DOI)000428697300005 ()29195021 (PubMedID)
Tillgänglig från: 2017-12-14 Skapad: 2017-12-14 Senast uppdaterad: 2019-05-21Bibliografiskt granskad
4. Association between marginal jawbone loss and the onset of rheumatoid arhtritis and relationship to plasma levels of RANKL
Öppna denna publikation i ny flik eller fönster >>Association between marginal jawbone loss and the onset of rheumatoid arhtritis and relationship to plasma levels of RANKL
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2018 (Engelska)Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 70, nr 4, s. 508-515Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
Wiley-Blackwell, 2018
Nationell ämneskategori
Reumatologi och inflammation
Forskningsämne
reumatologi; odontologi
Identifikatorer
urn:nbn:se:umu:diva-146131 (URN)10.1002/art.40394 (DOI)000428697300005 ()29195021 (PubMedID)
Tillgänglig från: 2018-04-03 Skapad: 2018-04-03 Senast uppdaterad: 2019-05-20Bibliografiskt granskad

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