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Antibodies against mutated citrullinated vimentin are a better predictor of disease activity at 24 months in early rheumatoid arthritis than antibodies against cyclic citrullinated peptides
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
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2008 (English)In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 35, no 6, 1002-1008 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To evaluate the predictive values for disease progression of various antibodies against citrullinated peptide proteins (ACPA) and their relation to PTPN22 1858C/T polymorphism and HLA-DRB1 alleles in early rheumatoid arthritis (RA).

METHODS: The ACPA, e.g., antibodies against mutated citrullinated vimentin (MCV), cyclic citrullinated peptides (CCP) type 2 and 3 (both of IgG isotype) and 3.1 (of both IgG and IgA isotypes), were analyzed at baseline in patients with early RA (n = 210) and in population controls (n = 102) using an enzyme immunoassay. A receiver-operating characteristic curve was constructed for each antibody. Disease activity [swollen and tender joints, visual analog scale for global health, and erythrocyte sedimentation rate (ESR)] was evaluated at baseline and regularly for 24 months. Radiographs of hands and feet were graded using the Larsen score.

RESULTS: Patients with anti-MCV antibodies had significantly less reduction in Disease Activity Score (DAS28) over time (p < 0.01), and significantly increased area under the curve (AUC) for DAS28 (p < 0.05), ESR (p < 0.01), C-reactive protein (p < 0.01), and swollen joint count (p = 0.057) compared to those without. Corresponding differences were not found in patients with anti-CCP2, CCP3, and CCP3.1 antibodies. Radiological progression (p < 0.0001-0.01) and radiological outcome (p < 0.0001-0.01) at 24 months were significantly predicted by all ACPA after baseline adjustments. PTPN22 T variant and HLA-DRB1 alleles were not related to radiological progression or inflammatory activity over time.

CONCLUSION: Anti-MCV antibodies are associated with a more severe RA disease, as measured by DAS28, ESR, and swollen joint count over time, compared with anti-CCP2, CCP3, and CCP3.1 antibodies. Radiological progression was predicted equally by all 4 autoantibodies.

Place, publisher, year, edition, pages
2008. Vol. 35, no 6, 1002-1008 p.
Keyword [en]
anti-cyclic citrullinated peptide 2, antibodies anti-cyclic citrullinated peptide 3 antibodies, anti-mutated citrullinated vimentin antibodies, early rheumatoid arthritis, rheumatoid factors
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:umu:diva-19191ISI: 000256503900013PubMedID: 18398946OAI: oai:DiVA.org:umu-19191DiVA: diva2:201549
Available from: 2009-03-05 Created: 2009-03-05 Last updated: 2014-05-07Bibliographically approved
In thesis
1. Pathogenetic factors of importance for the development and progression of rheumatoid arthritis
Open this publication in new window or tab >>Pathogenetic factors of importance for the development and progression of rheumatoid arthritis
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation eventually leading to the destruction of cartilage and bone. The aetiopathogenesis is not completely understood, but previous studies have shown that the disease is multifactorial with genetic, environmental and hormonal factors involved. Immune cells, e.g., T- and B-cells, and macrophages, migrate into the joints, with increased expression of numerous soluble factors such as cytokines, chemokines and adhesion molecules functionally active both locally and systemically. Analyses of blood samples from the Medical Biobank in Umeå from individuals before the onset of symptoms of joint disease showed that anti-citrullinated protein/peptide antibodies (ACPA) preceded the development of disease by years and this finding has been confirmed by other studies.                                        

The aim of this thesis was to identify signs of activation of the immune system analysed as up-regulation of pro- and anti-inflammatory cytokines, sero-positivity for autoantibodies, and genetic factors identified as relevant for the development and disease progression of RA. The concentrations of 30 cytokines and chemokines were measured in blood samples from individuals before the onset of symptoms, and when diagnosed with RA, together with population-based matched controls using a multiplex system. The predictive value of different isotypes (IgG, IgA, and IgM) of ACPA and rheumatoid factor (RF) before onset of symptoms and different types of ACPA (e.g., mutated citrullinated vimentin, MCV) were analysed for disease development and progression in patients with early RA and controls from Northern Sweden. These factors were related to the genetic markers, HLA- shared epitope (SE) alleles and the 1858C/T polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene.                           

In paper I, it was shown that in individuals who later developed RA (i.e., pre-patients) the levels of several cytokines and related factors that represent the adaptive immune system (Th1, Th2, and T regulatory cell related factors) were significantly elevated compared with controls, whereas, after the onset of disease the involvement of the immune system was more general and widespread. In paper II, the presence of different isotypes (IgM, IgA and IgG) of ACPA in pre-patients, patients and controls was evaluated showing that both the IgG and IgA isotype predicted the onset of RA by years with the IgG isotype having the highest predictive value. In paper III, the association of the 1858T variant of PTPN22 with RA was confirmed. Furthermore, the association was restricted to autoantibody positive disease and this variant was correlated with an earlier age for disease onset. In paper IV, anti-MCV antibodies were identified as being associated with a more severe disease course of RA, measured by disease activity score, erythrocyte sedimentation rate, and swollen joint count over time compared with anti-CCP2, anti-CCP3, and anti-CCP3.1 antibodies.                                                                                               

In conclusion, individuals who later developed RA had increased concentrations of inflammatory markers reflecting an activation of the immune system years before the clinical symptoms of the disease developed. Also, the presence of ACPA of IgG and IgA isotype prior to disease onset predicted the development of RA. The PTPN22 1858T variant was associated with sero-positive RA and anti-MCV antibodies were associated with a higher inflammatory activity compared with anti-CCP2, -CCP3 and -CCP3.1 antibodies. These findings together present a possibility to better predict the development and progression of RA.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2012. 80 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1490
Keyword
rheumatoid arthritis, cytokines, autoantibodies, isotypes, PTPN22, HLA-SE
National Category
Rheumatology and Autoimmunity
Research subject
Medicine, rheumatology
Identifiers
urn:nbn:se:umu:diva-54003 (URN)978-91-7459-403-4 (ISBN)
Public defence
2012-05-03, Sal B, 9 tr, byggnad 1D, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council, K2003-74XD-14705-01, K2007-52X-20307-01-3, K2008-52X-20611-01-3, K2010-52X-20307-04-3
Available from: 2012-04-12 Created: 2012-04-11 Last updated: 2012-04-12Bibliographically approved
2. Early rheumatoid arthritis aspects of severity and co-morbidity
Open this publication in new window or tab >>Early rheumatoid arthritis aspects of severity and co-morbidity
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background Rheumatoid arthritis (RA) is a systemic progressive destructive joint disease with an increased risk for co-morbidity and premature death if untreated. Cardiovascular disease (CVD) is the main cause of death but also other co-morbid conditions contribute to the patient’s shorter life expectancy. Inflammation is important for the development of CVD, but knowledge of its relationship with other co-morbidities is sparse. Early disease modifying anti rheumatic drugs (DMARDs) can suppress disease activity and improve the long-term outcome. The aim of this thesis was to evaluate prospectively aspects of disease activity and severity in a large cohort of patients with early RA. Predictive and prognostic markers, e.g., antibodies against citrullinated proteins/peptides (ACPAs), occurring in early disease and with implications for disease outcome and co-morbidity were evaluated.

Methods Patients with early RA (i.e., symptomatic for ≤12 months) have, since December 1995, been consecutively included in a large survey of prospective and observational studies on the progression of RA and the development of co-omorbidity. Autoantibodies, inflammatory, genetic markers and radiographs have been analyzed. In paper I, 210 RA patients and 102 controls were followed regularly for two years. The predictive value of four different ACPAs in relation to disease activity and radiological progression was evaluated. In Paper II (n = 700) and in Papers III-IV (n =950), patients with early RA from the four northern-most counties of Sweden were followed regularly for 5 years. Data on risk factors and co-morbidity was collected, according to the study protocol, from clinical records and self-reported questionnaires from patients at inclusion into the study cohort and after five years. The predictive value of traditional and potential disease related risk factors for new cardiovascular events (CVE) was evaluated (II). In Paper III, the impact of age at the onset RA, stratified as being young onset RA (<58 years; YORA) and late onset RA (≥58 years; LORA) on disease activity, severity and chosen treatment, was evaluated. In Paper IV, the development of new co-morbidities after RA onset and their relation to inflammatory activity was assessed.

Results The presence of anti-mutated citrullinated vimentin (MCV ) antibodies was associated with a more severe disease course, estimated by disease activity score, erythrocyte sedimentation rate (ESR) and swollen joint count after 24 months, compared with anti-CCP2, anti-CCP3, and anti CCP3.1 antibodies. In Paper II, the incidence of a new CVE during 5 years was explained by several of the traditional CV risk factors, and potentiated by a high disease activity. Treatment with DMARDs decreased the risk. In Paper III, LORA patients were associated with greater disease activity/severity at disease onset and over time compared with YORA who were more often ACPA positive. YORA patients were treated earlier with DMARDs, whilst LORA patients were more often treated with corticosteroids and less so with DMARDs early in the course of their disease. In Paper IV, 53%of patients already had one or more co-morbidities already at the onset of RA. After 5 years, 41% of the patients had developed at least one new co-morbidity. ESR at baseline and accumulated disease activity were associated with a new co-morbidity after five years.

Conclusion Early RA patients sero-positive for anti- MCV antibodies appeared to have a higher disease activity over time. The occurrence of a new CVE in early RA patients was predicted by traditional risk factors for CVD which were potentiated by a high disease activity. Treatment with DMARDs decreased the risk. Patients with young onset of RA were associated with a higher frequency of ACPA. Late onset of RA was associated with higher disease activity/severity at inclusion and over time. However, LORA patients were more often treated with corticosteroids and less so with DMARDs early in the disease course. Development of a new co-morbidity during the five years following diagnosis was related to ESR.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2014. 85 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1651
Keyword
Early rheumatoid arthriti, ACPA, cardiovascular co-morbidity, age at onset, pharmacological therapy, severity, disease activity, co-morbidity
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-88477 (URN)978-91-7601-059-4 (ISBN)
Public defence
2014-05-28, Hörsal Major Groove, Norrlands Universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2014-05-07 Created: 2014-05-06 Last updated: 2014-05-07Bibliographically approved

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Innala, LenaKokkonen, HeidiEriksson, CatharinaJidell, ErikBerglin, EwaRantapää Dahlqvist, Solbritt

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