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Early rheumatoid arthritis aspects of severity and co-morbidity
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
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 [en]
Early rheumatoid arthriti, ACPA, cardiovascular co-morbidity, age at onset, pharmacological therapy, severity, disease activity, co-morbidity
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:umu:diva-88477ISBN: 978-91-7601-059-4 (print)OAI: oai:DiVA.org:umu-88477DiVA: diva2:715848
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
List of papers
1. 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
Open this publication in new window or tab >>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
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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.

Keyword
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:nbn:se:umu:diva-19191 (URN)000256503900013 ()18398946 (PubMedID)
Available from: 2009-03-05 Created: 2009-03-05 Last updated: 2017-12-13Bibliographically approved
2. Cardiovascular events in early rheumatoid arthritis (RA) are a result of inflammatory burden and traditional risk factors: a five year prospective study
Open this publication in new window or tab >>Cardiovascular events in early rheumatoid arthritis (RA) are a result of inflammatory burden and traditional risk factors: a five year prospective study
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2011 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 13, no 4, R131- p.Article in journal (Refereed) Published
Abstract [en]

Introduction Co-morbidity and mortality due to cardiovascular disease (CVD) are increased in patients with rheumatoid arthritis (RA). Most published studies in this field are retrospective or cross sectional. We investigated the presence of traditional and disease related risk factors for CVD at the onset of RA and during the first 5 years following diagnosis. We also evaluated their potential for predicting a new cardiovascular event (CVE) during the 5 year follow-up period and the modulatory effect of pharmacological treatment.

Methods All patients from the four northern-most counties of Sweden with early RA are since December 1995 consecutively recruited at diagnsosis (T0) into a large survey on the progress of the disease. Information regarding cardiovascular co-morbidity and related predictors was collected from clinical records and supplemented with questionnaires. By April 2008, 700 patients had been included of whom 442 patients had reached the 5-year follow-up (T5).

Result Among the 442 patients who reached T5 during the follow-up period, treatment for hypertension increased from 24.5 to 37.4% ( p<0.001)), diagnosis of diabetes mellitus (DM) from 7.1 to 9.5%(p<0.01) whilst smoking decreased from 29.8 to 22.4 % ( p<0.001) and the BMI from 26.3 to 25.8( p<0.05) , respectively. By T5, 48 patients had suffered a new CVE of which 12 were fatal. A total of 23 patients died during the follow-up period. Age at disease onset, male sex, a previous CVE, DM, treatment for hypertension, triglyceride level, cumulative disease activity (AUC DAS28), extra-articular disease, corticosteroid use, shorter duration of treatment with DMARDs and use of COX-2 inhibitors increased the hazard rate for a new CVE. A raised ESR at inclusion and AUC DAS28 at 6 months increased the hazard rate of CVE independently whilst DMARD treatment was protective in multiple Cox extended models adjusted for sex and CV risk factors. The risk of a CVE due to inflammation was potentiated by traditional CV risk factors.

Conclusion The occurrence of new CV events in very early RA was explained by traditional CV risk factors and was potentiated by high disease activity. Treatment with DMARDs decreased the risk. The results may have implications for cardio-protective strategies in RA.

National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-45903 (URN)10.1186/ar3442 (DOI)000297150200022 ()21843325 (PubMedID)
Available from: 2011-08-19 Created: 2011-08-19 Last updated: 2017-12-08Bibliographically approved
3. Age at onset determines severity and choice of treatment in early rheumatoid arthritis
Open this publication in new window or tab >>Age at onset determines severity and choice of treatment in early rheumatoid arthritis
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2012 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no 10, S908-S908 p.Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
John Wiley & Sons, 2012
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-61976 (URN)000309748305065 ()
Conference
Annual Scientific Meeting of the American-College-of-Rheumatology (ACR) and Association-of-Rheumatology-Health-Professionals (ARHP), NOV 09-14, 2012, Washington, DC
Available from: 2012-12-14 Created: 2012-12-04 Last updated: 2017-12-06Bibliographically approved
4. Comorbidity in patients with early rheumatoid arthritis: does inflammation matter?
Open this publication in new window or tab >>Comorbidity in patients with early rheumatoid arthritis: does inflammation matter?
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(English)Manuscript (preprint) (Other academic)
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-88498 (URN)
Available from: 2014-05-07 Created: 2014-05-07 Last updated: 2014-05-07Bibliographically approved

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