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Predictors of disease onset and progression in early rheumatoid arthritis: A clinical, laboratory and radiological study
Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

To diagnose rheumatoid arthritis (RA) during the early stages of the disease is often difficult. The disease course shows great inter-individual variation from mild, self-limiting to very severe destruc-tive disease with extra-articular manifestations. Early aggressive treatment with potentially toxic drugs has been shown to improve the long-term outcome. Thus, it is desirable to make an early reliable di-agnosis and to identify those patients who would benefit from being treated most aggressively.

The aim of this thesis was to evaluate laboratory and clinically markers of inflammation as predic-tors of disease course, to compare dual-energy X-ray absorptiometry (DXA) and conventional radiog-raphy (CR) as measures of joint destruction and to investigate the significance of antibodies against cyclic citrullinated peptide (anti-CCP antibodies), rheumatoid factors (RFs) and HLA shared epitope (SE) alleles for the relative risk of future development of RA and as predictors of disease severity in patients with early RA.

Patients with RA of recent onset are included in the early RA programme at the Department of Rheumatology, University Hospital, Umeå and are followed longitudinally. The prediction of markers of inflammation for bone loss and radiological outcome was analyzed in the first 43 patients recruited. Radiographs of hands and feet (Larsen score) and bone mineral density (BMD) in hands (DXA), were assessed at baseline, after 1 and 2 years. The disease activity was evaluated clinically and by labora-tory tests. Radiological damage increased significantly during the study and was particularly corre-lated with Larsen score at baseline. BMD in hands decreased significantly in postmenopausal women and the decrease was greater than in healthy matched controls. Radiological progression and bone loss in hands was retarded by an early response to therapy.

In a case-control study within the Medical Biobank and the Maternity cohort of Northern Sweden, patients from the early RA programme were identified among blood donors from whom samples had been collected years before onset of symptoms. The prevalence of anti-CCP antibodies and RFs (IgA-RF, IgG-RF and IgM-RF) was investigated in samples from 83 individuals (pre-patients) and com-pared with matched controls. SE alleles were assessed in a sub-group of 59 individuals. Anti-CCP antibodies and RFs preceded onset of RA by several years and increased in prevalence closer to dis-ease onset. Anti-CCP antibodies and IgA-RF significantly predicted the onset of RA. The combination of anti-CCP antibodies and SE alleles was associated with a high relative risk for future development of RA.

In a later co-analysis between the register of patients in the early RA programme (n=138) and the Medical Biobank and the Maternity cohort, 93 pre-patient samples were identified. The significance of SE alleles and of the presence of anti-CCP antibodies and RFs before and at disease onset for disease activity and severity was studied. Radiographs of hands and feet were assessed at baseline and after 2 years (Larsen score). The presence of anti-CCP antibodies in pre-patient samples and at baseline was associated with radiological damage, as was presence of all RFs at baseline. A higher titre of anti-CCP antibodies was associated with greater radiological progression. The titre was lowered by a therapeutic response. In multiple logistic regression analyses anti-CCP antibodies, IgA-RF, ESR and swollen joint count predicted greater radiological progression, whilst a therapeutic response predicted a lesser pro-gression.

In conclusion, anti-CCP antibodies and IgA-RF are predictors for future onset of RA and for radio-logical destruction and progression. The combination of anti-CCP antibodies and SE alleles is associ-ated with a high relative risk for future RA. Therapeutic response decreases the radiological progres-sion and the bone loss in hands and lowers the titre of anti-CCP antibodies. Conventional radiography is a better measure of joint destruction than DXA.

Place, publisher, year, edition, pages
Umeå: Folkhälsa och klinisk medicin , 2006. , 62 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1001
Keyword [en]
Medicine, early, rheumatoid, arthritis, anti-CCP, antibodies, factors, radiological, outcome, disease, onset
Keyword [sv]
Medicin
National Category
Dermatology and Venereal Diseases
Research subject
Medicine
Identifiers
URN: urn:nbn:se:umu:diva-669ISBN: 91-7264-003-0 (print)OAI: oai:DiVA.org:umu-669DiVA: diva2:144188
Public defence
2006-01-27, D, 9 tr, Tandläkarhögskolan, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2006-01-02 Created: 2006-01-02 Last updated: 2009-09-28Bibliographically approved
List of papers
1. Predictors of radiological progression and changes in hand bone density in early rheumatoid arthritis
Open this publication in new window or tab >>Predictors of radiological progression and changes in hand bone density in early rheumatoid arthritis
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2003 (English)In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 42, no 2, 268-275 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To identify predictors for radiological and functional outcome and bone loss in the hands in early rheumatoid arthritis (RA) during the first 2 yr of disease and to study the relationship between these variables.

METHODS: An inception cohort of consecutively recruited patients was examined at baseline and after 12 and 24 months using X-rays of hands and feet, clinical [28-joint count, Health Assessment Questionnaire (HAQ), global visual analogue scale (VAS), grip strength] and laboratory (erythrocyte sedimentation rate, C-reactive protein, markers of bone formation and resorption) measurements and dual-energy X-ray absorptiometry measurements of the hands.

RESULTS: Joint destruction increased significantly during the study, with the Larsen score at baseline as the strongest predictor. Radiological progression and bone loss over 24 months were significantly retarded in patients responding to therapy. The effects of the shared epitope and initial high inflammatory activity on radiological progression were overridden by the therapeutic response. Radiological progression correlated significantly with bone loss. Global VAS, Larsen score and HAQ at inclusion significantly predicted change in HAQ over time.

CONCLUSIONS: Radiological progression and bone loss were retarded by early therapeutic response. Bone loss was related to radiological progression.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-21636 (URN)10.1093/rheumatology/keg077 (DOI)12595621 (PubMedID)
Available from: 2009-04-14 Created: 2009-04-14 Last updated: 2017-12-13Bibliographically approved
2. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis.
Open this publication in new window or tab >>Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis.
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2003 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 48, no 10, 2741-2749 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-4907 (URN)10.1002/art.11223 (DOI)14558078 (PubMedID)
Available from: 2006-01-02 Created: 2006-01-02 Last updated: 2011-04-01Bibliographically approved
3. A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis.
Open this publication in new window or tab >>A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis.
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2004 (English)In: Arthritis Research & Therapy, ISSN 1478-6362, Vol. 6, no 4, R303-R308 p.Article in journal (Refereed) Published
Keyword
Adult, Aged, Arthritis; Rheumatoid/blood/*etiology, Autoantibodies/*adverse effects/*biosynthesis, Case-Control Studies, Cohort Studies, Female, HLA-DR Antigens/*immunology, Humans, Male, Middle Aged, Peptides; Cyclic/*immunology, Rheumatoid Factor/blood
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-12915 (URN)10.1186/ar1187 (DOI)15225365 (PubMedID)
Available from: 2007-11-23 Created: 2007-11-23 Last updated: 2015-04-22Bibliographically approved
4. Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgA-RF at disease onset.
Open this publication in new window or tab >>Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgA-RF at disease onset.
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2006 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 65, no 4, 453-458 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To evaluate the significance of antibodies against cyclic citrullinated peptide (anti-CCP) and rheumatoid factors (RFs), before the onset of rheumatoid arthritis and when presenting as early disease (baseline), for disease activity and progression. METHODS: 93 of a cohort of 138 patients with early rheumatoid arthritis (<12 months of symptoms) had donated blood before symptoms of rheumatoid arthritis (defined as pre-patients) and were identified from among blood donors within the Medical Biobank of northern Sweden. Disease activity (erythrocyte sedimentation rate (ESR), C reactive protein, joint score, global visual analogue scale) and radiological destruction in hands and feet (Larsen score) were assessed at baseline and after two years. Anti-CCP antibodies and RFs were analysed using enzyme immunoassays. HLA shared epitope (SE) alleles (DRB1*0401/0404) were identified. RESULTS: Patients with anti-CCP antibodies before disease onset had significantly higher Larsen score at baseline and after two years. In multiple regression analyses baseline values of anti-CCP/IgA-RF/IgG-RF/IgM-RF, swollen joint count, and Larsen score significantly predicted radiological outcome at two years. In logistic regression analyses, baseline values of anti-CCP antibodies/IgA-RF, therapeutic response at six months, and swollen joint count/ESR significantly predicted radiological progression after two years. The baseline titre of anti-CCP antibodies was higher in patients with radiological progression and decreased significantly in those with response to therapy. SE allele carriage was associated with a positive test for anti-CCP antibodies in pre-patients and in early rheumatoid arthritis. CONCLUSIONS: Presence of anti-CCP antibodies before disease onset is associated with more severe radiological damage. The titre of anti-CCP antibodies is related to disease severity.

Identifiers
urn:nbn:se:umu:diva-20691 (URN)10.1136/ard.2005.041376 (DOI)16176994 (PubMedID)
Available from: 2009-03-24 Created: 2009-03-24 Last updated: 2017-12-13

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