Markers of collagen metabolism in the assessment of rheumatoid arthritis.

With special reference to cross-linked carboxyterminal telopeptide of type I collagen (ICTP)

Sari Åman

Department of Internal Medicine

Abstract

The purpose of the present study was to investigate the value of different markers of collagen metabolism in assessing the disease process and further disease progression in patients with inflammatory arthritis, mainly rheumatoid arthritis (RA).

In a series of 59 patients with RA and knee joint effusion, the level of synovial fluid (SF) carboxyterminal telopeptide of type I collagen (ICTP), a marker for type I collagen degradation, was associated with the Larsens grade of the corresponding joint (p < 0.001). The mean SF concentrations of ICTP and the markers of type I and III collagen synthesis (the aminoterminal propeptides of type I and III procollagens, PINP and PIIINP) were higher than those in serum. In addition, the levels of these markers correlated with each other in both serum and SF (p < 0.001 in both occasions).

In a three-year follow-up study of 44 RA patients from the abovementioned series and 11 patients with other chronic arthritides, a high SF ICTP level turned out to reflect accelerated radiological progression in the assessed joint (p < 0.05). Contrary to this, the results on the SF leukocyte level were contradictory.

In a population-based cross-sectional series of 90 patients with advanced RA, elevated baseline serum ICTP levels discriminated the patients with a need for total joint replacement surgery from those with milder disease (p = 0.001) in a three-year follow-up.In a study of 52 patients with recent onset RA, the changes in BMD during a two-year follow-up were not associated with the serum level of markers of type I collagen metabolism. In this series, however, the decrease in BMD (measured in the spine and the femoral neck) was smaller than earlier reported.

In a three-year follow-up series of 63 patients with early RA, the patients with simultaneously elevated serum ICTP (> 4.6 mg/l) and RF positivity at baseline, had an increased risk for progressive joint disease (an increase in Larsens score > 20 as assessed from radiographs of hands and feet) with an odds ratio of 9.1 (95% CI 2.5 to 32.9). A risk profile of this kind may be useful in early disease assessment to identify the patients who will need the most active drug therapy.

Table of Contents

Acknowledgements

Abbreviations

List of original articles

1. Introduction

2. Review of the literature

2.1. Rheumatoid arthritis (RA)

2.2. Seronegative spondylarthropathies

2.3. Markers used in the diagnosis and assessment of RA

2.3.1. Genetic markers
2.3.2. Immunologic markers
2.3.3. Acute phase reactants

2.4. Type I-III collagens

2.4.1. Type I collagen
2.4.2. Type II collagen
2.4.3. Type III collagen

2.5. Non-collagenous bone formation markers

2.6. Products of type I and III collagen synthesis

2.6.1. Carboxyterminal propeptide of type I procollagen (PICP)
2.6.2. Aminoterminal propeptide of type I procollagen (PINP)
2.6.3. Aminoterminal propeptide of type III procollagen (PIIINP)

2.7. Degradation products of type I collagen

2.7.1. Collagen cross-links

2.8. Non-collagenous bone resorption markers

2.9. Collagen degradation enzymes

2.10. Synovial fluid analysis

2.10.1. Non-collagenous synthesis and breakdown products of synovial membrane, bone and cartilage in synovial fluid and serum

2.11. Osteoporosis

2.11.1. Bone mineral density and its measurement
2.11.2. Osteoporosis in rheumatoid arthritis

3. Purpose of the present study

4. Subjects and methods

4.1. Patients
4.2. Clinical examinations
4.3. Laboratory examinations
4.4. Measurement of RF
4.5. Radiographic examinations
4.6. Markers of collagen metabolism
4.7. Measurement of bone mineral density
4.8. Statistical analysis

5.1. Assessment of the disease process in inflammatory arthritis by serum and synovial fluid analysis (Studies I and IV)

5.1.1. Study I
5.1.2. Study IV

5.2. Relation of serum ICTP to the need for total joint replacement surgery (Study II)

5.3. Incidence of osteoporosis in a two-year follow-up of early RA (Study III)

5.3.1. Bone mineral density values
5.3.2. Serum PINP and ICTP concentrations
5.3.3. Laboratory, clinical and radiographic findings

5.4. Prediction of disease progression by ICTP, RF and CRP (Study V)

6. Discussion

6.1. Assessment of collagen metabolism in serum and synovial fluid

6.1.1. Study I
6.1.2. Study IV

6.2. Type I collagen degradation and need for total joint replacement surgery (Study II)

6.3. Incidence of osteoporosis (Study III)

6.4. Prediction of disease progression by ICTP, rheumatoid factor and C-reactive protein (Study V)

6.5. Biochemical and immunologic markers for diagnosis and outcome measurement in early RA

7. Conclusions

List of Tables
4-1. Basic demographic findings in the five studies at baseline. Study IV is a follow-up of study I with 44 of the RA patients from study I and 11 patients with other arthritides.
4-2. Physical function.
5-1. Median concentrations of three markers of collagen metabolism in the serum of 59 patients with rheumatoid arthritis (RA) and 90 healthy age- and sex-matched controls. ¶ = tested in 57 patients, S-ICTP = serum cross-linked carboxyterminal telopeptide of type I collagen, S PINP and S-PIIINP = serum aminoterminal propeptides of type I and type III procollagens, respectively. ** = p < 0.01, *** = p < 0.001, between groups.
5-2. Mean (SE) ratios of the three markers of collagen metabolism in synovial fluid in relation to radiographic findings in the joint (Larsen’s grade).
5-3. Correlations between the concentrations of the three markers of collagen metabolism in the synovial fluid (SF) and serum (S) of patients with rheumatoid arthritis.
5-4. Correlations between the markers of disease activity and collagen metabolism in patients with rheumatoid arthritis. ESR = erythrocyte sedimentation rate, CRP = C-reactive protein.
5-5. Distribution of Larsen’s grades of knee joints at entry and at the three-year visit.
5-6. Serum and synovial fluid markers of collagen metabolism and synovial fluid leukocytes in patients (44 RA, 7 chronic seronegative spondylarthropathy and 4 juvenile RA) with stable and deteriorating Larsen’s grade of knee joint at 0 and 3 years’ visit. S = serum, SF = synovial fluid, ICTP = cross-linked carboxyterminal telopeptide of type I collagen, PINP = aminoterminal propeptide of type I procollagen, PIIINP = aminoterminal propeptide of type III procollagen. * = p < 0.05.
5-7. Relation between the serum concentrations of ICTP at the baseline of a three-year follow-up and the number of total joint replacement operations. Altogether 18 total joint replacement were made on 10 patients. ICTP = cross-linked carboxyterminal telopeptide of type I collagen.
5-8. BMD values (g/cm²⁾ with Z and T scores in 52 patients with early rheumatoid arthritis (RA) at 0 and 24 months. ^a = based on the Finnish normal data by Kröger et al. (1992a, 1992b), BMD = bone mineral density, Z score = value of BMD as a fraction of the SD of the previously published normal value for patient’s sex and decade of age, T score = value of BMD as a fraction of the SD of the previously published normal value for the young adults (20-40 y) of the same sex.
5-9. Laboratory, clinical and radiographic findings of the patients during a 2-year follow-up. ICTP = cross-linked carboxyterminal telopeptide of type I collagen in serum (upper limit of reference interval 4.6 µg/l, Hakala et al. 1993), PINP = aminoterminal propeptide of type I procollagen in serum (upper limit of reference interval 67.9 µg/l, Study I), HAQ = Health Assessment Questionnaire, n.d. = not done.
5-10. Relation of some laboratory tests and their combinations at baseline to Larsen’s score. RF = Rheumatoid factor, CRP = C-reactive protein, ICTP = cross-linked carboxyterminal telopeptide of type I collagen, IQR = Inter-quartile range, * = Mann-Whitney rank-sum test with Bonferroni correction.
5-11. Age- and sex-adjusted risk (OR) of different abnormal laboratory tests for progressive joint disease (change in Larsen’s score > 20) calculated by logistic regression analysis. CI = Confidence interval. For abbreviations, see Table 5-10.
6-1. Biochemical and immunologic markers for diagnosis and outcome measurement in early RA. RF = rheumatoid factor, CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, COMP = cartilage oligomeric matrix protein, BSP = bone sialoprotein, ICTP = cross-linked carboxyterminal telopeptide of type I collagen, PYD = pyridinoline, DPYD = deoxypyridinoline.

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