Division of Rheumatology, Department of Internal Medicine, University of Oulu, Oulu,
1 Orton Rehabilitation Centre, Invalid Foundation, Helsinki,
2 Division of Rheumatology, Department of Medicine, Helsinki University Central Hospital, Helsinki,
3 Department of Clinical Chemistry, University of Oulu, Oulu,
4 Rheumatism Foundation Hospital, Heinola and
5 Helsinki City Hospital, Helsinki, Finland
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Abstract |
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Method. We tested the value of baseline values of RF, CRP and ICTP for the prediction of radiological joint progression over 3 yr in 63 consecutive patients with early RA who were treated with the saw-tooth strategy.
Results. Age- and sex-adjusted risks as odds ratios (95% confidence intervals) of elevated serum ICTP, RF positivity and increased CRP for progressive joint disease (defined as an increase of >20 in Larsen's index on radiographs of the hands and feet) were 3.9 (1.3, 11.9), 3.9 (1.0, 15.5) and 2.6 (0.9, 7.5), respectively. Better prediction was achieved when the tests were used in combination, and where there was both elevated ICTP and positive RF the odds ratio was 9.1 (2.5, 32.9). This test combination showed good sensitivity and specificity (71 and 77%, respectively), with a positive predictive value of 65% and a likelihood ratio of 3.1.
Conclusion. This kind of risk profile, in which the tests used reflect different aspects of the disease process, may be useful in early disease assessment to find patients who will need the most active drug therapy.
KEY WORDS: Prognosis, Joint destruction, Collagen degradation, ICTP, C-reactive protein, Rheumatoid factor, Rheumatoid arthritis.
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Introduction |
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An example of a biochemical test to assess bone metabolism is the cross-linked carboxyterminal telopeptide of type I collagen (ICTP) [8], a marker of type I collagen degradation. The ICTP assay has turned out to be a reliable marker of increased type I collagen degradation in situations that include local destruction of bone tissue, such as multiple myeloma [9], bone metastases from carcinomas [10] and both early [11, 12] and advanced [13] RA. On the other hand, the circulating ICTP levels do not reflect accelerated or retarded physiological bone resorption, such as is seen in the postmenopausal state or during oestrogen replacement therapy [14].
In the previous analyses of the present series of early RA, we showed serum rheumatoid factor (RF), CRP and ICTP to have predictive value for radiological joint damage in a 3-yr follow-up [11, 15]. This RA series was treated with the saw-tooth strategy, i.e. another individually tailored disease-modifying anti-rheumatic drug (DMARD) was introduced if the previous one had to be withdrawn because of side-effects or drug inefficacy. In the present series our aim was to test whether disease prediction could be improved in a case where a marker of tissue degradation, i.e. serum ICTP, was used in combination with a common laboratory test, such as RF or CRP. Such an analysis could be used to differentiate patients who will need the most aggressive therapy from those who can be treated with DMARD monotherapy.
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Patients and methods |
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Clinical, radiological and laboratory assessment
The clinical variables of disease activity included the assessment of the number of swollen joints and the Ritchie articular index [17]. A visual analogue scale (VAS) was used to assess pain. CRP (normal value <10 mg/l), RF and ICTP were assessed at entry. A Kone specific automated clinical chemistry analyser (Kone Instruments, Espoo, Finland) was used for immunoturbidimetric measurements of RF. An assay modification using chemical inactivation of C1q with polyvinyl sulphonate was used as previously described [18]. This method shows 95% of healthy subjects to have an RF level <20 IU/ml, which was taken as the cut-off point for seropositivity.
Radiographs of the hands and feet taken at entry and after 3 yr were evaluated with the method of Larsen et al. [19] by the same observer (T.H.) consecutively and without knowledge of the clinical data. The joints assessed included eight proximal interphalangeal joints, two interphalangeal (IP) joints of the thumbs, 10 metacarpophalangeal joints, the left and right wrists, 10 metatarsophalangeal joints and two hallux IP joints. The scores for the wrists were multiplied by 5. The maximum possible total score was 210. We followed the proposed modified rules for Larsen's scoring system, in which a score of 1 is used for periarticular osteoporosis/joint swelling if these are major features [20]. We have tested the reproducibility of the modified Larsen method [21]. The interobserver reproducibility (intraclass correlation coefficient) was 0.90, and the intraobserver reproducibility for two observers was 0.98 and 0.99.
Altogether 38% (24/63) of the patients had progressive erosive disease course during the follow-up (change in Larsen score >20).
Measurement of serum ICTP concentration
Serum samples were collected in the morning and stored at -20°C until analysed. ICTP was measured by radioimmunoassay as described earlier [8, 11]. The reference interval of serum ICTP is 1.64.6 µg/l [13]. The standard and tracer antigens of the test are cross-linked ICTP collagen liberated by digestion from decalcified human femoral bone with bacterial collagenase. The ICTP antigen isolated after either trypsin or bacterial collagenase digestion contains three peptides originating in two type I collagen molecules and a mature, trivalent collagen cross-link joining these. In addition, cathepsin K destroys its antigenicity, indicating that the increased amounts of circulating ICTP cannot be derived from normal (osteoclastic cathepsin K-mediated) physiological bone resorption [22].
Statistical analysis
The significance of the difference in Larsen score values between the groups formed according to the baseline laboratory values was determined by the MannWhitney rank-sum test with Bonferroni correction for multiple comparisons. For all the tests, P < 0.05 was considered significant.
In the preliminary analysis, Spearman's rank correlation coefficient test was used to analyse the relationship between different variables at disease onset and the change in the Larsen score during the follow-up. The variables tested were age, ESR, CRP, baseline Larsen score, ICTP, quantitative RF, Ritchie articular index, number of swollen joints, VAS pain, HLA-DR4 status and the duration of symptoms. Of the above variables, the six first showed a statistically significant correlation with the change in the Larsen score. We estimated the age- and sex-adjusted risks of dichotomously expressed CRP, RF and ICTP tests or their combinations for radiological progression by multivariate logistic regression analysis. A score of 20 was used as the cut-off point for the change in Larsen score from baseline to 36 months, and the upper limit of the normal range as the cut-off point for the laboratory variables. ESR, which is closely related to CRP, was omitted from the model. The results were expressed as odds ratios (OR) with 95% confidence intervals (CI). The sensitivity, specificity, positive predictive value and likelihood ratio were calculated for the laboratory test results and their combinations.
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Results |
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Discussion |
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In the present series of patients, we assessed the power of abnormal laboratory test results to predict the disease process. It was shown that progressive joint disease (change in Larsen score >20 over 3 yr) was more likely to occur in a patient who had, at diagnosis, elevated serum ICTP (>4.6 µg/l) combined with either positive RF (OR 9.1, 95% CI 2.5, 32.9) or elevated CRP (10 mg/l) (OR 6.2, 95% CI 1.8, 21.3) or had both positive RF and abnormal CRP (OR 5.7, 95% CI 1.7, 19.0) than in a patient without simultaneous presentation of these changes. We think that the prediction achieved by the combination of elevated ICTP with positive RF is of sufficient accuracy to be considered for clinical use as it shows high sensitivity (71%) and specificity (77%), and a positive predictive value of 65%. When any of the tests was used alone the associations were weaker, and in the case of CRP the relationship was not statistically significant.
The treatment schedule used in the present series was a typical saw-tooth strategy. Thus, the DMARD instituted initially was replaced by another in case of inefficacy or side-effects. Despite the relatively good clinical response, however, which was reflected in the rapid mean decline of CRP, ICTP declined more gradually and most patients showed radiological progression [11]. A randomized study of early RA from Finland showed that DMARD combination therapy retards radiological progression more effectively than monotherapy [23]. How this is reflected in tissue-derived degradation products is not yet known. However, the present risk profile could be useful in differentiating patients who will need the most aggressive therapy from those with a mild disease course, who can be treated with a single DMARD.
Several studies have shown that CRP correlates with radiological progression [24]. On the other hand, RF is still postulated to be the most powerful single predictor of erosive disease in spite of the huge number of laboratory measures tested since the 1940s [7]. Other factors, including poor function, female gender, articular index, the HLA-DRB1 shared epitope and acute-phase reactants, may influence the outcome adversely, but are either no better than RF or unreliable when used alone [7]. There are, however, some data to show that the presence of both the RA-associated HLA epitope and RF positivity give satisfactory prediction of erosive joint disease in early RA [25]. It should be noted, however, that HLA-DR4 status showed no prognostic value for radiological progression in our earlier analysis made from this same series [26].
Type I collagen accounts for about 90% of the organic matrix of bone and is the major matrix protein in tendons, ligaments and soft connective tissues. Thus, an assessment of its breakdown is thought to be useful in diseases in which there is connective tissue degradation, such as RA. No comparative study of the different measures of type I collagen degradation has been performed in early RA, but a recent cross-sectional analysis of these markers in advanced RA showed serum ICTP together with urinary pyridinoline to be superior to urinary excretion of deoxypyridinoline, the aminoterminal cross-linked telopeptide of type I collagen (NTx) and CrossLapsTM (XL) in discriminating between patients with RA and controls [27]. ICTP and pyridinoline also had minimal short-term, day-to-day variability, and the authors proposed that evaluating these measures may be useful in the assessment of the effectiveness of new, potentially disease-modifying therapies [27]. In contrast to urinary pyridinoline excretion, serum ICTP assay is readily available and easy to perform [28].
The epitope measured by the ICTP assay has been localized [22]. Studies of the in vitro degradation of the ICTP antigen by various proteinases suggest that the increased circulating concentrations of ICTP found in several clinical situations, such as bone metastases and RA, are probably produced by matrix metalloproteinases, whereas cathepsin K-mediated, osteoclastic resorption destroys ICTP antigenicity [22].
Serum ICTP has been shown to correlate with the extent of joint inflammation, as measured by the Lansbury index in early RA [12]. In addition, compared with other collagen-derived peptides, the synovial fluid:serum ratio of this collagen marker is rather low [29]. Hence, it seems that the elevation of ICTP in the sera of patients with RA is mostly due to its direct liberation from the periarticular bone and synovial tissue of inflamed joints into the circulation [13, 28].
In the present series, the idea was to test the value of a tissue (collagen) degradation marker, serum ICTP, in combination with classical laboratory tests, i.e. CRP and RF, particularly as each marker represents different aspects of the disease process. It was found that initially elevated serum ICTP combined with abnormal RF could serve as a predictive combination for an aggressive disease course in early RA.
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Acknowledgments |
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Notes |
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References |
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