Prediction of disease progression in early rheumatoid arthritis by ICTP, RF and CRP. A comparative 3-year follow-up study

S. Åman, L. Paimela1, M. Leirisalo-Repo2, J. Risteli3, H. Kautiainen4, T. Helve5 and M. Hakala

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


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective.  To test the predictive value of the cross-linked carboxyterminal telopeptide of type I collagen (ICTP; a marker of type I collagen degradation), rheumatoid factor (RF) and C-reactive protein (CRP) for disease progression in patients with early rheumatoid arthritis (RA)

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.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Though in many cases rheumatoid arthritis (RA) is a progressive joint disease, its course is variable and individual, and there is a lack of reliable tests to assess its outcome. Of the traditional markers of the disease process used in inflammatory arthritis, radiographs mostly measure irreversible changes, while the erythrocyte sedimentation rate (ESR) reflects inflammatory activity [1]. X-rays have often been used as a gold standard when measuring the outcome in RA [2]. Although acute-phase reactants, such as C-reactive protein (CRP) and ESR, measure inflammation rather than tissue destruction [1, 3], they have been shown to correlate with subsequent erosiveness [46]. Recently, a number of promising biochemical markers of bone or cartilage degradation have been tested as measures of ongoing tissue destruction in joints, but none has proved sensitive enough to be useful in clinical practice [1]. It can be postulated that a combination of such markers rather than a single test would have a better prognostic value for aggressive joint disease [1, 7].

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.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Table 1Go shows the basic demographic characteristics of the 63 consecutive patients with early RA who were included in the study. All patients had newly diagnosed RA [16] with disease duration of <1 yr when assessed from the onset of the first symptoms. At the time of diagnosis, 73% (46/63) of the patients were RF-positive (RF >=20 IU/ml) and 57% (36/63) had joint erosions in the hands, feet or both. All the patients had normal kidney and liver function tests.


View this table:
[in this window]
[in a new window]
 
TABLE 1. Baseline demographic characteristics

 
None of the patients had previously received any DMARDs. Intramuscular gold treatment was instituted in 83% (52/63), sulphasalazine in 12% (8/63) and hydroxychloroquine in 5% (3/63) of the patients. If the DMARD therapy had to be withdrawn during follow-up because of side-effects or because of drug inefficacy, other DMARDs, individually tailored for each patient, were introduced (D-penicillamine, oral gold, azathioprine and methotrexate). The mean number of DMARDs used per patient during the 3-yr follow-up was 2.3 (range 1–6). Only three of the patients used peroral corticosteroids continuously (5–7.5 mg prednisolone daily).

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 1.6–4.6 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 Mann–Whitney 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.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Table 2Go shows the relationship of the initial CRP, ICTP and RF values and their combinations with the baseline Larsen score and the change in Larsen score from 0 to 3 yr. All the single tests (normal/negative vs elevated/positive) categorized patients into two prognostic groups with regard to the median change in Larsen score during the follow-up. This effect further strengthened when the laboratory tests were used in combination.


View this table:
[in this window]
[in a new window]
 
TABLE 2. Relationship of some laboratory tests and their combinations at baseline to Larsen score

 
Table 3Go shows the age- and sex-adjusted risks (OR) of different abnormal laboratory tests for progressive joint disease (change in Larsen score >20). It can be seen that different test combinations were the strongest predictors: elevated ICTP and positive RF (OR 9.1), ICTP and elevated CRP (OR 6.2), and CRP and RF (OR 5.7). The presence of any abnormal laboratory test value alone had low specificity, but the presence of both elevated ICTP and positive RF gave a sensitivity and specificity of >70% with a positive predictive value of 65%, and a likelihood ratio of 3.1 (Table 4Go).


View this table:
[in this window]
[in a new window]
 
TABLE 3. Age- and sex-adjusted risk (OR) of different abnormal laboratory tests for progressive joint disease (change in Larsen score >20)

 

View this table:
[in this window]
[in a new window]
 
TABLE 4. Laboratory features of the subsets with high risk of progressive joint disease (PJD)

 


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
There has been an intensive search for different outcome markers, such as tests measuring bone and cartilage degradation, to distinguish early RA cases with an aggressive disease course from those with a milder course. An ideal marker should be reliable, reproducible, sensitive, simple and inexpensive. Unfortunately, there is no consensus about the tests which should be generally used for disease prediction in RA. The lack of agreement concerning the current gold standard against which any new prognostic indicator should be compared further complicates the situation [7]. Thus, our main guides to therapy at present are the standard clinical and laboratory tests, such as ESR and CRP, and radiographs.

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.


    Acknowledgments
 
This study was supported in part by grants from the Health Research Council of the Academy of Finland, Oulu University Hospital and the Wilhelm and Else Stockman Foundation.


    Notes
 
Correspondence to: M. Hakala, Department of Internal Medicine, University of Oulu, FIN-90220 Oulu, Finland. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Peel N, Eastell R, Russell G. Markers of bone and collagen breakdown in early inflammatory arthritis. Baillieres Clin Rheumatol1992;6:351–72.[ISI][Medline]
  2. Brower AC. Use of radiograph to measure the course of rheumatoid arthritis. The gold standard versus fool's gold. Arthritis Rheum1990;33:316–24.[ISI][Medline]
  3. Kushner I. C-reactive protein in rheumatology. Arthritis Rheum1991;34:1065–8.[ISI][Medline]
  4. Möttönen T. Prediction of erosiveness and rate of development of new erosions in early rheumatoid arthritis. Ann Rheum Dis1988;47:648–53.[Abstract]
  5. Wollheim F, Pettersson H, Saxne T, Sjöblom K. Radiographic assessment in relation to clinical and biochemical variables in rheumatoid arthritis. Scand J Rheumatol1988;17:445–53.[ISI][Medline]
  6. Caruso I, Santandrea S, Puttini P, Boccassini L, Montrone F, Cazzola M et al. Clinical, laboratory and radiographic features in early rheumatoid arthritis. J Rheumatol1990;17:1263–7.[ISI][Medline]
  7. Young A, van der Heijde D. Can we predict aggressive disease? Baillieres Clin Rheumatol1997;11:27–48.[ISI][Medline]
  8. Risteli J, Elomaa I, Niemi S, Novamo A, Risteli L. Radioimmunoassay for the pyridinoline cross-linked carboxyterminal telopeptide of type I collagen: A new serum marker of bone collagen degradation. Clin Chem1993; 39:635–40.[Abstract/Free Full Text]
  9. Elomaa I, Virkkunen P, Risteli L, Risteli J. Serum concentration of the cross-linked carboxyterminal telopeptide of type I collagen (ICTP) is a useful prognostic indicator in multiple myeloma. Br J Cancer1992;66:337–41.[ISI][Medline]
  10. Aruga A, Kolzumi M, Hotta R, Takahashi S, Ogata E. Usefulness of bone metabolic markers in the diagnosis and follow-up of bone metastasis from lung cancer. Br J Cancer1997;76:760–4.[ISI][Medline]
  11. Paimela L, Leirisalo-Repo M, Risteli L, Hakala M, Helve T, Risteli J. Type I collagen degradation product in serum of patients with early rheumatoid arthritis. Relationship to disease activity and radiological progression in a 3-year follow-up. Br J Rheumatol1994;33:1012–6.[ISI][Medline]
  12. Kotaniemi A, Isomäki H, Hakala M, Risteli L, Risteli J. Increased type I collagen degradation in early rheumatoid arthritis. J Rheumatol1994;21:1593–6.[ISI][Medline]
  13. Hakala M, Risteli L, Manelius J, Nieminen P, Risteli J. Increased type I collagen degradation correlates with disease severity in rheumatoid arthritis. Ann Rheum Dis1993;52:866–9.[Abstract]
  14. Hassager C, Risteli J, Risteli L, Christiansen C. Effect of the menopause and hormone replacement therapy on the carboxyterminal pyridinoline cross-linked telopeptide of type I collagen. Osteoporosis Int1994;4:349–52.[ISI][Medline]
  15. Paimela L, Palosuo T, Leirisalo-Repo M, Helve T, Aho K. Prognostic value of quantitative measurement of rheumatoid factor in early rheumatoid arthritis. Br J Rheumatol1995;34:1146–50.[ISI][Medline]
  16. Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum1988;31:315–24.[ISI][Medline]
  17. Ritchie DM, Boyle JA, McInnes JM et al. Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Q J Med1968;37:393–406.[ISI][Medline]
  18. Nykänen M, Palosuo T, Aho K, Sahi K, von Essen R. Improved immunoturbidimetry for rheumatoid factor testing. J Clin Pathol1993;46:1065–6.[Abstract]
  19. Larsen A, Dale K, Eek M. Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol Diagn1977;18:481–91.[ISI]
  20. Scott DL, Houssien DA, Laasonen L. Proposed modification to Larsen's scoring methods for hand and wrist radiographs. Br J Rheumatol1995;34:56.[ISI][Medline]
  21. Paimela L, Laasonen L, Helve T, Leirisalo-Repo M. Comparison of the original and the modified Larsen methods and the Sharp method in scoring radiographic progression in early rheumatoid arthritis. J Rheumatol1998;25:1063–6.[ISI][Medline]
  22. Sassi M-L, Eriksen H, Risteli L, Niemi S, Mansell J, Gowen M, Risteli J. Immunochemical characterization of assay for the carboxyterminal telopeptide of human type I collagen. Loss of antigenicity by treatment with cathepsin K. Bone2000;26:367–73.
  23. Möttönen T, Hannonen P, Leirisalo-Repo M et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. Lancet1999;353:1568–73.[ISI][Medline]
  24. Otterness IG. The value of C-reactive protein measurement in rheumatoid arthritis. Semin Arthritis Rheum1994;24:91–104.[ISI][Medline]
  25. Gough A, Faint F, Salmon M, Hassell A, Wordsworth, Pilling D et al. Genetic typing of patients with inflammatory arthritis at presentation can be used to predict outcome. Arthritis Rheum1994;37:1166–70.[ISI][Medline]
  26. Paimela L, Leirisalo-Repo M, Helve T, Koskimies S. The prognostic value of HLA DR4 and B27 antigens in early rheumatoid arthritis. Scand J Rheumatol1993;22:220–4.[ISI][Medline]
  27. St Clair E, Moak S, Wilkinson W, Sanders L, Lang T, Greenwald R. A cross sectional analysis of 5 different markers of collagen degradation in rheumatoid arthritis. J Rheumatol1998;25:1472–9.[ISI][Medline]
  28. Cortet B, Flipo R-M, Pigny P et al. Is bone turnover a determinant of bone mass in rheumatoid arthritis? J Rheumatol1998;25:2339–44.[ISI][Medline]
  29. Hakala M, Åman S, Luukkainen R et al. Application of markers of collagen metabolism in serum and synovial fluid for assessment of disease process in patients with rheumatoid arthritis. Ann Rheum Dis1995;54:886–90.[Abstract]
Submitted 25 June 1999; revised version accepted 14 March 2000.