| Markers of collagen metabolism in the assessment of rheumatoid arthritis.: With special reference to cross-linked carboxyterminal telopeptide of type I collagen (ICTP) | ||
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Table 5-1 shows that the mean concentrations of the three markers of collagen metabolism were higher in the sera of the patients with RA than in the controls.
Table 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.
| Concentration (µg/l) | RA patients | Controls | |
|---|---|---|---|
| S-ICTP | 5.3 | *** | 3.0 |
| Value > (mean + 2SD) (% of patients) | 58 | ||
| S-PINP ¶ | 42.7 | ** | 33.0 |
| Value > (mean + 2SD) (% of patients) | 19 | ||
| S-PIIINP ¶ | 4.6 | *** | 3.1 |
| Value > (mean + 2SD) (% of patients) | 42 |
The median (SD, range) SF concentrations were 16.7 (18.1, 2.8-96.9) µg/l for ICTP, 782 (903, 118-5017) µg/l for PINP, and 1478 (857, 278-4781) µg/l for PIIINP. The SF:S ratios for the individual markers of collagen metabolism were 4.0 (95% CI 3.3-4.8) for ICTP, 25.2 (95% CI 19.7-30.8) for PINP, and 340 (95% CI 295-385) for PIIINP.
Because the volume of joint effusion may change rapidly, making the assessment of concentrations inappropriate, we also calculated the values as ratios of one compound to another, which are shown in relation to the radiographic state (Larsen’s grade) of the corresponding joint in Table 5-2.
Table 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).
| Larsen’s grade | Marker ratio | ||
|---|---|---|---|
| PINP:ICTP | PIIINP:ICTP | PIIINP:PINP | |
| 0-1 | 71.3 (14.9) | 120.4 (21.0) | 1.7 (0.4) |
| 2 | 61.1 (12.4) | 95.2 (17.6) | 2.1 (0.3) |
| 3 | 61.8 (15.4) | 92.9 (21.8) | 2.1 (0.4) |
| 4-5 | 36.2 (17.6) | 62.2 (24.9) | 1.7 (0.4) |
Table 5-3 gives the correlations observed between the levels of the different markers of collagen metabolism in the serum and synovial fluid of patients.The strongest correlations emerged between PIIINP and ICTP in serum and between PINP and PIIINP in SF. In addition, the two markers of synthesis in SF had distinct correlations with SF-ICTP. A significant correlation was also found between the synovial fluid and serum concentrations of each individual marker.
Table 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.
| SF (p) | S (p) | ||||||
|---|---|---|---|---|---|---|---|
| ICTP | PINP | PIIINP | ICTP | PINP | |||
| SF-PINP | rs | 0.69 (<0.001) | |||||
| SF-PIIINP | rs | 0.65 (<0.001) | 0.86 (< 0.001) | ||||
| S-ICTP | rs | 0.55 (<0.001) | 0.32 (0.016) | 0.34 (0.010) | |||
| S-PINP | rs | 0.42 (0.001) | 0.29 (0.027) | 0.33 (0.013) | 0.50 (<0.001) | ||
| S-PIIINP | rs | 0.54 (<0.001) | 0.39 (0.003) | 0.39 (0.003) | 0.81 (<0.001) | 0.53 (<0.001) | |
In the controls, the following correlations were found between the serum concentrations of the markers of collagen metabolism: rs = 0.48, p < 0.001 for PINP vs ICTP; rs = 0.51, p < 0.001 for PIIINP vs ICTP; rs = 0.34, p = 0.001 for PINP vs PIIINP. The balance of type I collagen metabolism, as assessed by the ratio (mean(SD)) of S-PINP:S-ICTP, was in favour of degradation in the patients compared with the controls: 9.4 (5.4) and 12.1 (4.9), respectively (p < 0.001).
Table 5-4 shows the correlations between the indicators of disease activity and those of collagen metabolism. Both S-ICTP and S-PIIINP showed positive correlations with the disease activity markers. None of the markers in SF correlated with the number of leukocytes or the number of polymorphonuclear leukocytes in SF.
The S-PINP values did not differ relative to menopausal state, but increased S-ICTP and S-PIIINP concentrations were more common among the postmenopausal women, who also more often had signs of active disease (increased CRP values and high joint swelling scores), which are known to be associated with both increased S-ICTP and S-PIIINP.
Table 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.
| Marker of disease activity | Marker of collagen metabolism (rs(p)) | ||
|---|---|---|---|
| S-ICTP | S-PINP | S-PIIINP | |
| ESR | 0.43 (< 0.001) | -0.07 (NS) | 0.23 (NS) |
| CRP | 0.59 (< 0.001) | 0.09 (NS) | 0.48 (< 0.001) |
| Ritchie index | 0.46 (< 0.001) | 0.06 (NS) | 0.37 (0.005) |
| Joint swelling score | 0.65 (< 0.001) | 0.21 (NS) | 0.60 (< 0.001) |
Of the markers of collagen metabolism, SF-ICTP was most closely related to the erosive state of the knee joint (Larsen’s grade). The mean SF-ICTP concentrations in Larsen’s grades 0-1, 2, 3, and 4-5 were 14.7, 17.5, 22.7, and 43.6 µg/l, respectively; that in the combination of Larsen’s grades 4-5 differed significantly from that in the other groups (p < 0.05 in multiple comparisons). The corresponding values for SF-PIIINP were 1305, 1314, 2058 and 2023 µg/l (p = 0.014), and the SF-PIIINP values in Larsen’s grades 3 and 4-5 differed significantly from those in the grades 0-1 and 2 (p < 0.05 in multiple comparisons). The mean SF-PINP concentrations were 821 µg/l in Larsen’s grades 0-1, 855 µg/l in group 2, 1531 µg/l in grade 3 and 1353 µg/l in grades 4-5 (NS).
The S-ICTP and S-PIIINP values were significantly lower in the patients currently receiving a SAARD compared with those not taking these drugs: the median values were 4.9 µg/l vs 8.7 µg/l for S-ICTP (p = 0.010), and 4.5 µg/l vs 5.5 mg/l for S-PIIINP (p = 0.021). The corresponding values for S-PINP were 40.6 µg/l vs 68.4 µg/l (p = 0.055). No significant differences in the mean serum levels of the markers were found between the patients taking or not taking peroral corticosteroids, but the SF levels of all the markers were significantly higher in the patients taking peroral corticosteroids than in those not receiving this treatment. The explanation for this difference may be multifactorial, but the patients on oral corticosteroids had significantly more often higher Larsen’s grades in the knee under study than did those not taking these drugs. There was an association between the time elapsed since the last intra-articular injection of corticosteroids and the SF-ICTP levels (p = 0.007); the patients who had recently received an intra-articular injection more often had lower levels of the marker.
At entry, SF ICTP correlated positively with Larsen’s grade. Table 5-5 shows the distribution of Larsen’s grades at entry and at the three-year visit. The median SF-ICTP concentrations in the baseline Larsen’s grade groups 0-4 were 10.8, 15.5, 12.5, 18.3 and 33.8 µg/l, respectively (p = 0.009). The radiological grade deteriorated in 22 (40%) patients, but remained stable in 33 patients (60%).
Table 5-5. Distribution of Larsen’s grades of knee joints at entry and at the three-year visit.
| Larsen’s grade | Baseline | 3 years |
|---|---|---|
| n (%) | n (%) | |
| 0 | 12 (21.8) | 7 (12.7) |
| 1 | 15 (27.3) | 16 (29.1) |
| 2 | 14 (25.5) | 11 (20.0) |
| 3 | 11 (20.0) | 13 (23.6) |
| 4 | 3 (5.5) | 7 (12.7) |
| 5 | 0 (0) | 1 (1.8) |
| Total | 55 (100) | 55 (100) |
Table 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.
| Variable | Patients with stable Larsen’s grade | Patients with deteriorating Larsen’s grade | p value of Mann-Whitney test |
|---|---|---|---|
| median (range) | median (range) | ||
| S-ICTP (µg/l) | 4.1 (1.7-14.8) | 5.2 (1.1-24.2) | 0.456 |
| (n = 33) | (n = 21) | ||
| SF-ICTP (µg/l) | 14.0 (2.8-42.3) | 17.6 (7.1-64.6) | 0.035* |
| (n = 33) | (n = 22) | ||
| S-PINP (µg/l) | 41.3 (15.0-111.3) | 44.2 (23.8-90.70) | 0.458 |
| (n = 32) | (n =20) | ||
| SF-PINP (µg/l) | 731.0 (118.0-5017.0) | 869.5 (147.0-2462.0) | 0.345 |
| (n = 31) | (n = 20) | ||
| S-PIIINP (µg/l) | 3.9 (1.8-7.4) | 4.4 (2.1-11.7) | 0.209 |
| (n = 30) | (n = 20) | ||
| SF-PIIINP (µg/l) | 1099.0 (438.0-4781.0) | 1378.0 (278.0-3905.0) | 0.412 |
| (n = 31) | (n = 21) | ||
| SF leukocytes (109/l) | 11.2 (3.6-54.8) | 5.2 (0.1-18.7) | 0.012* |
| (n = 32) | (n = 21) | ||
| SF polymorphonuclear leukocytes (109/l) | 7.1 (1.0-45.5) | 2.7 (0-14.1) | 0.018* |
| (n = 32) | (n = 21) |
Table 5-6 shows the median baseline values of the different markers in both groups. The median SF-ICTP concentration was significantly higher in the patients with a deteriorating Larsen’s grade than in those with a stable value (p = 0.035). When tested only in the patients with RA (n = 44), an equal difference in SF-ICTP was found between the above groups; i.e. the median level of ICTP was 14.0 µg/l (range 2.8-42.3 µg/l) for the 25 RA patients with stable disease and 18.3 µg/l (range 7.1-64.6 µg/l) for the 19 subjects whose disease was deteriorating, though the difference did not reach statistical significance (p = 0.063). Instead, the median levels of both SF total leukocytes (p = 0.012) and polymorphonuclear leukocytes (p = 0.018) were statistically higher in the patients with a stable grade. A comparison of the diagnostic subgroups showed that the association did not hold in the RA group, but was more pronounced in the other inflammatory arthropathies, i.e., the median was 9.8 x 109/l for stable disease and 11.0 x 109/l for progressive disease in the RA group, while the corresponding values in the other diagnostic groups were 12.6 x 109/l and 2.2 x 109/l. There was no statistically significant difference for S-ICTP, S-PIIINP, SF-PINP or SF-PIIINP between the above groups either in the whole series or in the diagnostic subgroups. The mean SF:S ratio of ICTP was 3.1 (SD 1.8) for the patients with a stable Larsen’s grade, and 4.5 (3.3) for those with a deteriorating Larsen’s grade (NS).
There was no statistical difference between the patients with a stable or deteriorating Larsen’s grade with regard to treatment with DMARDs or peroral corticosteroid therapy during the follow-up.