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Rheumatology 2001; 40: 544-551
© 2001 British Society for Rheumatology

Original Papers

Cytokines, metalloproteinases, their inhibitors and cartilage oligomeric matrix protein: relationship to radiological progression and inflammation in early rheumatoid arthritis. A prospective 5-year study

P. Roux-Lombard, K. Eberhardt1, T. Saxne1, J.-M. Dayer and F. A. Wollheim1

Division of Immunology and Allergy, Department of Internal Medicine, University Hospital of Geneva, Switzerland and
1 Department of Rheumatology, Lund University Hospital, Lund, Sweden


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To assess how serum concentrations of some cytokines, proteases and their inhibitors and cartilage oligomeric matrix protein (COMP) relate to the evolution of clinical disease and joint damage in early rheumatoid arthritis (RA).

Methods. Annual assessment was performed in 24 RA patients subdivided into three groups according to disease severity as determined by the radiological progression rate. All patients were followed for 5 yr after inclusion. Functional status, Larsen's radiographic index in hands and feet (joint damage score, JDS) and C-reactive protein (CRP) were assessed annually and compared with interleukin (IL)-6, IL-10, the IL-1 receptor antagonist (IL-1Ra), promatrix metalloproteinase 3 (proMMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1) and COMP, which were determined by specific immunological tests.

Results. The median JDS was initially between 4.5 and 7. During the study time the progression of JDS was 1 (median) for patients with slow progression, 33 for patients with intermediate progression and 62 for patients with rapid progression. Changes in CRP and proMMP-3 concentrations over time differed significantly between the groups, but no significant difference was observed for IL-1Ra, TIMP-1 or COMP. ProMMP-3 was closely related to CRP at each time point. IL-6 correlated significantly with CRP at the last four annual follow-up examinations. CRP and proMMP-3 correlated with JDS at the last two or three examinations and the combined levels of these markers over 5 yr correlated significantly with joint damage progression (Spearman rank correlation 0.73 and 0.74 respectively). IL-1Ra showed a weak negative correlation with JDS, and COMP tended to correlate with JDS only at the start. The initial proMMP-3 concentration was the only significant variable predicting rapidly developing joint damage, but the predictive value was low.

Conclusions. ProMMP-3 correlated closely at all time points with CRP, but gave little or no additional clinical information regarding inflammation or radiographic progression. IL-1Ra and TIMP-1 showed weaker, acute-phase-like variation, which may reflect pathogenic agonist/inhibitor imbalance in the evolution of RA. COMP, in contrast, did not reflect the inflammatory CRP-related component of the disease or the destructive aspect in this study.

KEY WORDS: Rheumatoid arthritis, Metalloproteinases, ProMMP-3, TIMP-1, IL-1Ra, COMP, CRP, Radiographic progression.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Rheumatoid arthritis (RA) is a potentially severe and crippling disease, but its course and progression rate show pronounced variation among individuals. Early aggressive therapy is now widely advocated in the hope of improving the long-term outcome for patients. This strategy carries the risk of exposure to toxic therapies in cases that may have a benign prognosis even without such therapy. The need for reliable early predictors of the course of disease is therefore increasing. Clinical features, early radiological changes and C-reactive protein (CRP) are commonly used predictors [1]. In addition, the presence of rheumatoid factor (RF) and certain HLA antigens have been found to be predictive in some [2, 3] but not in other [4, 5] studies.

Cytokines, proteases and their inhibitors have been identified as key players in the rheumatoid inflammation and destruction of joints, and several attempts have been made to use these as markers of disease severity. Thus, high levels of interleukin 6 (IL-6) in synovial fluid (SF) and in serum have been reported [6–8]. SF concentrations are some 1000 times higher than serum levels, indicating intra-articular production of IL-6 [6, 9, 10]. The IL-6 concentration in SF has also been found to correlate with clinical and laboratory markers of synovitis [11, 12]. However, no advantage over conventional markers has emerged.

Both tumour necrosis factor (TNF) and IL-1 are involved in rheumatoid inflammation, and their formation can be demonstrated in tissue specimens and in serum of some patients [13–16]. However, their relationships with disease activity were inconsistent [17–21]. The IL-1 receptor antagonist (IL-1Ra) is a physiological inhibitor of IL-1 and is present in substantial amounts in both SF and serum [22, 23]. It has many features of an acute-phase reactant [24] but has not been investigated as a putative predictive marker in RA.

IL-10 is a pleiotropic cytokine with both anti- and proinflammatory features. It can inhibit the formation of TNF and IL-1 and increase the formation of soluble TNF receptors and IL-1Ra [25, 26]. It can protect against joint destruction when administered in animal models of arthritis [27, 28].

The matrix-degrading metalloproteinases (MMPs), which include collagenases, gelatinases and stromelysins, have been found in large amounts in joint tissues and SF in RA [29]. The family of MMPs have the potential to degrade almost all components of the extracellular matrix that are found within the connective tissues. On the basis of substrate preference, these enzymes are divided into collagenases (MMP-1, -8 and -13), gelatinases (MMP-2 and -9) and stromelysins (MMP-3 and -10), but the three groups share amino acid homology [30].

Stromelysin-1 or MMP-3 has a wide substrate specificity and is capable of degrading numerous components of the extracellular matrix [31]. Tissue inhibitors of metalloproteinases (TIMPs) are known to inhibit all classes of active MMPs, and under normal conditions they balance the activity of these enzymes. Concentrations of both MMP-3 and TIMP-1 are elevated in RA serum and correlate with CRP and erythrocyte sedimentation rate (ESR) but not with destruction in cross-sectional studies [32, 33].

Cartilage oligomeric matrix protein (COMP) is an integral component of cartilage, and its release has been correlated with later joint destruction in RA [34, 35]. Although not specific to cartilage, it is most abundant in this tissue.

The putative usefulness of one or more of these biological species as markers in patients with RA can be tested only in well-characterized series of patients who are followed longitudinally and are assessed simultaneously with conventional techniques. In this report we used this approach in early RA patients with varying radiological progression rates over the first 5 yr.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
The study group consisted of 24 patients participating in a larger prospective study of the course and outcome of RA at the Department of Rheumatology, Lund University Hospital. The inclusion criteria for the prospective study were definite RA with disease duration less than 2 yr in patients aged 18 yr or more [36].

The 24 patients in this study were allocated to three contrasting groups differing in the pattern of joint damage progression during the first 5 yr of follow-up: group 1 had slow progression, group 2 had intermediate progression and group 3 had rapid joint destruction. They were examined at least once a year by the use of a standard protocol. Disability was assessed with a Swedish version of the disability index of the Stanford Health Assessment Questionnaire (HAQ) [37]. The range of this index is 0–3. Radiographic examination of the hands and feet was performed at the start of the study and annually thereafter, with standard film and an anterior–posterior projection. Findings were scored by the Larsen method, which grades changes from 0 (normal) to 5 (maximal damage) [38]. Thirty-two joints were evaluated. The wrist score was multiplied by 5, then all scores were added to give a joint damage score (JDS) with a theoretical range of 0–200. The scoring procedure is described in detail elsewhere [39].

RF of the IgM class was analysed with an enzyme-linked immunosorbent assay (ELISA) [40]. HLA-DRB alleles were typed by restriction fragment length polymorphism analysis with sequence-specific primers as described previously [4].

Demographic, clinical and radiological data for the three groups are shown in Table 1Go.


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  		TABLE 1. Demographic and clinical data

 
The mean duration of joint symptoms at inclusion was 11.1 (S.D. 6.1) months. The median JDS at baseline was 7 (range 6–11) for group 1, 4 (3–11) for group 2 and 4.5 (3–14.25) for group 3 and did not differ significantly between the groups.

During follow-up, 16 patients were treated with disease-modifying anti-rheumatic drugs (DMARDs) (two patients in group 1, five patients in group 2 and nine patients in group 3). Ten patients were treated with chloroquine, seven with D-penicillamine, two with Myocrisin and two with sulphasalazine. One patient in group 2 and seven patients in group 3 were treated with more than one drug.

Biochemical analyses
Analyses were performed on samples taken at the start of the study and annually thereafter for 5 yr. CRP was measured by immunoassay. Stromelysin (MMP-3) was measured in its proenzyme form (proMMP-3) in serum using a commercially available enzyme immunoassay (Bindazyme ProMMP-3; The Binding Site, Birmingham, UK) because only the proenzyme form of stromelysin was detected in rheumatoid joint fluid and is likely to be the predominant form in the circulation [41]. Indeed, any active enzyme in plasma is likely to be complexed to the non-specific protease inhibitor {alpha}2-macroglobulin and thus inaccessible to detection by immunoassay. The antibody used in this kit was raised against the proenzyme form of stromelysin, which is not captured by {alpha}2-macroglobulin. The sensitivity of the assay is 2.1 ng/ml. The normal range in human serum is 5–30 ng/ml.

TIMP-1 was measured with a commercially available enzyme immunoassay (Biotrak, TIMP-1; Amersham, Little Chalfont, UK) that recognizes total human TIMP-1, i.e. both free and complexed TIMP-1. The sensitivity of the assay is 1.25 ng/ml. The normal range in human serum is 280–520 ng/ml.

Cytokine levels were measured using commercially available quantitative sandwich enzyme immunoassays: QuantikineTM human IL-10, QuantikineTM human IL-1Ra (R&D Systems, UK) and IL-6 EASIATM (Medgenix, Fleurus, Belgium). The normal ranges of IL-10, IL-1Ra and IL-6 in human serum are less than 8, 106–1552 and less than 100 pg/ml respectively.

COMP levels were measured only at three time points—at the start of the study and after 2 and 5 yr—with an ELISA using polyclonal antiserum [42].

Statistical methods
The Kruskal–Wallis test or the {chi}2 test was used to assess differences between groups. Correlations were evaluated by calculating the Spearman rank correlation coefficient (rS).

In some of the calculations we used the mean of the concentrations of the biological markers at the six measurement points (these will be referred to as combined mean values over time). This was possible because linear regression analyses for each laboratory measure with time as the independent variable showed no significant time dependence.

The Cox regression model was used to try to predict the risk of rapid progression in joint damage over the 5 yr by means of demographics, genetic markers, RF status and clinical variables at baseline. An increase in JDS of 30 or more was defined as the event of interest. A forward stepwise approach was used.

To compensate for multiple testing, the level of significance was set at 0.01 for all statistical tests.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Gender tended to differ between the three groups, women being more prevalent in the group developing most joint damage (P=0.03). The prevalence of RF or the shared epitope showed no significant difference (Table 1Go). Mean values over the 5 yr for CRP, IL-1Ra, proMMP-3, TIMP-1 and COMP did not differ significantly between men and women.

Only a minority of the patients had detectable levels of IL-10 in serum. Thus, at the different measurement points the number of patients with detectable IL-10 was 1 (year 1), 0 (year 2), 1 (year 3), 3 (year 4), 6 (year 5) and 4 (year 6). Two patients in group 1 had detectable IL-10 on three occasions. Because of the small number of positive IL-10 tests, no further statistical analyses could be performed.

The number of patients with detectable levels of IL-6 was also small. The numbers at each time point were seven (year 1), seven (year 2), nine (year 3), seven (year 4), nine (year 5) and seven (year 6), and there was no difference between the groups. Mean combined levels of IL-6 over time were not calculated because of the small number of positive tests.

Table 2Go displays the medians and ranges of the combined mean concentrations for years 0–5 for the different biological variables according to patient group. CRP and proMMP-3 differed significantly between the groups. The slightly higher median and range for IL-1Ra in group 3 was due to two outliers.


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  		TABLE 2. Median (range) values of combined mean concentrations over 5 yr

 
Correlations between the various markers and CRP at each time point for all 24 patients were calculated. ProMMP-3 consistently showed the strongest correlation. IL-6 correlated significantly with CRP at the last four examinations. IL-1Ra and TIMP-1, on the other hand, correlated significantly with CRP only at one time point each (Table 3AGo). When the overall correlations were calculated, the closer correlation was again found between CRP and proMMP-3 (Table 3BGo). There was no significant correlation between COMP and proMMP-3, either at any time point or for the combined levels over the whole period. This lack of correlation also applied when COMP was compared with the other markers (results not shown).


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  		TABLE 3.

 
ProMMP-3 and CRP showed the strongest correlations of all laboratory variables with JDS at each time point. IL-6 correlated with JDS only at one time point and COMP tended to correlate with JDS at the start of the study (rS=0.448), but this correlation was not statistically significant (Table 4Go).


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  		TABLE 4. Correlations (rS) between all laboratory variables and JDS at each observation point in all 24 patients

 
Table 5Go displays correlations between the combined means of all biological markers and the joint damage progression over the study period. ProMMP-3 and CRP correlated best with joint damage progression, whereas COMP and joint damage progression were not correlated with each other.


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  		TABLE 5. Correlations (rS) between joint damage progression in hands and feet and combined mean values over 5 yr of some laboratory variables in all 24 patients

 
No significant correlations were found between HAQ progression over 5 yr and the biological markers (detailed data not shown). The strongest correlation was found for proMMP-3 (rS=0.352, not significant). The correlation between HAQ and joint damage progression was 0.168.

Fourteen of the patients had achieved a joint damage progression of 30 or more during the study period (one after 1 yr, five after 2 yr, 10 after 3 yr, 13 after 4 yr and 14 after 5 yr). ProMMP-3 at baseline was the only significant variable in the Cox regression model predicting the risk of rapid progression of joint damage (P<0.01). The hazard ratio for proMMP-3 was 1.0115 (95% confidence interval 1.0033–1.0197).


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
The investigation of disease markers in RA serves several purposes. It may confirm suspected disease mechanisms or reveal new ones, it may define objective tools to study drug actions or experimental models, or it may have more practical clinical aims, as in the present work. There has been a paucity of critical prospective studies in RA in which conventional laboratory tests have been compared with newer biological markers. The prospective approach is a prerequisite if the prognostic or predictive features of the markers being studied are to be assessed. Also, the clinical material must be characterized carefully. For this reason we concentrated this study on three small but contrasting groups of patients with pronounced differences in the rate of radiological progression. (The small size of the sample of patients could be criticized.) However, such an approach will identify only the more robust markers, which in turn may become clinically useful.

Consequently, it was not surprising to find that neither RF positivity nor the presence of the shared epitope on one or two alleles was discriminative enough to show up. However, the combination of CRP and proMMP-3 levels over time did show a good correlation with the rate of radiological progression. In this sense, the laboratory measures fared better than disability assessed by the HAQ, which showed a very weak correlation with radiographic damage. On the other hand, CRP and proMMP-3 are not very useful as predictors. In this study, the initial proMMP-3 level was the only significant variable, but the increased risk of rapidly progressive joint damage with higher levels of proMMP-3 was very low. The weak performance of the presence of the shared epitope and RF positivity is not in conflict with published evidence—it simply shows the limited degree of information added to clinical practice in established disease.

This study was not intended to analyse the putative effects of DMARD therapy on the variables we studied. DMARDs were administered according to conventional clinical judgement, and the time of sampling was unrelated to the start or discontinuation of DMARD therapy. Any influences are probably marginal and would not obscure the differences between groups.

Proinflammatory cytokines, here represented by TNF-{alpha} and IL-6, are intimately involved in the arthritic process of RA and have been found in synovial fluid and serum in active disease [11–21, 43]. The pathogenic importance of IL-1 and TNF is amply confirmed by the recent therapeutic use of inhibitors [44]. Nevertheless, the variability of the results obtained in numerous studies tends to imply that neither cytokine could serve as a disease marker with the methods available. We cannot exclude the possibility that ultrasensitive assays might show a correlation with destructive disease, and it is likely that the use of larger groups would have revealed differences between the patient groups with the present method for IL-6. Previous studies have shown correlations of IL-6 with ESR, CRP, the articular index, morning stiffness and synovial fluid leucocytosis [11, 12]. However, no study has shown any clinical advantage of knowledge of the serum IL-6 level in an individual patient, and our results exclude a correlation with joint damage.

IL-10 is of interest as a putative therapeutic agent in RA, according to animal work [27, 28]. Previous reports on IL-10 in RA are contradictory. Both elevated [45–47] and reduced [48] levels of IL-10 have been published. It seems unlikely from these and the present results that IL-10 is a useful candidate marker in RA at present. However, we cannot exclude the possibility that a more sensitive test might reveal a relative IL-10 deficiency in some instances.

IL-1Ra is of particular interest as a disease marker, and has been found to be regulated similarly to acute-phase proteins [24]. Although its concentration was not greatly elevated, IL-1Ra was correlated with CRP (Table 5Go). Because it is a physiological protector against IL-1 signalling [49] and because a reduced ratio of IL-1Ra to IL-1 has been found in synovial fluid in RA [22], it is of interest that, with the exception of a few outliers, IL-1Ra concentrations in RA serum were not substantially increased. This could represent a failure to mount a strong IL-1Ra response matching the increased local synthesis of IL-1, and setting the stage for IL-1-driven tissue breakdown. It is important to note that, in order to block IL-1 completely, IL-1Ra must be present in 10- to 100-fold molecular excess [49].

Evidence that serum MMP-3 is increased in RA as a direct result of increased cytokine activity is derived from studies using biological inhibitors of TNF-{alpha}. RA patients receiving infusions of either neutralizing antibodies to TNF-{alpha} or a fusion molecule containing soluble TNF receptors showed a marked reduction in the circulating proMMP-3 level [44]. This study confirms a close correlation between proMMP-3 and CRP [32, 50], and consequently with joint damage as measured by the Larsen index. MMPs are secreted as inactive precursors that require extracellular processing to generate active substrate-degrading enzyme. Mature active MMPs are then subject to regulation by MMP-specific tissue inhibitors of metalloproteinases—the TIMPs. So far TIMP-1, -2 and -3 have been described, of which TIMP-1 is the most widely distributed. It inhibits all active MMPs by reversible non-covalent binding to form an inactive complex [51]. High levels of TIMP-1 in synovial fluid compared with serum indicate that the joint is a dominating source of circulating TIMP-1.

The integrity of the extracellular matrix is dependent on a delicate balance between synthesis and degradation, in which MMPs and TIMPs have a key role. It could be hypothesized that RA patients show relative inability to produce adequate amounts of TIMPs to balance the increased activation of MMPs. The present results neither support nor exclude such a mechanism. However, they show that determination of the level of TIMP-1 did not contribute prognostic or other clinically useful information that was better than that derived from assay of proMMP-3 alone. In this sense, our study is complementary to previous work, which was not longitudinal and did not focus on patients with early disease [32, 33, 50, 52, 53].

An important observation in this study is the lack of correlation between serum levels of COMP and the other variables, which indicates that serum COMP does not reflect the inflammatory component of the disease. Thus, the inflammatory process in the synovium or the more generalized systemic inflammation do not influence COMP turnover to any extent that affects serum concentrations. A role for COMP as a marker that reflects the turnover of cartilage has been documented in previous work from our group. In this study, however, there was no correlation between serum COMP and the progression of joint damage, and no correlation between baseline COMP and joint damage progression. This is not surprising, as the aim of the study was to investigate the relationship between COMP and variables reflecting inflammation. Furthermore, the patients were selected from a cohort in which COMP had already been shown not to be of prognostic value [54]. The lack of a correlation with joint damage progression contrasts with findings in studies of the progression of damage in large joints, which might suggest that the contribution of the hands and feet to the circulation is too small to show against the background of circulating COMP [34]. Another explanation could be the choice of radiographic scoring system, i.e. the Larsen index, which is a composite index that does not separate joint space narrowing from other features. The feasibility of COMP as a marker for structural damage of cartilage has been verified in animal models of destructive arthritis [55]. In other experiments, elevated COMP levels became normal upon structure-protective therapy but not therapy that only controlled inflammation [56].

The COMP assay used in the present study should be considered a first-generation assay, i.e. the antibodies that were used recognize both intact and fragmented COMP, which means that small changes in the release of, for example, fragments resulting from degradation might escape recognition. Novel assays that selectively detect fragments resulting from degradation or intact protein will increase the utility of COMP as a marker for cartilage involvement in RA.

We conclude that biological markers need to be assessed critically in defined clinical studies, preferably using a longitudinal approach. Repeated CRP determination is at present the best marker for clinical use to monitor the evolution of disease in RA. ProMMP-3 is nearly as good as, but not better than, CRP. COMP is a measure of tissue processes that are distinct from the acute-phase reaction.


   Acknowledgments
 
We thank Carmelina DeLuca for expert technical assistance. This work was supported in part by grant 31–50930.97 from the Swiss National Science Foundation and a grant from the Hans Wilsdorf Foundation (Switzerland). Grants were also obtained from The Swedish Medical Research Council, the King Gustav V 80-year-Fund, The Kock Foundation and the Swedish Rheumatism Association.


   Notes
 
Correspondence to: P. Roux-Lombard, Division of Immunology and Allergy, University Hospital of Geneva, 1211 Geneva 14, Switzerland. Back


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 4 July 2000; Accepted 4 December 2000


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