Collagenase 3 as a prognostic marker for rheumatoid arthritis

Details Collagenase 3 as a prognostic marker for rheumatoid arthritis Collagenase 3 as a prognostic marker for rheumatoid arthritis

2002-05-06

2004-06-29

Gitomer, Ralph (Department: 1651)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

C435S023000

Reexamination Certificate

active

06756197

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to the use of collagenase 3 for detecting destructive joint diseases, especially as a prognostic marker for the clinical course of rheumatoid arthritis (RA) and its genetic predisposition.
RA is a chronically inflammatory disease, predominantly of the joints. The aetiology of the disease as well as relevant pathogenetic mechanisms have remained unknown up to the present. With it being a chronic disease, patients are affected by it for years or decades. The clinical course of the disease is very heterogeneous, changing over the course of the years and decades, and cannot be forecast as yet. An early, adequate forecasting of the progression of the disease to be expected and recognition of the start of a serious progression of the disease in good time arc of great importance for the patient and the doctor treating the patient, in order to treat the chronic disease, which has been incurable up to now, efficiently at least in the early stages and thus to decelerate or stop a progression as early as possible. This particularly relates to the stoppage of the process of the progredient cartilage and bone destruction.
Medicinal therapies available at present are effective, albeit frequently connected with serious side-effects. This is connected both with the effective mechanism of the medications themselves, simultaneous combined administration and the necessity of a life-long therapy for years and decades. Currently, combination therapies of
(a) steroid preparations
(b) immune suppressiva and cytostatics, so-called disease-modifying anti-rheumatic drugs (DMARD, so-called basic therapeutics) and
(c) non-steroidal anti-inflammatory medications are in use.
On the Heterogeneity and Pathogenesis of RA
RA is a chronically inflammatory disease characterized by a high degree of heterogeneity, which affects the pattern of the disease, the capability of reacting to therapeutic measures (internal and surgical) and the prognosis of the disease. The clinical heterogeneity is associated with a variety of histo-pathological alterations in the synovial membrane of the joints affected. This clinical and histo-pathological heterogeneity of the disease, combined with insufficient knowledge about aetiology and relevant pathogenetic mechanisms, have led to very insufficient treatment results of RA patients up to now. Within the first two years after the on-set of the disease, about one-third of the RA patients have to give up their professional activity. In internal medicine/rheumatological departments, the share of RA patients is above 50%, in institutions of orthopaedic rheumatology even about 75%. The expenditure for long-term medicinal therapies and stationary therapeutic measures are above-average. The prevalence of the disease amounts to about 1% in the overall population. The pathogenetic measures in the joints affected include a chronic inflammation, an abnormal immune response and a hyperplasia of the synovial membrane. The chronically inflammatory and hyperplastic synovial membrane invades into neighbouring cartilage and bone structures, thus leading to a progredient joint destruction. The clinical end point of the disease is decisively determined by the cartilage and bone destruction, which lead to a loss of function of the joints and to invalidity. However, the anti-inflammatory therapy currently in the foreground of medical therapies only has a low influence on the progression of the cartilage and bone destruction. There are indications for the fact that chronic inflammation and progredient cartilage and bone destruction are rather to be regarded as two separate pathophysiologic entities in a common pathogenetic process.
Prognostic markers available or known up to now for the progression of RA
(1) The currently safest markers used in routing in clinical practice for the progression of RA are systemic inflammation parameters such as the erythrocyte sedimentation rate, above all the C-reactive protein (CRP) and, with limitations, other acute-phase proteins. These parameters correlate best with the current acute inflammatory activity in the organism and are the decisive parameters for an anti-inflammatory therapy. As the systemic chronic inflammation and the progredient joint destruction are only conditionally connected with one another pathogenetically, the meaningfulness of these parameters for the prognosis and the progression of the disease is very limited overall, in particular for the progredient cartilage and bone destruction.
(2) The existence of a positive rheumatoid factor is valued as an indicator for a disturbed immune response. However, it is not specific for RA and the meaningfulness for the progression of the disease is limited.
(3) It is further known that certain patterns of antigens which can be detected on the cell surface of lymphocytes and other tissue cells (so-called HLA antigens) are associated with more severe course of RA. Due to the large variety of the HLA antigens and their various epidemiological distribution, comments on the forecast of the RA are only possible in a very limited way. Correlations to the progredient joint destruction were not found.
BRIEF SUMMARY OF THE INVENTION
Reliable prognostic markers of the disease are thus decisive for an early adequate medical treatment and the justification of such a therapy with regard to the side-effects also to be considered.
Therefore, the invention was based on the task of finding corresponding reliable parameters and providing corresponding markers which are particularly suited for RA.
The invention is based on the knowledge that collagenase 3 is involved in the process of progredient cartilage and bone destruction. For the progredient cartilage and bone destruction in RA, various proteases, but above all the matrix metalloprotcinases (MMPs) are responsible, these being able to cleave various components of the extra-cellular matrix. Collagenase 3 as a representative of the MMP family is of particular interest for the cartilage and bone destruction in destructive joint diseases, such as RA. On the one hand, collagenase 3 possesses a high catalytic activity towards collagen type II, the main collagen component of hyaline cartilage, compared with other human collagenases and other MMP's, and cleaves a broad range of other components of the extra-cellular matrix with high efficiency. On the other hand, it has been shown that collagenase 3 can only be detected in adult human tissues under pathological conditions, for example in the growth of malignant tumours, in chronic wounds, as well as in arthritic cartilage and in the synovial membrane in RA. It can therefore be presupposed that this MMP plays a decisive role in the progredient cartilage and bone destruction, in particular also in RA, due to the substrate specificity and the expression pattern of collagenase 3.
An increased concentration of various MMPs was detected in the synovial fluid of RA patients. However, a correlation to systemic inflammation parameters such as BSG and CRP was only shown for stromelysin 1. In addition, no correlation was detected between the collagenolytic activity in the synovial fluid and the degree of cartilage and bone destruction.
In the invention, collagenase 3 is used as a prognostic marker in destructive diseases of the joints, preferably for the detection of a progression of RA.


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Wernicke, D. et al. “Cloning of Collagenase 3 from the Synovial Membrane and its Expression in Rheumatoid Arthritis and Osteoarthritis” The Journal of Rheumatology, vol. 23, No. 4, pp. 590-595, 1996.*
Reboul, P. et al. “The New Collagenases, Collagenase 3, Is Expressed and Synthesized by Human Chondrocytes but not by Synoviocytes” Journal of Clinical Investigatio

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