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Rheumatoid Arthritis (RA) is a systemic autoimmune disease, characterized by chronic synovitis and erosive polyarthritis causing eventual joint destruction and disability.
The diagnosis of RA combines the patient history of joint pain and stiffness, physical examination, imaging techniques, histological synovial analysis and laboratory tests including blood tests for serological biomarkers.
Markers related to RA appear at different stages in the development of the disease, implying that each marker represents a different role in RA. Considering the common disease activity indicators are unspecific for arthritis, novel biomarkers such as inflammatory cytokines, destructive enzymes and breakdown products from components of cartilage, have been rapidly developed for predicting structural destruction progression in RA.
Matrix metalloproteinases (MMPs) are a group of extracellular enzymes playing a key role in normal and pathological tissue remodeling and have the ability to degrade all components of the extracellular matrix.
Matrix metalloproteinase-3 (MMP-3) is produced predominantly by chondrocytes and synovial fibroblasts. MMP-3 plays a major role in degradation of various components of cartilage, such as proteoglycans, gelatins, laminin, fibronectin and collagen types III, IV, IX and X. Also, it activates pro-MMPs 1, 7, 8, 9 and 13, which are capable of degrading intact collagen type II.
Serum MMP‐3 levels in RA are correlated with disease activity, erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) levels in both cross sectional and longitudinal studies. With respect to its prognostic potential, elevated serum concentrations of MMP-3 have been found to correlate with RA disease severity, radiographic progression, and response to treatment. The reduction of serum MMP-3 was recently considered as a secondary therapeutic target, particularly in RA patients receiving biological therapies.
Increased levels of MMP-3 have been also noted in synovial fluid and blood samples from patients with knee OA, but it is still unclear whether it is related to the degree of joint space narrowing and disease progression or not.
The need for easy tools for early prediction of rheumatoid arthritis course is a must. from this point of view, we aim to investigate the usefulness and specificity of the serum and synovial concentrations of MMP-3 as an indicator of disease activity, damage and prognosis.
This is a case control observational study that includes two groups:
The case group is a convenient sample of forty patients with early RA (less than 1 year duration), fulfilling the 2010 ACR\EULAR classification criteria for rheumatoid arthritis.
The control group consists of twenty patients with knee osteoarthritis diagnosed using the ACR classification criteria for knee OA, and twenty age and sex matched healthy adult volunteers.
All patients were recruited from Rheumatology outpatient clinic and inpatients in the department of Internal Medicine-Rheumatology division in Ain Shams university hospital.
Patients with any connective tissue disease causing inflammatory arthritis (other than rheumatoid arthritis), malignancy, multiple sclerosis, myasthenia gravis, and Alzheimer disease were excluded from the study.
We measured serum and synovial fluid levels of matrix metalloproteinase-3 (MMP-3) in early rheumatoid arthritis patients, and assessed its relation to disease activity and degree of joint destruction.
It was found that serum MMP-3 levels were significantly higher in the RA group than in the OA group and healthy controls. In addition, serum MMP-3 levels were significantly higher in the OA group than healthy controls.
Moreover, the synovial levels of MMP-3 measured in patients indicated for arthrocentesis showed significantly higher values in RA patients as compared to OA patients. There was significant correlation between serum and SF concentrations of MMP-3 in RA patients, but not in OA patients.
We found significant relation between serum levels of MMP3 and RA disease activity both clinically and laboratory. Serum MMP-3 levels significantly correlated with RA disease activity clinically as measured by DAS-ESR. In addition, serum MMP-3 levels significantly correlated with some laboratory measures of disease activity of RA; CRP, Anti-CCP, and RF titres.
On imaging assessment, serum levels correlated with grades of synovitis detected by B Mode Ultrasound and vascular signals visible on colored Doppler flow in the examined joints, assessed by OMERACT ultrasound scoring system. Also, serum MMP-3 levels were found significantly higher in patients with erosive RA than non-erosive RA.
There was a highly significant relation between severity of knee osteoarthritis measured by K/L score and serum levels of MMP-3.
We detected the best cutoff value of serum MMP3 to discriminate between RA patients and healthy controls at 50 ng/ml, which yielded 95% sensitivity and 100% specificity. While the best cut off value of serum MMP3 to discriminate OA patients from healthy controls was defined at >27ng/ml, with sensitivity of 60%, specificity of 90%.
In conclusion, our findings strongly suggest that elevated serum levels of MMP-3 can be used as a specific diagnostic and prognostic marker for RA. Elevated serum MMP-3 level is an indicator of disease activity in early RA patients, and can reflect the degree of joint damage too.