Destructive enzyme may help guide early targeted therapy for those at risk
Continuously elevated serum matrix metalloproteinase-3 (MMP-3) for 3-6 months predicted 1-year radiographic progression in rheumatoid arthritis (RA), according to a small prospective cohort study in Arthritis Research and Therapy.
Elevated serum MMP-3 at months 0, 1, 3, and 6 and C-reactive protein (CRP) at month 1 were significant predictors of 1-year radiographic progression, with odds ratios of 10.5-27.0 for MMP-3 at the follow-up time points (all P<0.05), and an OR of 7.4 for CRP at one month (P=0.011), according to Lie Dai, MD, PhD, at Sun Yat-sen Memorial Hospital in Guangzhou, China, and colleagues.
The investigators suggested that monitoring of dynamic serum MMP-3 combined with core disease activity indicators may help predict radiographic progression and guide treatment decisions in RA.
They noted that core disease activity indicators such as erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), and CRP have been of limited value in predicting progressive joint destruction in RA.
And while MMP-3 plays an essential role in joint destruction, elevated levels have been found even in remission patients. Secreted by synovial fibroblasts and chondrocytes in joints, the active form of this enzyme accelerates joint destruction by degrading aggrecan core protein, cartilage link protein, fibronectin, and collagen types IV, VII, IX and XI, Dai and colleagues noted.
They recruited 60 patients with active RA (Simplified Disease Activity Index >3.3) being managed at the hospital with a treat-to-target strategy from December 2010 to December 2013. Patients were assessed clinically and for serum MPP-3 at months 0, 1, 3, 6, and 12. X-ray assessments of hand/wrist were done at baseline and month 12, with a change of total Sharp score of >0.5 units defined as radiographic progression.
The cohort's median age was 48 (51 in progressive patients), 77% were female (63% in the progressive group), and the median disease duration was 24 months. All patients had poor prognostic characteristics: 93% had bony erosions, 84% were RF-positive, 82% were anticyclic citrullinated peptide antibody-positive, and 54% had functional limitations. Overall, the median baseline MMP-3 level was 175 ng/mL but in the group that progressed it was 316 ng/mL.
Of the 56 patients who completed 1-year follow-up, 29% showed radiographic progression and 9% had rapid radiographic progression. Serum MMP-3 levels and all core disease activity indicators (except for ESR) were significantly higher in progressives than nonprogressives at 12 months.
Among 16 progressive patients, 69% achieved their therapeutic targets, but 56% of these had continuous elevated serum MMP-3, and 38% had both continuous elevated serum MMP-3 and normal C-reactive protein at month 6.
The predictive accuracy of serum MMP-3 for 1-year radiographic progression was 0.721 with a cutoff point of 159 ng/mL (P=0.010, positive predictive value 46.7 % and negative predictive value 92.3 %).
Subgroup studies showed that dynamic serum MMP-3 might be helpful for predicting radiographic progression in patients achieving their therapeutic targets since elevated serum MMP-3 at month 3 was a significant predictor of 1-year rapid radiographic progression.
Commenting on the study, Ziv Paz, MD, MPH, a rheumatologist at Beth Israel Deaconess Medical Center in Boston, said, "The discrepancy between improved clinical symptoms and worsening radiological progression is one of the biggest challenges in the current era of RA management. The use of MMP-3 as a biomarker is novel and linked to disease pathophysiology, as this enzyme has an important role in the breakdown of the joint's related structures."
Acknowledging the study's limitations, Dai and colleagues pointed to its design as a real-world cohort study, with all patients recruited and treated with various regimens at a single center. "Further multicenter studies of the combined strategy of both disease activity and serum MMP-3 driven therapy with the same treatment in all centers are needed," they wrote.
Moreover, all study patients had poor prognostic features, which might confound the prediction of radiographic progression. "More new-onset RA patients without bony erosion are needed in future to investigate whether serum MMP-3 could predict radiographic progression in these patients," Dai and colleagues wrote.
Added Harvard's Paz: "This study opens the door for a new group of biomarkers which can help to identify the group of patients who would progress, guide intensified targeted treatments at early stages of the disease, and potentially prevent damage."
This study was
supported by the National Natural Science Foundation of China and the
Guangdong Natural Science Foundation. The authors disclosed no
relationships with industry.
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