Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) Study Group. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial
To identify disease characteristics leading to progression of joint damage in patients with early rheumatoid arthritis (RA) treated with methotrexate (MTX) versus those treated with infliximab plus MTX.
Patients who had not previously been treated with MTX with active RA were randomly assigned to receive escalating doses of MTX up to 20 mg/week plus placebo or infliximab at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. Radiographic joint damage was assessed using the modified Sharp/van der Heijde score (SHS). The relationship between disease activity measures at baseline and week 14, as well as those averaged over time, were examined in relation to the change in SHS from baseline through week 54.
C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and swollen joint count were associated with greater joint damage progression in the MTX-only group, while none of these parameters was associated with progression in the infliximab plus MTX group. Mean changes in SHS among patients in the highest CRP (> or = 3 mg/dl) and ESR (> or = 52 mm/hour) tertiles in the MTX-only group were 5.62 and 5.89, respectively, compared with 0.73 and 1.12 in the infliximab plus MTX group (P < 0.001). Patients with greater joint damage at baseline (SHS > or = 10.5) showed less progression with infliximab plus MTX compared with MTX alone (-0.39 versus 4.11; P < 0.001). Patients receiving MTX alone who had persistently active disease at week 14 showed greater radiographic progression of joint damage than those taking MTX plus infliximab.
High CRP level, high ESR, or persistent disease activity was associated with greater radiographic progression in the group taking MTX alone, while little radiographic progression was seen in patients receiving both MTX and infliximab, regardless of the abnormal levels of these traditional predictors.
"In this study, we found significant correlations between synovial MMP-3 and serum MMP-3, CRP, or ESR and significant correlation between serum MMP-3 and synovitis score with high sensitivity of serum MMP-3 in diagnosing high grade or low grade synovitis by ROC curve. Previous studies of clinical and imaging assessments of synovitis emphasize the importance of repeated assessments of synovitis due to the weak prognostic value with single measure [33–35]. Compared to the device-depended imaging assessment and invasive synovial biopsy, serum MMP-3 is more suitable for repeated assessments of synovitis and it may be an alternative noninvasive biomarker of synovitis for clinical practice. "
[Show abstract][Hide abstract] ABSTRACT: Objective:
To explore the correlation between matrix metalloproteinase- (MMP-) 3 and histological synovitis in rheumatoid arthritis (RA).
Serum MMP-3 of 62 patients with active RA was detected by ELISA. Serial synovial tissue sections from all RA patients, 13 osteoarthritis, and 10 orthopedic arthropathies patients were stained with hematoxylin and eosin and immunohistochemically for MMP-3, CD3, CD20, CD38, CD68, and CD15.
The percentage of lining MMP3+ cells was significantly higher in RA patients especially with high grade synovitis and it was significantly correlated with Krenn's synovitis score (r = 0.574, P < 0.001) and sublining inflammatory cells. Multivariate stepwise linear regression analysis revealed that the association of the percentage of lining MMP3+ cells with activation of synovial stroma, sublining CD68+ macrophages, and CD15+ neutrophils was stronger than other histological indicators. The percentage of lining MMP3+ cells was significantly correlated with serum MMP-3 in RA (r = 0.656, P < 0.001). Serum MMP-3 was higher in RA patients with high grade synovitis than that of low grade synovitis and significantly correlated with synovitis score and activation of synovial stroma subscore (all P < 0.05).
Serum MMP-3 may be an alternative noninvasive biomarker of histological synovitis and RA diagnosis.
Mediators of Inflammation 07/2014; 2014(1):179284. DOI:10.1155/2014/179284 · 3.24 Impact Factor
"In recent years, the use of tumor necrosis factor inhibitors (TNFi) has resulted in an improvement in the treatment of RA patients by reducing both inflammation and joint damage [2-4], and their clinical use has become widespread. However, a percentage of patients do not respond adequately to this therapy; therefore, the current use of these agents is based on a trial-and-error approach [5,6]. "
[Show abstract][Hide abstract] ABSTRACT: We aimed to elucidate the role of four polymorphisms identified in a genome-wide association study (GWAS) analyzing the response of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). These genetic variants were significantly associated in this large study done by Plant et al. However, none of them reached GWAS significance and two subsequent studies failed to replicate these associations.
The four polymorphisms, rs12081765, rs1532269, rs17301249 and rs7305646, were genotyped in a total of 634 TNFi treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the disease activity score using 28 joints counts (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and non-responder patients were compared. In addition, our data were combined with previously reported studies in a meta-analysis including 2,998 RA patients.
None of the four genetic variants showed association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis.
Our data suggest that the rs12081765, rs1532269, rs17301249 and rs7305646 genetic variants do not have a role as genetic predictors of the TNFi treatment outcome.
"The significantly increased erosion and joint space narrowing scores observed at the end of the follow-up period in the seropositive RA patients support previous observations that many RA patients exhibit radiographic progression, even though clinically they are in a state of low disease activity  . Worsening of radiological parameters in these patients at the end of the study was associated with significant upregulation of MMP-9 and cathepsin K gene expression in the peripheral blood compared with baseline values. "
[Show abstract][Hide abstract] ABSTRACT: We evaluated changes in gene expression of mTOR, p21, caspase-3, ULK1, TNF α , matrix metalloproteinase (MMP)-9, and cathepsin K in the whole blood of rheumatoid arthritic (RA) patients treated with methotrexate (MTX) in relation to their rheumatoid factor status, clinical, immunological, and radiological parameters, and therapeutic response after a 24-month follow-up. The study group consisted of 35 control subjects and 33 RA patients without previous history of MTX treatment. Gene expression was measured using real-time RT-PCR. Decreased disease activity in patients at the end of the study was associated with significant downregulation of TNF α expression. Downregulation of mTOR was observed in seronegative patients, while no significant changes in the expression of p21, ULK1, or caspase-3 were noted in any RA patients at the end of the study. The increase in erosion numbers observed in the seropositive patients at the end of the follow-up was accompanied by upregulation of MMP-9 and cathepsin K, while seronegative patients demonstrated an absence of significant changes in MMP-9 and cathepsin K expression and no increase in the erosion score. Our results suggest that increased expression of MMP-9 and cathepsin K genes in the peripheral blood might indicate higher bone tissue destruction activity in RA patients treated with methotrexate. The clinical study registration number is 0120.0810610.
International Journal of Rheumatology 11/2013; 2013:457876. DOI:10.1155/2013/457876
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