TY - JOUR
AU - Ishiguro, Naoki
AB - Abstract Objective: This study aimed to determine whether serum matrix metalloproteinase-3 (MMP-3) levels can predict remission in rheumatoid arthritis (RA) patients treated with adalimumab (ADA). Methods: Subjects were 114 RA patients continuously treated with ADA for 52 weeks. Predictive factors at baseline and 4 weeks after initiation of ADA therapy for the achievement of remission (28-point count Disease Activity Score-CRP (DAS28-CRP) < 2.3) at 52 weeks were evaluated by multivariate logistic regression analysis. Results: DAS28-CRP at 4 weeks (odds ratio (OR) 0.614, 95% confidence interval (CI) 0.382–0.988) and improvement in serum MMP-3 levels at 4 weeks (OR 1.057, 95% CI 1.002–1.032) were independent predictors of remission at 52 weeks. The best cut-off level of DAS28-CRP and improvement in serum MMP-3 levels at 4 weeks for predicting remission at 52 weeks was 3.73 (sensitivity: 90%, specificity: 50%, area under the receiver operating characteristic curve (AUC): 62%) and 39.93% (sensitivity: 47%, specificity: 83%, AUC: 64%), respectively. Conclusion: Our findings suggest that a high rate of improvement in serum MMP-3 levels at 4 weeks after initiation of ADA therapy can predict remission at 52 weeks in RA patients. Rheumatoid arthritis, matrix metalloproteinase-3, MMP-3, adalimumab, remission Introduction Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis which leads to cartilage degradation, subchondral bone erosion and eventual disability [1]. Serum matrix metalloproteinase-3 (MMP-3) is an enzyme produced by synoviocytes, serves as a marker of synovitis that reflects actual joint destruction in patients with RA, can be used to predict joint destruction in this patient population [2–13] and is correlated with disease activity [14]. In RA patients treated with tocilizumab, normalization of C-reactive protein (CRP) and serum MMP-3 levels can predict low disease activity and remission [15]. In patients with RA who discontinue tocilizumab, normalization of serum MMP-3 levels is associated with long-term low disease activity [16]. However, little is known about the relationship between serum MMP-3 levels and remission in RA patients treated with tumor necrosis factor (TNF) inhibitors. Here, we found that disease activity at 4 weeks after initiation of adalimumab (ADA) therapy dramatically decreases in RA patients. This study aimed to determine whether serum MMP-3 levels at 4 weeks and improvements in serum MMP-3 levels at 4 weeks after initiation of ADA therapy can predict remission at 52 weeks in RA patients. Methods Study population and evaluations Subjects were all 114 RA patients continuously treated with ADA for 52 weeks in the Tsurumai Biologics Communication Registry (TBCR) [17,18]. All patients were treated with ADA at a standard regimen of 40 mg every alternate week, with no dose escalation. A Japanese multicenter registry of patients with RA starting treatment with biologics in 2008 was developed to explore the long term prognosis of treatment with biologics in clinical practice. Data were collected prospectively from 2008, as well as retrospectively for patients who had been treated with biologics up until 2008. All 2827 patients registered in the TBCR as of April 2015 met the 1987 ACR classification criteria for RA. Patient anonymity was maintained during data collection, and security of personal information was strictly controlled. This study was approved by the Ethics Committee of Nagoya University Graduate School of Medicine. Written informed consent was obtained from all participants in this study. We examined factors contributing to remission (28-point count Disease Activity Score-CRP (DAS28-CRP) < 2.3] at 52 weeks using baseline data, DAS28-CRP, CRP levels, and serum MMP-3 levels at 4 weeks, and improvement in DAS28-CRP, CRP levels and serum MMP-3 levels at 4 weeks after initiation of ADA therapy. We then determined best cutoff values for predicting remission at 52 weeks and examined whether a higher remission rate can be obtained at 52 weeks by combining best cutoff values. DAS28-CRP is known to both significantly underestimate disease activity and overestimate improvement in disease activity compared with DAS28-ESR [19]. The present study used different criteria from those used in DAS28-ESR. Disease activity was categorized as follows: DAS28-CRP remission (DAS28-CRP <2.3), LDA (2.3 ≤ DAS28-CRP <2.7), moderate disease activity (2.7 ≤ DAS28-CRP ≤4.1) and high disease activity (DAS28-CRP >4.1). These criteria were defined based on a large Japanese cohort study [20]. Serum levels of MMP-3 were determined by Latex Immunoassay (Panaclear MMP-3 ‘Latex’; Kyowa Pharma Chemical, Takaoka, Japan). Lower values of 121.0 ng/mL (men) and 59.7 ng/mL (women) were used for serum MMP-3 normalization categorization. Statistical analysis SPSS 22 (SPSS, Inc., Chicago, IL) was used for statistical analyses. Results for continuous variables are presented as mean and standard deviation (SD), and results for categorical variables as proportions. Comparisons of rates between groups were performed with the chi-squared test or Mann–Whitney U-test. Univariate and multivariate logistic regression analyses were performed to determine predictive factors at baseline and 4 weeks after initiation of ADA therapy for achievement of remission at 52 weeks. DAS28-CRP at baseline, CRP at baseline, serum MMP-3 at baseline, DAS28-CRP at 4 weeks, CRP at 4 weeks, serum MMP-3 at 4 weeks, improvement in DAS28-CRP at 4 weeks, improvement in CRP levels at 4 weeks and improvement in serum MMP-3 levels at 4 weeks were adjusted for the following baseline variables: age, female, duration of disease, previous biologics, prednisone use, and methotrexate use. p < .05 was considered statistically significant. Receiver operating characteristic (ROC) curves were generated to assess factors that predict achievement of remission at 52 weeks, based on area under the ROC curve (AUC) analysis. This analysis was also used to determine cut-off points for achievement of remission at 52 weeks. The best cutoff point was identified as the maximum point of the Youden index. Results Table 1 summarizes the demographics and clinical characteristics of subjects at baseline and 4 weeks after initiation of ADA therapy. We divided patients into two groups based on disease activity at 52 weeks: the remission group and non-remission group. Improvement in serum MMP-3 levels at 4 weeks significantly differed between the remission and nonremission groups. Table 1. Demographics and clinical characteristics of subjects at baseline and 4 weeks after initiation of adalimumab therapy. Disease activity at 52 weeks Variables All patients (N = 114) Remission (N = 55) Nonremission (N = 59) p Value At baseline  Age (years) 58 ± 14 58 ± 14 59 ± 14 .766b  Female, n (%) 90 (79%) 43 (78%) 47 (80%) .971a  Duration of disease (years) 15 ± 14 13 ± 14 18 ± 14 .500b  Steinbrocker classification stage (I . II/III . IV %) 27/73 36/64 17/83 –  Functional class (1.2/3.4%) 65/35 69/31 61/39 –  Previous biologics, % 28% 26% 29% .953a  Prednisone use, % 54% 51% 58% .581a  Prednisone dose (mg/day) 4.5 ± 2.0 4.3 ± 2.2 4.7 ± 1.9 .468b  Methotrexate use, % 86% 87% 85% .906a  Methotrexate dose (mg/week) 7.5 ± 2.2 7.7 ± 2.4 7.3 ± 1.9 .557b  DAS28-CRP 4.2 ± 1.2 4.0 ± 1.2 4.4 ± 1.2 .124b  CRP (mg/dL) 2.1 ± 2.4 2.2 ± 2.2 2.0 ± 2.5 .375b  Serum MMP-3 (ng/mL) 260 ± 304 316 ± 380 208 ± 200 .075b At 4 weeks  DAS28-CRP 3.2 ± 1.2 2.8 ± 1.0 3.4 ± 1.3 .083b  CRP (mg/dL) 0.76 ± 1.35 0.63 ± 0.95 0.88 ± 1.64 .707b  Serum MMP-3 (ng/mL) 151 ± 133 146 ± 116 157 ± 147 .747b  Improvement in DAS28-CRP at 4 weeks (%) 31.4 ± 23.0 36.8 ± 22.4 27.6 ± 22.9 .060b  Improvement in CRP levels at 4 weeks (%) 46.0 ± 70.6 49.7 ± 79.2 42.6 ± 62.1 .101b  Improvement in serum MMP-3 levels at 4 weeks (%) 22.6 ± 38.2 31.1 ± 39.3 14.7 ± 35.6 <.05b Disease activity at 52 weeks Variables All patients (N = 114) Remission (N = 55) Nonremission (N = 59) p Value At baseline  Age (years) 58 ± 14 58 ± 14 59 ± 14 .766b  Female, n (%) 90 (79%) 43 (78%) 47 (80%) .971a  Duration of disease (years) 15 ± 14 13 ± 14 18 ± 14 .500b  Steinbrocker classification stage (I . II/III . IV %) 27/73 36/64 17/83 –  Functional class (1.2/3.4%) 65/35 69/31 61/39 –  Previous biologics, % 28% 26% 29% .953a  Prednisone use, % 54% 51% 58% .581a  Prednisone dose (mg/day) 4.5 ± 2.0 4.3 ± 2.2 4.7 ± 1.9 .468b  Methotrexate use, % 86% 87% 85% .906a  Methotrexate dose (mg/week) 7.5 ± 2.2 7.7 ± 2.4 7.3 ± 1.9 .557b  DAS28-CRP 4.2 ± 1.2 4.0 ± 1.2 4.4 ± 1.2 .124b  CRP (mg/dL) 2.1 ± 2.4 2.2 ± 2.2 2.0 ± 2.5 .375b  Serum MMP-3 (ng/mL) 260 ± 304 316 ± 380 208 ± 200 .075b At 4 weeks  DAS28-CRP 3.2 ± 1.2 2.8 ± 1.0 3.4 ± 1.3 .083b  CRP (mg/dL) 0.76 ± 1.35 0.63 ± 0.95 0.88 ± 1.64 .707b  Serum MMP-3 (ng/mL) 151 ± 133 146 ± 116 157 ± 147 .747b  Improvement in DAS28-CRP at 4 weeks (%) 31.4 ± 23.0 36.8 ± 22.4 27.6 ± 22.9 .060b  Improvement in CRP levels at 4 weeks (%) 46.0 ± 70.6 49.7 ± 79.2 42.6 ± 62.1 .101b  Improvement in serum MMP-3 levels at 4 weeks (%) 22.6 ± 38.2 31.1 ± 39.3 14.7 ± 35.6 <.05b The two groups (remission and non-remission groups) were based on disease activity at 52 weeks. Values are presented as mean ± standard deviation (SD) unless stated otherwise. p Values were calculated with the achi-squared test or bMann–Whitney U-test. C-reactive protein (CRP), Disease Activity Score in 28 joints (DAS28-CRP). Remission: DAS28-CRP <2.3. Nonremission: DAS28-CRP ≥2.3. Open in new tab Table 1. Demographics and clinical characteristics of subjects at baseline and 4 weeks after initiation of adalimumab therapy. Disease activity at 52 weeks Variables All patients (N = 114) Remission (N = 55) Nonremission (N = 59) p Value At baseline  Age (years) 58 ± 14 58 ± 14 59 ± 14 .766b  Female, n (%) 90 (79%) 43 (78%) 47 (80%) .971a  Duration of disease (years) 15 ± 14 13 ± 14 18 ± 14 .500b  Steinbrocker classification stage (I . II/III . IV %) 27/73 36/64 17/83 –  Functional class (1.2/3.4%) 65/35 69/31 61/39 –  Previous biologics, % 28% 26% 29% .953a  Prednisone use, % 54% 51% 58% .581a  Prednisone dose (mg/day) 4.5 ± 2.0 4.3 ± 2.2 4.7 ± 1.9 .468b  Methotrexate use, % 86% 87% 85% .906a  Methotrexate dose (mg/week) 7.5 ± 2.2 7.7 ± 2.4 7.3 ± 1.9 .557b  DAS28-CRP 4.2 ± 1.2 4.0 ± 1.2 4.4 ± 1.2 .124b  CRP (mg/dL) 2.1 ± 2.4 2.2 ± 2.2 2.0 ± 2.5 .375b  Serum MMP-3 (ng/mL) 260 ± 304 316 ± 380 208 ± 200 .075b At 4 weeks  DAS28-CRP 3.2 ± 1.2 2.8 ± 1.0 3.4 ± 1.3 .083b  CRP (mg/dL) 0.76 ± 1.35 0.63 ± 0.95 0.88 ± 1.64 .707b  Serum MMP-3 (ng/mL) 151 ± 133 146 ± 116 157 ± 147 .747b  Improvement in DAS28-CRP at 4 weeks (%) 31.4 ± 23.0 36.8 ± 22.4 27.6 ± 22.9 .060b  Improvement in CRP levels at 4 weeks (%) 46.0 ± 70.6 49.7 ± 79.2 42.6 ± 62.1 .101b  Improvement in serum MMP-3 levels at 4 weeks (%) 22.6 ± 38.2 31.1 ± 39.3 14.7 ± 35.6 <.05b Disease activity at 52 weeks Variables All patients (N = 114) Remission (N = 55) Nonremission (N = 59) p Value At baseline  Age (years) 58 ± 14 58 ± 14 59 ± 14 .766b  Female, n (%) 90 (79%) 43 (78%) 47 (80%) .971a  Duration of disease (years) 15 ± 14 13 ± 14 18 ± 14 .500b  Steinbrocker classification stage (I . II/III . IV %) 27/73 36/64 17/83 –  Functional class (1.2/3.4%) 65/35 69/31 61/39 –  Previous biologics, % 28% 26% 29% .953a  Prednisone use, % 54% 51% 58% .581a  Prednisone dose (mg/day) 4.5 ± 2.0 4.3 ± 2.2 4.7 ± 1.9 .468b  Methotrexate use, % 86% 87% 85% .906a  Methotrexate dose (mg/week) 7.5 ± 2.2 7.7 ± 2.4 7.3 ± 1.9 .557b  DAS28-CRP 4.2 ± 1.2 4.0 ± 1.2 4.4 ± 1.2 .124b  CRP (mg/dL) 2.1 ± 2.4 2.2 ± 2.2 2.0 ± 2.5 .375b  Serum MMP-3 (ng/mL) 260 ± 304 316 ± 380 208 ± 200 .075b At 4 weeks  DAS28-CRP 3.2 ± 1.2 2.8 ± 1.0 3.4 ± 1.3 .083b  CRP (mg/dL) 0.76 ± 1.35 0.63 ± 0.95 0.88 ± 1.64 .707b  Serum MMP-3 (ng/mL) 151 ± 133 146 ± 116 157 ± 147 .747b  Improvement in DAS28-CRP at 4 weeks (%) 31.4 ± 23.0 36.8 ± 22.4 27.6 ± 22.9 .060b  Improvement in CRP levels at 4 weeks (%) 46.0 ± 70.6 49.7 ± 79.2 42.6 ± 62.1 .101b  Improvement in serum MMP-3 levels at 4 weeks (%) 22.6 ± 38.2 31.1 ± 39.3 14.7 ± 35.6 <.05b The two groups (remission and non-remission groups) were based on disease activity at 52 weeks. Values are presented as mean ± standard deviation (SD) unless stated otherwise. p Values were calculated with the achi-squared test or bMann–Whitney U-test. C-reactive protein (CRP), Disease Activity Score in 28 joints (DAS28-CRP). Remission: DAS28-CRP <2.3. Nonremission: DAS28-CRP ≥2.3. Open in new tab Figure 1 shows the categorical distribution of disease activity status at baseline and 52 weeks after initiation of ADA therapy. In patients continuously treated with ADA for 52 weeks, the rate of remission at 52 weeks was 48.2%. Figure 1. Open in new tabDownload slide Categorical distribution of disease activity status at baseline and 52 weeks in 114 RA patients continuously treated with ADA for 52 weeks. HDA: high disease activity; MDA: moderate disease activity; LDA: low disease activity; REM: remission. Figure 1. Open in new tabDownload slide Categorical distribution of disease activity status at baseline and 52 weeks in 114 RA patients continuously treated with ADA for 52 weeks. HDA: high disease activity; MDA: moderate disease activity; LDA: low disease activity; REM: remission. Mean DAS28-CRP levels at 52 weeks after initiation of ADA therapy in the remission and non-remission groups were 1.6 and 3.2, respectively. Mean serum MMP-3 levels at 52 weeks after initiation of ADA therapy in the remission and non-remission groups were 77.8 (ng/mL) and 114.1 (ng/mL), respectively. We also evaluated factors that predict the achievement of remission at 52 weeks after ADA therapy. Univariate logistic regression analysis revealed that DAS28-CRP at 4 weeks (odds ratio (OR), 0.646; 95% confidence interval (CI), 0.420–0.996] and improvement in serum MMP-3 levels at 4 weeks (OR, 1.052; 95% CI, 1.002–1.023) were significantly associated with achievement of remission at 52 weeks after initiation of ADA therapy (Table 2). Multivariate logistic regression analysis revealed that DAS28-CRP at 4 weeks (OR, 0.614; 95% CI, 0.382–0.988) and improvement in serum MMP-3 levels at 4 weeks (OR, 1.057; 95% CI, 1.002–1.032) were significantly associated with achievement of remission at 52 weeks after initiation of ADA therapy (Table 3). Table 2. Predictive factors for achievement of remission at 52 weeks. Univariate Variables OR (95% CI) p Value At baseline  Age (years) 0.997 (0.972–1.023) .841  Female 0.915 (0.372–2.252) .847  Duration of disease (years) 0.974 (0.942–1.007) .121  Previous biologics 0.861 (0.304–2.439) .778  Prednisone use 0.754 (0.358–1.590 .458  Methotrexate use 1.234 (0.426–3.578) .698  DAS28-CRP 0.756 (0.551–1.037) .083  CRP (mg/dL) 1.040 (0.889–1.215) .626  Serum MMP-3 (ng/mL) 1.001 (1.000–1.003) .076 At 4 weeks  DAS28-CRP 0.646 (0.420–0.996) <0.05  CRP (mg/dL) 0.861 (0.639–1.159) .324  Serum MMP-3 (ng/mL) 0.999 (0.997–1.002) .660  Improvement in DAS28-CRP at 4 weeks (%) 1.018 (0.996–1.041) .103  Improvement in CRP levels at 4 weeks (%) 1.001 (0.996–1.007) .593  Improvement in serum MMP-3 levels at 4 weeks (%) 1.052 (1.002–1.023) <.05 Univariate Variables OR (95% CI) p Value At baseline  Age (years) 0.997 (0.972–1.023) .841  Female 0.915 (0.372–2.252) .847  Duration of disease (years) 0.974 (0.942–1.007) .121  Previous biologics 0.861 (0.304–2.439) .778  Prednisone use 0.754 (0.358–1.590 .458  Methotrexate use 1.234 (0.426–3.578) .698  DAS28-CRP 0.756 (0.551–1.037) .083  CRP (mg/dL) 1.040 (0.889–1.215) .626  Serum MMP-3 (ng/mL) 1.001 (1.000–1.003) .076 At 4 weeks  DAS28-CRP 0.646 (0.420–0.996) <0.05  CRP (mg/dL) 0.861 (0.639–1.159) .324  Serum MMP-3 (ng/mL) 0.999 (0.997–1.002) .660  Improvement in DAS28-CRP at 4 weeks (%) 1.018 (0.996–1.041) .103  Improvement in CRP levels at 4 weeks (%) 1.001 (0.996–1.007) .593  Improvement in serum MMP-3 levels at 4 weeks (%) 1.052 (1.002–1.023) <.05 Odds ratios (ORs) and 95% confidence intervals (CIs) were determined with univariate logistic regression analysis. Open in new tab Table 2. Predictive factors for achievement of remission at 52 weeks. Univariate Variables OR (95% CI) p Value At baseline  Age (years) 0.997 (0.972–1.023) .841  Female 0.915 (0.372–2.252) .847  Duration of disease (years) 0.974 (0.942–1.007) .121  Previous biologics 0.861 (0.304–2.439) .778  Prednisone use 0.754 (0.358–1.590 .458  Methotrexate use 1.234 (0.426–3.578) .698  DAS28-CRP 0.756 (0.551–1.037) .083  CRP (mg/dL) 1.040 (0.889–1.215) .626  Serum MMP-3 (ng/mL) 1.001 (1.000–1.003) .076 At 4 weeks  DAS28-CRP 0.646 (0.420–0.996) <0.05  CRP (mg/dL) 0.861 (0.639–1.159) .324  Serum MMP-3 (ng/mL) 0.999 (0.997–1.002) .660  Improvement in DAS28-CRP at 4 weeks (%) 1.018 (0.996–1.041) .103  Improvement in CRP levels at 4 weeks (%) 1.001 (0.996–1.007) .593  Improvement in serum MMP-3 levels at 4 weeks (%) 1.052 (1.002–1.023) <.05 Univariate Variables OR (95% CI) p Value At baseline  Age (years) 0.997 (0.972–1.023) .841  Female 0.915 (0.372–2.252) .847  Duration of disease (years) 0.974 (0.942–1.007) .121  Previous biologics 0.861 (0.304–2.439) .778  Prednisone use 0.754 (0.358–1.590 .458  Methotrexate use 1.234 (0.426–3.578) .698  DAS28-CRP 0.756 (0.551–1.037) .083  CRP (mg/dL) 1.040 (0.889–1.215) .626  Serum MMP-3 (ng/mL) 1.001 (1.000–1.003) .076 At 4 weeks  DAS28-CRP 0.646 (0.420–0.996) <0.05  CRP (mg/dL) 0.861 (0.639–1.159) .324  Serum MMP-3 (ng/mL) 0.999 (0.997–1.002) .660  Improvement in DAS28-CRP at 4 weeks (%) 1.018 (0.996–1.041) .103  Improvement in CRP levels at 4 weeks (%) 1.001 (0.996–1.007) .593  Improvement in serum MMP-3 levels at 4 weeks (%) 1.052 (1.002–1.023) <.05 Odds ratios (ORs) and 95% confidence intervals (CIs) were determined with univariate logistic regression analysis. Open in new tab Table 3. Predictive factors for achievement of remission at 52 weeks. Variables Multivariate Adjusted OR (95% CI) p Value At baseline  DAS28-CRP 0.795 (0.514–1.230) .302  CRP (mg/dL) 0.989 (0.820–1.193) .908  Serum MMP-3 (ng/mL) 1.001 (0.999–1.003) .180 At 4 weeks  DAS28-CRP 0.614 (0.382–0.988) <.05  CRP (mg/dL) 0.739 (0.508–1.074) .113  Serum MMP-3 (ng/mL) 0.998 (0.995–1.002) .355  Improvement in DAS28-CRP at 4 weeks (%) 1.026 (0.998–1.055) .730  Improvement in CRP levels at 4 weeks (%) 1.005 (0.996–1.014) .266  Improvement in serum MMP-3 levels at 4 weeks (%) 1.057 (1.002–1.032) <.05 Variables Multivariate Adjusted OR (95% CI) p Value At baseline  DAS28-CRP 0.795 (0.514–1.230) .302  CRP (mg/dL) 0.989 (0.820–1.193) .908  Serum MMP-3 (ng/mL) 1.001 (0.999–1.003) .180 At 4 weeks  DAS28-CRP 0.614 (0.382–0.988) <.05  CRP (mg/dL) 0.739 (0.508–1.074) .113  Serum MMP-3 (ng/mL) 0.998 (0.995–1.002) .355  Improvement in DAS28-CRP at 4 weeks (%) 1.026 (0.998–1.055) .730  Improvement in CRP levels at 4 weeks (%) 1.005 (0.996–1.014) .266  Improvement in serum MMP-3 levels at 4 weeks (%) 1.057 (1.002–1.032) <.05 Odds ratios (ORs) and 95% confidence intervals (CIs) were determined with multivariate logistic regression analysis. DAS28-CRP at baseline, CRP at baseline, serum MMP-3 at baseline, DAS28-CRP at 4 weeks, CRP at 4 weeks, serum MMP-3 at 4 weeks, improvement in DAS28-CRP at 4 weeks, improvement in CRP levels at 4 weeks and improvement in serum MMP-3 levels at 4 weeks were adjusted for the following baseline variables: age, female, duration of disease, previous biologics, prednisone use and methotrexate use. Open in new tab Table 3. Predictive factors for achievement of remission at 52 weeks. Variables Multivariate Adjusted OR (95% CI) p Value At baseline  DAS28-CRP 0.795 (0.514–1.230) .302  CRP (mg/dL) 0.989 (0.820–1.193) .908  Serum MMP-3 (ng/mL) 1.001 (0.999–1.003) .180 At 4 weeks  DAS28-CRP 0.614 (0.382–0.988) <.05  CRP (mg/dL) 0.739 (0.508–1.074) .113  Serum MMP-3 (ng/mL) 0.998 (0.995–1.002) .355  Improvement in DAS28-CRP at 4 weeks (%) 1.026 (0.998–1.055) .730  Improvement in CRP levels at 4 weeks (%) 1.005 (0.996–1.014) .266  Improvement in serum MMP-3 levels at 4 weeks (%) 1.057 (1.002–1.032) <.05 Variables Multivariate Adjusted OR (95% CI) p Value At baseline  DAS28-CRP 0.795 (0.514–1.230) .302  CRP (mg/dL) 0.989 (0.820–1.193) .908  Serum MMP-3 (ng/mL) 1.001 (0.999–1.003) .180 At 4 weeks  DAS28-CRP 0.614 (0.382–0.988) <.05  CRP (mg/dL) 0.739 (0.508–1.074) .113  Serum MMP-3 (ng/mL) 0.998 (0.995–1.002) .355  Improvement in DAS28-CRP at 4 weeks (%) 1.026 (0.998–1.055) .730  Improvement in CRP levels at 4 weeks (%) 1.005 (0.996–1.014) .266  Improvement in serum MMP-3 levels at 4 weeks (%) 1.057 (1.002–1.032) <.05 Odds ratios (ORs) and 95% confidence intervals (CIs) were determined with multivariate logistic regression analysis. DAS28-CRP at baseline, CRP at baseline, serum MMP-3 at baseline, DAS28-CRP at 4 weeks, CRP at 4 weeks, serum MMP-3 at 4 weeks, improvement in DAS28-CRP at 4 weeks, improvement in CRP levels at 4 weeks and improvement in serum MMP-3 levels at 4 weeks were adjusted for the following baseline variables: age, female, duration of disease, previous biologics, prednisone use and methotrexate use. Open in new tab For patients who continued treatment for 52 weeks, the best cutoff value of DAS28-CRP levels at 4 weeks for predicting remission at 52 weeks was 3.73, as determined by ROC analysis (sensitivity: 89.66%, specificity: 50.00%, AUC: 62.33%). In addition, the best cutoff value of improvement in serum MMP-3 levels at 4 weeks for predicting remission at 52 weeks was 39.93% (sensitivity: 47.27%, specificity: 83.05%, AUC: 63.73%) (Figure 2). Figure 2. Open in new tabDownload slide Association of improvement in serum MMP-3 levels at 4 weeks and DAS28-CRP at 4 weeks for achievement of remission at 52 weeks. Receiver operating characteristic (ROC) curves were used to determine the best cutoff for improvement in serum MMP-3 levels and DAS28-CRP at 4 weeks for predicting remission at 52 weeks. The table shows the cutoff value, area under the ROC curve (AUC), 95% confidence interval (CI), sensitivity, specificity, positive predictive value, negative predictive value and positive likelihood ratio of improvement in serum MMP-3 levels at 4 weeks and DAS28-CRP at 4 weeks for achievement of remission at 52 weeks. Figure 2. Open in new tabDownload slide Association of improvement in serum MMP-3 levels at 4 weeks and DAS28-CRP at 4 weeks for achievement of remission at 52 weeks. Receiver operating characteristic (ROC) curves were used to determine the best cutoff for improvement in serum MMP-3 levels and DAS28-CRP at 4 weeks for predicting remission at 52 weeks. The table shows the cutoff value, area under the ROC curve (AUC), 95% confidence interval (CI), sensitivity, specificity, positive predictive value, negative predictive value and positive likelihood ratio of improvement in serum MMP-3 levels at 4 weeks and DAS28-CRP at 4 weeks for achievement of remission at 52 weeks. We then examined whether a higher remission rate can be obtained at 52 weeks by combining the best cut-off values of DAS28-CRP levels at 4 weeks and improvement in serum MMP-3 levels at 4 weeks for predicting remission at 52 weeks. Among 114 RA patients continuously treated with ADA for 52 weeks, four groups were generated based on the best cutoff values of DAS28-CRP and improvement in serum levels of MMP-3 at 4 weeks for predicting remission at 52 weeks: (a) the both HL-DAS (high levels of DAS28-CRP at 4 weeks >3.73) and LR-MMP (low rate of improvement in serum MMP-3 levels at 4 weeks <39.93%) group, (b) the LL-DAS group (low levels of DAS28-CRP at 4 weeks <3.73), (c) the HR-MMP group (high rate of improvement in serum MMP-3 levels at 4 weeks >39.93%) and (d) the both LL-DAS and HR-MMP group. We evaluated the rate of remission at 52 weeks for these four groups. Rates of remission at 52 weeks in the both HL-DAS and LR-MMP group, the LL-DAS group, the HR-MMP group and the both LL-DAS and HR-MMP group were 11.8%, 56.5%, 72.2% and 81.0%, respectively. Rates of remission at 52 weeks in the LL-DAS group, the HR-MMP group, and the both LL-DAS and HR-MMP group were significantly higher than in the both HL-DAS and LR-MMP group. The rate of remission at 52 weeks in the both LL-DAS and HR-MMP group was significantly higher than in the LL-DAS group; however, the difference was not significant after Bonferroni correction (Figure 3). Figure 3. Open in new tabDownload slide Low levels of DAS28-CRP at 4 weeks and a high rate of improvement in serum MMP-3 levels at 4 weeks predict achievement of remission at 52 weeks. HL-DAS group: high levels of DAS28-CRP at 4 weeks >3.73. LR-MMP group: low rate of improvement in serum MMP-3 levels at 4 weeks <39.93%. LL-DAS group: low levels of DAS28-CRP at 4 weeks <3.73. HR-MMP group: high rate of improvement in serum MMP-3 levels at 4 weeks >39.93%. Among 114 RA patients continuously treated with ADA for 52 weeks, four groups were generated based on the best cutoff values of DAS28-CRP and improvement in serum levels of MMP-3 at 4 weeks for predicting remission at 52 weeks: both HL-DAS (high levels of DAS28-CRP at 4 weeks >3.73) and LR-MMP (low rate of improvement in serum MMP-3 levels at 4 weeks <39.93%) group, LL-DAS group (low levels of DAS28-CRP at 4 weeks <3.73), HR-MMP group (high rate of improvement in serum MMP-3 levels at 4 weeks >39.93%) and both LL-DAS and HR-MMP group. Differences with a p value <.05 were considered statistically significant. Figure 3. Open in new tabDownload slide Low levels of DAS28-CRP at 4 weeks and a high rate of improvement in serum MMP-3 levels at 4 weeks predict achievement of remission at 52 weeks. HL-DAS group: high levels of DAS28-CRP at 4 weeks >3.73. LR-MMP group: low rate of improvement in serum MMP-3 levels at 4 weeks <39.93%. LL-DAS group: low levels of DAS28-CRP at 4 weeks <3.73. HR-MMP group: high rate of improvement in serum MMP-3 levels at 4 weeks >39.93%. Among 114 RA patients continuously treated with ADA for 52 weeks, four groups were generated based on the best cutoff values of DAS28-CRP and improvement in serum levels of MMP-3 at 4 weeks for predicting remission at 52 weeks: both HL-DAS (high levels of DAS28-CRP at 4 weeks >3.73) and LR-MMP (low rate of improvement in serum MMP-3 levels at 4 weeks <39.93%) group, LL-DAS group (low levels of DAS28-CRP at 4 weeks <3.73), HR-MMP group (high rate of improvement in serum MMP-3 levels at 4 weeks >39.93%) and both LL-DAS and HR-MMP group. Differences with a p value <.05 were considered statistically significant. Discussion Synovial tissue in RA patients can produce cytokines that aggravate the inflammatory response, with uncontrolled synovitis leading to joint damage. While CRP is a widely used inflammatory biomarker produced by hepatocytes in response to pro-inflammatory cytokines such as TNF and interleukins during inflammation, it is a poor marker when assessing cumulative synovitis [21]. Previous studies have also failed to reach a consensus regarding correlations between cytokines such as IL-1, IL-6, and TNF-α and persistent synovitis [22,23]. Thus, novel serological biomarkers that more closely reflect particular aspects of synovitis and are differentially regulated in patients are needed. Matrix metalloproteinases (MMPs) are a large group of zinc-dependent proteases with the ability to degrade components of the extracellular matrix, such as collagen, elastin, gelatin and casein. MMP-3, a member of the MMP family, is produced in joints and is known to aggravate inflammation by activating various pro-MMPs, such as pro-MMP-1, pro-MMP-7, pro-MMP-8, pro-MMP-9, and pro-MMP-13 and cleaving extracellular components such as collagen types III, IX, and X, and telopeptides of collagen types I, II and XI [24]. In this study, we investigated whether serum MMP-3 levels at 4 weeks and improvement in serum MMP-3 levels at 4 weeks could predict remission at 52 weeks in RA patients treated with ADA. In patients treated with ADA for 52 weeks, both improvement in serum MMP-3 levels at 4 weeks and DAS28-CRP levels at 4 weeks were independent predictors of remission at 52 weeks. Improvement (>39.93%) in serum MMP-3 levels at 4 weeks predicted remission just as well as DAS28-CRP levels at 4 weeks, as reflected by their similar AUCs. If serum MMP-3 levels improved by 39.93% at 4 weeks after initiation of ADA therapy, the probability of achieving remission at 52 weeks was 72.22%. In other words, when serum MMP-3 levels did not improve by 39.93% at 4 weeks after ADA initiation, the probability of not achieving remission at 52 weeks was 62.82%. Although the rate of improvement (>39.93%) in serum MMP-3 levels at 4 weeks is associated with remission, the sensitivity of this cutoff value (47.27%) is low. In patients treated with ADA for 52 weeks, serum MMP-3 levels at 4 weeks was not an independent predictor of remission at 52 weeks. In addition, CRP levels at 4 weeks and improvement in CRP levels at 4 weeks did not independently predict remission at 52 weeks. These results suggest that a high rate of improvement in serum MMP-3 levels at 4 weeks predicted remission at 52 weeks just as well as DAS28 as an indicator of RA disease activity and response to treatment and highlight serum MMP-3 as being a superior biomarker to CRP for predicting remission at 52 weeks. Patients in remission at 52 weeks had higher levels of serum MMP-3 at baseline than nonremission patients. Moreover, patients in remission at 52 weeks had lower levels of serum MMP-3 at 4 weeks compared to non-remission patients. This suggests that patients with higher levels of serum MMP-3 at baseline have an opportunity to reduce their levels of MMP-3 and achieve remission. Therapies that achieve both DAS28 remission and normalization of serum MMP-3 levels would lead to better outcomes than therapies that achieve either of these targets alone in early RA [25]. In this study, low levels of DAS28-CRP at 4 weeks and a high rate of improvement in serum MMP-3 levels at 4 weeks predicted a higher rate of remission at 52 weeks for RA patients treated with ADA. We suggest that treatment strategy can be considered in the early stages of ADA therapy by using, in addition to DAS28, improvement in serum MMP-3 levels. To our knowledge, this is the first study to report that levels of serum MMP-3 predict remission in RA patients treated with ADA. This study has some limitations worth noting. First, serum levels of MMP-3 were influenced by whether the patient is male or female. Other than improvement in serum MMP-3 levels at 4 weeks, we did not take into account sex-based differences in our analyses. Second, the multicenter study design raises the possibility of selection bias, because the criteria for administration of ADA as well as insufficient efficacy and adverse events – the extent of which was determined by the rheumatologist at each institute – were not clearly defined. Third, the sample population was limited in size, and thus we could not fully adjust for factors in the analysis. Fourth, while there were no significant differences in prednisone and methotrexate use and dose at baseline between remission and non-remission groups, detailed data were not available regarding the use and dose of prednisone and methotrexate during the course of treatment up to 52 weeks. In conclusion, improvement in serum MMP-3 levels at 4 weeks was an independent predictor of remission at 52 weeks, and the best cutoff rate of improvement in serum MMP-3 levels at 4 weeks for predicting remission at 52 weeks was 40% in patients treated with ADA for 52 weeks. Our findings suggest that a high rate of improvement in serum MMP-3 levels at 4 weeks can be used to predict remission at 52 weeks in RA patients treated with ADA. Acknowledgements We thank Dr. Toshihisa Kanamono (Department of Orthopaedic Surgery, Nagano Red Cross Hospital, Nagano, Japan), Dr. Yukiyoshi Oh-ishi (Department of Rheumatology, Toyohashi Municipal Hospital, Toyohashi, Japan), Dr. Naoki Fukaya (Department of Orthopaedic Surgery, Kariya Toyota General Hospital, Kariya, Japan), Seiji Tsuboi (Department of Rheumatology, Shizuoka Kosei Hospital, Shizuoka, Japan), and Yoshito Eto (Department of Orthopaedic Surgery and Rheumatology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan) for their assistance. Conflict of interest Yosuke Hattori received grants from Chugai Pharmaceutical, Pfizer, Abbvie, UCB, Bristol-Myers Squibb and Janssen Pharmaceuticals. Toshihisa Kojima received grants from Chugai Pharmaceutical and lecture from Mitsubishi Tanabe Pharma, Takeda Pharmaceutical Company, Eisai, AbbVie, Bristol-Myers Squibb, Pfizer, Janssen Pharmaceuticals, Astellas Pharma, Taisho Toyama Pharmaceutical Company, Daiichi Sankyo Company and Chugai Pharmaceutical. Atsushi Kaneko received grants from Chugai Pharmaceutical, Pfizer, Abbvie, UCB, Bristol-Myers Squibb, and Janssen Pharmaceuticals. Daihei Kida received grants from Chugai Pharmaceutical, Pfizer, Abbvie, UCB, Bristol-Myers Squibb, and Janssen Pharmaceuticals. Yuji Hirano received speaking fees of $5000 and less per a year from Astellas Pharma, UCB, Takeda Pharmaceutical, Bristol-Myers Squibb and AYUMI Pharmaceutical, and speaking fees of $10,000 and less per a year from Mitsubishi Tanabe Pharma, Eisai, Abbvie, Chugai Pharmaceutical and Pfizer. Hideki Takagi received grants from Bristol-Myers Squibb, Mitsubishi Tanabe Pharmaceutical, and Takeda Pharmaceutical. 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TI - High rate of improvement in serum matrix metalloproteinase-3 levels at 4 weeks predicts remission at 52 weeks in RA patients treated with adalimumab
JF - Modern Rheumatology
DO - 10.1080/14397595.2017.1317320
DA - 2018-01-02
UR - https://www.deepdyve.com/lp/oxford-university-press/high-rate-of-improvement-in-serum-matrix-metalloproteinase-3-levels-at-N5oEUnVfqN
SP - 119
EP - 125
VL - 28
IS - 1
DP - DeepDyve
ER -