http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(1): 42–51 © 2013 Japan College of Rheumatology DOI 10.3109/14397595.2013.854051
ORIGINAL ARTICLE
Abatacept inhibits radiographic progression in patients with rheumatoid arthritis: a retrospective analysis of 6 months of abatacept treatment in routine clinical practice. The ALTAIR study Satoshi Kubo • Kazuyoshi Saito • Shintaro Hirata • Shunsuke Fukuyo Kunihiro Yamaoka • Norifumi Sawamukai • Masao Nawata • Shigeru Iwata • Yasushi Mizuno • Yoshiya Tanaka
•
Received: 5 November 2012 / Accepted: 12 February 2013 Ó Japan College of Rheumatology 2013
Abstract Objectives Our objectives in this study were to determine the inhibitory effects of abatacept on joint damage and its clinical efficacy and safety in patients with rheumatoid arthritis (RA). Methods Fifty Japanese patients with RA were treated with abatacept for 24 weeks in routine clinical practice. Results At week 24, 20 % of patients achieved clinical remission [Simplified Disease Activity Index (SDAI) B3.3], whereas 50 % were in remission or had a low disease activity. Structural remission [progression of modified total Sharp score (DmTSS) B0.5] was achieved in 76 % of patients. The DmTSS decreased significantly from 7.1 ± 7.3 at baseline to 1.8 ± 5.7 at week 24. C-reactive protein (CRP) was the only independent prognostic factor for joint damage progression at week 24, whereas SDAI and matrix metalloproteinase-3 levels were not. A very high proportion of patients with CRP levels \1.5 mg/dl (88 %) achieved structural remission. In terms of safety, the retention rate for all patients was favorable (80 %), and stomatitis was the only adverse event observed. No patient withdrew from the study because of infections. Conclusions Abatacept has favorable clinical and structural effects, inhibits radiographic progression, and has a good safety profile in routine clinical practice.
S. Kubo K. Saito S. Hirata S. Fukuyo K. Yamaoka N. Sawamukai M. Nawata S. Iwata Y. Mizuno Y. Tanaka (&) The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan e-mail: [email protected] Published online: 02 March 2013
Keywords Abatacept Rheumatoid arthritis Modified total Sharp score Radiographic outcome Japanese patients
Introduction Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and is characterized by synovitis that causes joint damage [1]. Conventional RA treatments focus on pain control. However, the introduction of biologics has made it possible to induce remission in many patients and inhibit joint damage, leading to a paradigm shift in RA treatment [2]. Under such circumstances, the treat to target approach was proposed in 2010, and overarching principles and recommendations for treating RA to target were clearly established [3]. Consequently, the goal of RA treatment changed to achieve clinical remission. An emphasis was placed on achieving remission as the primary objective of treatment, whereas secondary objectives include preventing structural damage to joints and improving physical function. Inflammatory cells (e.g., macrophages) and proinflammatory cytokines [e.g., tumor necrosis factor (TNF) and interleukin (IL)-6 produced by synovial fibroblasts] play important roles in RA pathogenesis. RA treatments targeting T cells have also been a focus of research, based on the results of a study showing the infiltration of numerous CD4-positive T cells and expression of major histocompatibility complex (MHC) class II molecules in the synovial membrane [4]. Another study showed a strong correlation between RA and the major histocompatibility antigen, human leukocyte antigen (HLA)-DR4 [5], whereas a more recent study revealed the importance of T-helper cells (Th)17 in RA [6].
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Abatacept is a fusion protein [cytotoxic T lymphocyte antigen (CTLA)4-Ig] composed of the Fc portion of human immunoglobulin G1 (Ig-G1) fused to extracellular-domain2 molecules of human CTLA-4. Abatacept prevents T-cell activation by inhibiting costimulatory signals by competing with CD28 molecules on T cells through specific binding to the costimulatory molecules (CD80/CD86) on antigenpresenting cells (APC). The safety and effectiveness of abatacept have been established in multiple clinical studies [7–11]. The 2012 Recommendations for RA Treatment recommend the use of abatacept as a first-line biologic, along with anti-TNF inhibitors [12]. However, few studies have reported the inhibitory effects of abatacept on joint damage in routine clinical practice. Therefore, this study, the Abatacept Leading Trial for RA on Imaging Remission (ALTAIR), was conducted to investigate the inhibitory effects of abatacept on joint damage and its clinical efficacy and safety.
Patients and methods Patients All patients, except those without radiographs, who started treatment with abatacept between 3 November 2010 and 29 September 2011 at our hospital were registered in the study. All patients had a diagnosis of RA defined using the American College of Rheumatology (ACR) criteria [13]. The study was conducted as a retrospective observation study using anonymized data. Abatacept was used within the health insurance coverage for RA in Japan. The reasons for discontinuation of abatacept treatment were recorded for all patients who discontinued treatment during the study period. This study was registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/) (UMIN00000 8285).
Clinical efficacy Disease activity was assessed using the Disease Activity Score 28 erythrocyte sedimentation rate (DAS28-ESR) [14] and Simplified Disease Activity Index (SDAI) [15, 16] scales. Functional impairment was assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI) [17]. Radiographs of hands and feet were obtained at baseline and week 24 for patients who completed the study or at discontinuation. Joint damage scores were assessed by two independent readers using the van der Heijde modified total Sharp score (mTSS) [18]. The twice-yearly progression (DmTSS) in mTSS was defined as yearly change. Subanalyses of clinical outcomes were assessed in subgroups stratified by DAS28-ESR [14] and SDAI/Clinical Disease Activity Index (CDAI) [15, 16] scores. Statistical analysis Patient characteristics are expressed as mean ± standard deviation (SD), medians [interquartile range (IQR)], or number (%). The last observation carried forward (LOCF) method was used for patients who discontinued before week 24 to include all patients in analyses. Wilcoxon signed rank tests were used to detect statistically significant differences in disease activity and functional impairment between baseline and week 24. Pearson’s v2 test was used to detect statistically significant differences in disease activity between assessment methods. Kaplan–Meier analysis was used to assess the rate of abatacept retention. Stepwise multiple regression analysis was performed to identify prognostic factors. The optimal cutoff value for the subgroup analysis was calculated using receiver operator characteristic (ROC) curve analysis. All reported P values are two sided and were not adjusted for multiple testing. The level of significance was taken as P \ 0.05. All analyses were conducted using SPSS software version 16.0 (SPSS Inc., Chicago, IL, USA).
Abatacept treatment Abatacept was prescribed to patients with RA uncontrolled by normal doses of existing disease-modifying antirheumatic drugs (DMARDs). The dosing regimen was based on patient weight (500 mg for \60 kg, 750 mg for 60–100 kg, and 1,000 mg for [100 kg). Abatacept was dissolved in 100 ml of normal saline, and the solution was administered as an intravenous infusion over a 30-min period at weeks 0, 2, and 4, and then every 4 weeks thereafter. Written informed consent for data collection was obtained from all patients according to the Declaration of Helsinki. Because this was a retrospective observational study, approval from an ethics review board was not deemed necessary.
Results Patient characteristics Fifty patients who started treatment with abatacept between November 2010 and September 2011 were enrolled in the study. Their characteristics are shown in Table 1. Mean age was 62.0 years, and most patients were women (84.0 %). Mean duration of illness was 10.0 years, and mean disease activity at baseline was 31.1 and 5.8 for SDAI and DAS28-ESR, respectively, indicating high disease activity. Mean HAQ-DI was 1.5, and mean mTSS was 60.1 (median 40.5; IQR 7.3–88.4). Mean DmTSS before
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Table 1 Patient characteristics at baseline Variables
Total (n = 50)
Age (years)
62.0 ± 14.2
Females [n (%)]
42 (84.0)
Disease duration (years)
10.0 ± 9.2
Stage (I/II/III/IV %)
(10.0/38.0/38.0/ 14.0)
Class (I/II/III/IV %)
(0.0/78.0/22.0/0.0)
Prior use of biologics [n (%)]
29 (58.0)
RF positive [n (%)] MTX use [n (%)]
40 (80.0) 37 (74.0)
MTX dose (mg/week)
9.6 ± 3.4
Fig. 1 Kaplan–Meier analysis of abatacept treatment retention
Oral steroid use [n (%)]
17 (34.0)
Oral steroid use (mg/daya)
3.1 ± 1.7
MMP-3 (ng/ml)
215.5 ± 166.0
Table 2 Reasons for discontinuation
SJC, 0–28
8.0 ± 4.6
Variables
All (n = 50)
TJC, 0–28
9.5 ± 6.0
ESR (mm/h)
53.1 ± 30.9
All discontinuations
10 (20 %)
CRP (mg/dl)
2.1 ± 2.1
PGA, VAS 0–100 mm
60.7 ± 23.4
SDAI
31.1 ± 12.3
CDAI
29.1 ± 11.7
DAS28-ESR
5.8 ± 1.2
HAQ-DI
1.5 ± 0.7
mTSS Median (IQR)
60.1 ± 67.8 40.5 (7.3–88.4)
Estimated yearly progression of mTSS (DmTSS)
7.1 ± 7.3
Median (IQR)
4.5 (2.2–8.4)
Values are mean ± standard deviation (SD) unless otherwise indicated RF rheumatoid factor, MTX methotrexate, MMP-3 matrix metalloproteinase 3, SJC swollen joint count, TJC tender joint count, ESR erythrocyte sedimentation rate, CRP C-reactive protein, PGA patient global assessment of disease activity, VAS visual analog scale, SDAI Simplified Disease Activity Index, CDAI Clinical Disease Activity Index, DAS Disease Activity Score, HAQ-DI Health Assessment Questionnaire Disability Index, mTSS modified total Sharp score, IQR interquartile range a
Prednisolone equivalent
the start of treatment was 7.1 (median 4.5; IQR 2.2–8.4). Of the 50 patients, 21 (42.0 %) were naı¨ve to biologics, and 29 (58.0 %) were previously treated with biologics. Concomitant medications included methotrexate (MTX) in 37 patients (74.0 %) and orally administered steroids in 17 (34.0 %) at mean doses of 9.6 mg/week and 3.1 mg/day (prednisolone equivalent), respectively. Other laboratory findings included rheumatoid factor (RF) positivity in 40 patients (80.0 %), with mean matrix metalloproteinase (MMP)-3, ESR, and C-reactive protein (CRP) levels of 215.5 ng/ml, 53.1 mm/h, and 2.1 mg/dl, respectively.
Lack of efficacy
9 (18 %)
Adverse events
1 (2 %)
Other reasons
0
Retention rate The retention rate is shown in Fig. 1. At week 24, 80 % of patients were still receiving abatacept treatment. The most common reason for discontinuation was inadequate effect (18 %) (Table 2); one patient (2 %) discontinued treatment because of an adverse event (frequent stomatitis) during abatacept treatment. No patient withdrew because of infection, such as bacterial pneumonia. Clinical efficacy The time course of SDAI recorded over 24 weeks is shown in Fig. 2a. Abatacept induced a significant improvement in SDAI from 31.1 ± 12.3 at baseline to 14.5 ± 13.9 at week 24. As shown, SDAI continued to improve over the 24 weeks of treatment. Changes in disease activity in patients stratified by SDAI (remission, SDAI B3.3; low, SDAI [3.3 to B11.0; moderate, SDAI [11.0 to B26.0; high, SDAI [ 26.0) are shown in Fig. 2b. At week 24, 20 % of patients achieved clinical remission. Overall, 50 % of patients achieved either remission or a low disease activity at the end of the study. Similar significant improvements in disease activity were also detected using the DAS28-ESR (Fig. 2c). The proportions of patients with remission or a low disease activity state were 16 % and 24 %, respectively, measured by the DAS28-ESR, and 20 % and 50 %, respectively, measured by the SDAI. Thus, these rates were higher when determined using the SDAI than with the DAS28-ESR
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Fig. 2 Effects of treatment with abatacept for 24 weeks on clinical outcomes. a Time course of SDAI. b Disease activity stratified according to SDAI. c Time course of DAS28-ESR. Values in a and c are for individual patients, whereas thick lines and error bar
represent means and standard deviations, respectively. SDAI Simplified Disease Activity Index, DAS28-ESR Disease Activity Score 28-Erythrocyte Sedimentation Rate
(Fig. 3a). In particular, the proportion of patients with a low disease activity state was significantly higher using SDAI than using DAS28-ESR. Changes in individual SDAI components are shown in Fig. 3b. The number of swollen joints (8.0 ± 4.6 to 3.0 ± 4.5), number of tender joints (9.5 ± 6.0 to 3.9 ± 6.2), patient global assessment of disease activity (6.1 ± 2.4 to 4.2 ± 2.8), evaluator global assessment of disease activity (5.5 ± 2.2 to 3.0 ± 2.5), and CRP (2.1 ± 2.1 to 0.9 ± 1.6 mg/dl) decreased significantly from baseline to week 24. The magnitude of change was greater for number of tender joints (5.6) and number of swollen joints (5.0) than the other three components. ESR (from 53.1 ± 30.9 to 43.0 ± 30.0 mm/h), MMP-3 (from 215.5 ± 166.0 to 152.1 ± 328.3 ng/ml), and RF (from 177.2 ± 355.5 to 121.0 ± 219.4 IU/ml) also improved significantly from baseline to week 24.
HAQ-DI Mean HAQ-DI improved moderately but significantly from 1.5 ± 0.7 to 1.3 ± 0.8 (Fig. 4a). Overall, 22 % of patients achieved functional remission at week 24, defined as HAQ-DI B 0.5 (Fig. 4b). Radiographic outcomes Mean DmTSS improved significantly from 7.1 ± 7.3 at baseline to 1.8 ± 5.7 at week 24 (Fig. 5a). This result indicates that abatacept inhibits joint damage. When mTSS was assessed separately as the erosion score (ES) and jointspace-narrowing score (JSN), significant improvements in the yearly progression rate were observed for both ES (from 3.8 ± 3.9 to 1.1 ± 3.7) and JSN (from 3.3 ± 3.7 to 0.7 ± 3.5) (Fig. 5b). Figure 5c shows a cumulative
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Fig. 3 a Proportions of patients who achieved remission or low disease activity defined according to SDAI, CDAI, and DAS28-ESR. b Values for individual components of the SDAI at baseline and at week 24. Values in b are means. Data were analyzed using the last observation carried forward (LOCF) method. SDAI Simplified Disease Activity Index, DAS28-ESR Disease Activity Score 28-Erythrocyte Sedimentation Rate, SJC swollen joint count, TJC tender joint count, PGA patient global assessment of disease activity, EGA evaluator global assessment of disease activity, CRP C-reactive protein
Fig. 4 Effects of treatment with abatacept for 24 weeks on: a time course of HAQ-DI, and b proportion of patients with HAQ-DI B 0.5. Values in a are for individual patients, whereas thick lines and error bar represent means and standard deviations, respectively. Data were analyzed using the last observation carried forward (LOCF) method. HAQ-DI Health Assessment Questionnaire Disability Index
scatterplot of DmTSS. At week 24, structural remission (defined as a change in DmTSS B 0.5) was achieved in 76.0 % of patients. However, rapid radiologic progression (DmTSS [ 5) was observed in six patients. We next performed subanalyses to identify factors associated with disease progression. Examination of prognostic factors at baseline contributing to DmTSS at week 24 revealed that CRP was an independent prognostic factor, whereas SDAI, MMP-3, and mTSS were not (Table 3).
Several other factors, including use of biologics or MTX, RF titer, and anticyclic citrullinated peptide (anti-CCP) antibody titer did not contribute to DmTSS. Based on these results, we determined the optimal cutoff value for baseline CRP using receiver operating characteristic (ROC) curve analysis. This analysis yielded a cutoff value of 1.5 mg/dl with a sensitivity and specificity of 75 % and 58 %, respectively, for DmTSS B 0.5 at week 24. Therefore, we performed subgroup analysis by stratifying patients
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Fig. 5 Abatacept inhibits radiographic progression: a Yearly progression in mTSS. b Yearly progression in ES and JSN. c Cumulative probability for a change in mTSS from baseline. Values in a and b are for individual patients, whereas thick lines and error bar represent means and standard deviations, respectively. Data were analyzed using the last observation carried forward (LOCF) method. mTSS modified total Sharp score, ES erosion score, JSN joint-space narrowing
according to CRP levels of 1.5 mg/dl. Abatacept inhibited progression of joint damage in both groups, with greater inhibitory effects in patients with baseline CRP \ 1.5 mg/ dl (Fig. 6a, b). A cumulative scatterplot of these data showed that structural remission was achieved in 64.0 % of patients with CRP C 1.5 mg/dl and in 88.0 % of patients with CRP \ 1.5 mg/dl (Fig. 6c). The cumulative scatterplot also revealed that the progression of joint damage was mild, even in patients with CRP \ 1.5 mg/dl and advanced joint damage.
We next determined the prognostic factors contributing to HAQ-DI at week 24. In this analysis, baseline HAQ-DI and baseline mTSS were identified as independent prognostic factors (Table 4), whereas the use of biologics or MTX, RF titer, and anti-CCP antibody titer, among others, did not. ROC curve analysis yielded an optimal cutoff mTSS value of 40.5. Therefore, we performed a subanalysis by stratifying patients according to mTSS of 40.5 (Fig. 6d, e). HAQ-DI improved significantly in patients with baseline mTSS \ 40.5 but not in patients with baseline mTSS C 40.5.
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Table 3 Independent predictors for progression of modified total Sharp score (DmTSS) at week 24 in multivariate analysis Variables
Standardized partial regression coefficient
P value
Age
–0.108
0.44
Sex (female)
–0.137
0.31
Disease duration Prior use of biologics
–0.009 0.009
0.95 0.95
MTX use
0.179
0.20
Oral steroid use
0.037
0.79
-0.100
0.47
0.064
0.64
RF titer (at baseline) Anti-CCP antibody titer (at baseline) MMP-3 (at baseline)
-0.14
0.41
CRP (at baseline)
0.372
0.01
SDAI (at baseline)
0.073
0.62
HAQ-DI (at baseline)
0.162
0.24
mTSS (at baseline)
0.223
0.99
MTX methotrexate, RF rheumatoid factor, CCP cyclic citrullinated peptide, MMP-3 matrix metalloproteinase 3, CRP C-reactive protein, SDAI Simplified Disease Activity Index, HAQ-DI Health Assessment Questionnaire Disability Index
Discussion The ALTAIR study was conducted to retrospectively examine the clinical efficacy and safety of abatacept in 50 patients with RA. Structural remission, corresponding to inhibition of joint damage progression, was achieved in approximately 75 % of patients treated with abatacept for 24 weeks. However, rapid radiologic progression (DmTSS [ 5) was observed in six patients (12 %). Therefore, we determined the prognostic factors for change in DmTSS at week 24 by multiple regression analysis. In this analysis, the only independent prognostic factor was CRP. Unexpectedly, SDAI and MMP-3 were not independently associated with the change in DmTSS at week 24. Notably, baseline disease activity and MMP-3, a marker for cartilage damage and the severity of joint damage, were not associated with joint damage in this study, whereas inflammatory activity at baseline was predictive of the progression of joint damage after 24 weeks of abatacept treatment. These results may be attributable to the biologic properties of abatacept, which do not directly block proinflammatory cytokine signaling, as observed with TNF and IL-6 receptor inhibitors, but instead inhibit T-cell activity. The stratified analysis according to the CRP cutoff value of 1.5 mg/dl, which was determined by ROC curve analysis, revealed that a very high proportion of patients with CRP \ 1.5 mg/dl (88 %) achieved structural remission and that patients with advanced joint damage experienced mild
progression. These results suggest that the production of proinflammatory cytokines by APCs is enhanced in patients with severe inflammatory activity, indicating that APCs play a major role in disease activity in these patients. By contrast, in patients with high disease activity but low inflammatory activity, lymphocytes rather than APCs may play a major role in disease activity, making these patients suitable targets for abatacept. In terms of clinical efficacy, we observed significant improvement in both SDAI and DAS28-ESR, with continual improvements in both scales over 24 weeks. The SDAI has a high sensitivity for joint damage and involves stringent criteria, and it has been used in many recent publications and in routine clinical practice. However, in this study, the proportion of patients in remission or with low disease activity was higher with the SDAI than with the DAS28-ESR. This may contribute to the inhibitory effects of abatacept on joint damage. Of note, among SDAI components, the greatest improvements were observed for the number of tender joints and the number of swollen joints. This suggests that the inhibitory effects of abatacept on joint damage are predominantly due to the faster improvement in subjective symptoms than of changes in laboratory findings. Significant improvements in functional assessment were also observed at week 24. Baseline severity of functional impairment and baseline mTSS were prognostic factors for functional improvement at week 24. These results indicate that patients with advanced joint damage at the start of abatacept treatment already have damagerelated physical disability (assessed by HAQ-DI) [19] and are less likely to achieve significant improvements in functional impairment. Although this outcome is common to all biologics and antirheumatic drugs, earlier initiation of appropriate therapy may facilitate functional remission in the future. Overall, 80 % of patients were still being treated with abatacept at week 24. This rate is similar to that reported for other biologics over 24 weeks of treatment with infliximab (n = 542/617, 88 %), etanercept (n = 299/349, 86 %), adalimumab (n = 194/229, 85 %), and tocilizumab (n = 178/207, 86 %) in routine clinical practice in our department. The retention rate is associated with drug efficacy and development of adverse events. In particular, the use of biologics greatly increases the risk of infections. However, no patient in this study discontinued treatment because of an infection. This result is consistent with those of previous studies in which the incidence of infection was lower in patients treated with abatacept compared with patients treated with other biologics [20, 21]. Several clinical trials have demonstrated that abatacept improves radiographic outcomes [7, 22, 23]. In the Abatacept in Patients with an Inadequate Response to
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Fig. 6 a, b Changes in DmTSS from baseline to week 24 (a) and cumulative probability of a change in DmTSS (b) in patients stratified by baseline CRP (\1.5 vs. C1.5 mg/dl). c Change in HAQ-DI in patients stratified by baseline mTSS (\40.5 vs. C40.5). Values in a and c are for individual patients, whereas thick lines and error bars represent means and standard deviations, respectively. Data were analyzed using the last observation carried forward (LOCF) method. DmTSS progression of modified total Sharp score, CRP C-reactive protein, HAQ-DI Health Assessment Questionnaire Disability Index
Methotrexate (AIM) study, inadequate responders to MTX received abatacept, and joint damage was inhibited in 46 % of patients 1 year later [22]. In the Abatacept Study to Gauge Remission and Joint Damage Progression in MTXnaı¨ve Patients with Early Erosive RA (AGREE) study, MTX-naı¨ve patients received either abatacept plus MTX or placebo plus MTX, and radiographic progression was inhibited in 61.2 % of patients in the former group versus 52.9 % in the latter group [23]. These clinical trials differ from our study in terms of patient characteristics and the scoring system used to evaluate joint damage (i.e., the Genant-modified Sharp scoring system). Whereas differences between the studies make it difficult to compare results of these earlier trials with those of our study, it is
notable that 76 % of patients in our study achieved structural remission in routine clinical practice, as opposed to the clinical trial setting in which patients with homogenous characteristics (e.g., age and disease activity) were enrolled. In our study, 74 % of patients received MTX in combination with abatacept. In the AGREE study, joint damage was inhibited in 52.9 % of patients treated with placebo plus MTX. However, MTX was not identified as a contributor to DmTSS in our study. Furthermore, joint damage progressed in just 1/13 patients on abatacept monotherapy. Of course, it is premature to evaluate the inhibitory effect of abatacept against joint damage with or without concomitant MTX, as scant data are available for patients
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Table 4 Independent predictors for HAQ-DI at week 24 in multivariate analysis Variables Age
Standardized partial regression coefficient
P value
0.096
0.28
-0.024
0.80
Disease duration Prior use of biologics
0.104 0.078
0.46 0.46
MTX use
0.002
0.99
Oral steroid use
0.121
0.20
RF titer (at baseline)
-0.077
0.42
Anti-CCP antibody titer (at baseline)
-0.119
0.22
0.013
0.89
CRP (at baseline)
-0.012
0.90
SDAI (at baseline)
-0.046
0.65
Sex (female)
MMP-3 (at baseline)
HAQ-DI (at baseline)
0.667
\0.001
mTSS (at baseline)
0.214
0.04
MTX methotrexate, RF rheumatoid factor, CCP cyclic citrullinated peptide, MMP-3 matrix metalloproteinase 3, CRP C-reactive protein, SDAI Simplified Disease Activity Index, HAQ-DI Health Assessment Questionnaire Disability Index, mTSS modified total Sharp score
treated without MTX. Nevertheless, MTX is accepted as the gold standard drug for treating RA, and its use should be strongly recommended in patients not contraindicated to MTX. Some limitations of this study warrant mention. First, results were obtained from a retrospective analysis of a small number of patients treated with abatacept for 24 weeks at a single center. Second, we did not include a control group of patients treated with other types of drugs. In conclusion, this study demonstrates that abatacept elicited functional improvement and inhibited progression of joint damage, with a good safety profile, in patients with RA treated within routine clinical practice. Subanalyses revealed that CRP at baseline was a prognostic factor for joint damage. Additionally, the incidence of infection during treatment with abatacept was low. Taken together, results of this study indicate that abatacept, which targets T cells rather than blocking proinflammatory cytokine signaling, enables personalized treatment according to the patient’s specific disease state. Individualized treatment is particularly important because of the heterogeneous features of RA. Acknowledgments The authors thank all medical staff in all institutions for providing the data. This work was supported in part by a Grant-In-Aid for Scientific Research from the Ministry of Health, Labour and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the University of Occupational and Environmental Health, Japan, through UOEH Grant for Advanced Research.
Conflicts of interest Y. Tanaka has received consulting fees, speaking fees, and/or honoraria from Mitsubishi-Tanabe Pharma Corporation, Abbott Japan Co., Ltd., Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Santen Pharmaceutical Co., Ltd., Pfizer Japan Inc., Astellas Pharma Inc., DaiichiSankyo Co., Ltd., GlaxoSmithKline K.K., Astra-Zeneca, Otsuka Pharmaceutical Co., Ltd., Actelion Pharmaceuticals Japan Ltd., Eli Lilly Japan K.K., Nippon Kayaku Co., Ltd., UCB Japan Co., Ltd., Quintiles Transnational Japan Co. Ltd., Ono Pharmaceutical Co., Ltd., and Novartis Pharma K.K. and has received research grants from Bristol-Myers Squibb, MSD K.K., Chugai Pharmaceutical Co., Ltd., Mitsubishi-Tanabe Pharma Corporation, Astellas Pharma Inc., Abbott Japan Co., Ltd., Eisai Co., Ltd. and Janssen Pharmaceutical K.K. K. Yamaoka has received consulting fees from Pfizer Japan Inc. All other authors have declared no conflicts of interest.
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Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthr Care Res (Hoboken). 2012;64:625–39. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthr Rheum. 1988;31:315–24. Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthr Rheum. 1995;38:44–8. Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthr Rheum. 2011;63: 573–86. Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, et al. American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis. 2011;70: 404–13. Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthr Rheum. 1980;23:137–45.
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18. van der Heijde D. How to read radiographs according to the Sharp/van der Heijde method. J Rheumatol. 2000;27:261–3. 19. Smolen JS, Aletaha D, Grisar JC, Stamm TA, Sharp JT. Estimation of a numerical value for joint damage-related physical disability in rheumatoid arthritis clinical trials. Ann Rheum Dis. 2010;69:1058–64. 20. Simon TA, Askling J, Lacaille D, Franklin J, Wolfe F, Covucci A, et al. Infections requiring hospitalization in the abatacept clinical development program: an epidemiological assessment. Arthr Res Ther. 2010;12:R67. 21. Singh JA, Wells GA, Christensen R, Tanjong Ghogomu E, Maxwell L, Macdonald JK, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011;2:CD008794. 22. Kremer JM, Russell AS, Emery P, Abud-Mendoza C, Szechinski J, Westhovens R, et al. Long-term safety, efficacy and inhibition of radiographic progression with abatacept treatment in patients with rheumatoid arthritis and an inadequate response to methotrexate: 3-year results from the AIM trial. Ann Rheum Dis. 2011;70:1826–30. 23. Westhovens R, Robles M, Ximenes AC, Nayiager S, Wollenhaupt J, Durez P, et al. Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors. Ann Rheum Dis. 2009;68:1870–7.
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ORIGINAL ARTICLE
Abatacept inhibits radiographic progression in patients with rheumatoid arthritis: a retrospective analysis of 6 months of abatacept treatment in routine clinical practice. The ALTAIR study Satoshi Kubo • Kazuyoshi Saito • Shintaro Hirata • Shunsuke Fukuyo Kunihiro Yamaoka • Norifumi Sawamukai • Masao Nawata • Shigeru Iwata • Yasushi Mizuno • Yoshiya Tanaka
•
Received: 5 November 2012 / Accepted: 12 February 2013 Ó Japan College of Rheumatology 2013
Abstract Objectives Our objectives in this study were to determine the inhibitory effects of abatacept on joint damage and its clinical efficacy and safety in patients with rheumatoid arthritis (RA). Methods Fifty Japanese patients with RA were treated with abatacept for 24 weeks in routine clinical practice. Results At week 24, 20 % of patients achieved clinical remission [Simplified Disease Activity Index (SDAI) B3.3], whereas 50 % were in remission or had a low disease activity. Structural remission [progression of modified total Sharp score (DmTSS) B0.5] was achieved in 76 % of patients. The DmTSS decreased significantly from 7.1 ± 7.3 at baseline to 1.8 ± 5.7 at week 24. C-reactive protein (CRP) was the only independent prognostic factor for joint damage progression at week 24, whereas SDAI and matrix metalloproteinase-3 levels were not. A very high proportion of patients with CRP levels \1.5 mg/dl (88 %) achieved structural remission. In terms of safety, the retention rate for all patients was favorable (80 %), and stomatitis was the only adverse event observed. No patient withdrew from the study because of infections. Conclusions Abatacept has favorable clinical and structural effects, inhibits radiographic progression, and has a good safety profile in routine clinical practice.
S. Kubo K. Saito S. Hirata S. Fukuyo K. Yamaoka N. Sawamukai M. Nawata S. Iwata Y. Mizuno Y. Tanaka (&) The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan e-mail: [email protected] Published online: 02 March 2013
Keywords Abatacept Rheumatoid arthritis Modified total Sharp score Radiographic outcome Japanese patients
Introduction Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and is characterized by synovitis that causes joint damage [1]. Conventional RA treatments focus on pain control. However, the introduction of biologics has made it possible to induce remission in many patients and inhibit joint damage, leading to a paradigm shift in RA treatment [2]. Under such circumstances, the treat to target approach was proposed in 2010, and overarching principles and recommendations for treating RA to target were clearly established [3]. Consequently, the goal of RA treatment changed to achieve clinical remission. An emphasis was placed on achieving remission as the primary objective of treatment, whereas secondary objectives include preventing structural damage to joints and improving physical function. Inflammatory cells (e.g., macrophages) and proinflammatory cytokines [e.g., tumor necrosis factor (TNF) and interleukin (IL)-6 produced by synovial fibroblasts] play important roles in RA pathogenesis. RA treatments targeting T cells have also been a focus of research, based on the results of a study showing the infiltration of numerous CD4-positive T cells and expression of major histocompatibility complex (MHC) class II molecules in the synovial membrane [4]. Another study showed a strong correlation between RA and the major histocompatibility antigen, human leukocyte antigen (HLA)-DR4 [5], whereas a more recent study revealed the importance of T-helper cells (Th)17 in RA [6].
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Abatacept is a fusion protein [cytotoxic T lymphocyte antigen (CTLA)4-Ig] composed of the Fc portion of human immunoglobulin G1 (Ig-G1) fused to extracellular-domain2 molecules of human CTLA-4. Abatacept prevents T-cell activation by inhibiting costimulatory signals by competing with CD28 molecules on T cells through specific binding to the costimulatory molecules (CD80/CD86) on antigenpresenting cells (APC). The safety and effectiveness of abatacept have been established in multiple clinical studies [7–11]. The 2012 Recommendations for RA Treatment recommend the use of abatacept as a first-line biologic, along with anti-TNF inhibitors [12]. However, few studies have reported the inhibitory effects of abatacept on joint damage in routine clinical practice. Therefore, this study, the Abatacept Leading Trial for RA on Imaging Remission (ALTAIR), was conducted to investigate the inhibitory effects of abatacept on joint damage and its clinical efficacy and safety.
Patients and methods Patients All patients, except those without radiographs, who started treatment with abatacept between 3 November 2010 and 29 September 2011 at our hospital were registered in the study. All patients had a diagnosis of RA defined using the American College of Rheumatology (ACR) criteria [13]. The study was conducted as a retrospective observation study using anonymized data. Abatacept was used within the health insurance coverage for RA in Japan. The reasons for discontinuation of abatacept treatment were recorded for all patients who discontinued treatment during the study period. This study was registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/) (UMIN00000 8285).
Clinical efficacy Disease activity was assessed using the Disease Activity Score 28 erythrocyte sedimentation rate (DAS28-ESR) [14] and Simplified Disease Activity Index (SDAI) [15, 16] scales. Functional impairment was assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI) [17]. Radiographs of hands and feet were obtained at baseline and week 24 for patients who completed the study or at discontinuation. Joint damage scores were assessed by two independent readers using the van der Heijde modified total Sharp score (mTSS) [18]. The twice-yearly progression (DmTSS) in mTSS was defined as yearly change. Subanalyses of clinical outcomes were assessed in subgroups stratified by DAS28-ESR [14] and SDAI/Clinical Disease Activity Index (CDAI) [15, 16] scores. Statistical analysis Patient characteristics are expressed as mean ± standard deviation (SD), medians [interquartile range (IQR)], or number (%). The last observation carried forward (LOCF) method was used for patients who discontinued before week 24 to include all patients in analyses. Wilcoxon signed rank tests were used to detect statistically significant differences in disease activity and functional impairment between baseline and week 24. Pearson’s v2 test was used to detect statistically significant differences in disease activity between assessment methods. Kaplan–Meier analysis was used to assess the rate of abatacept retention. Stepwise multiple regression analysis was performed to identify prognostic factors. The optimal cutoff value for the subgroup analysis was calculated using receiver operator characteristic (ROC) curve analysis. All reported P values are two sided and were not adjusted for multiple testing. The level of significance was taken as P \ 0.05. All analyses were conducted using SPSS software version 16.0 (SPSS Inc., Chicago, IL, USA).
Abatacept treatment Abatacept was prescribed to patients with RA uncontrolled by normal doses of existing disease-modifying antirheumatic drugs (DMARDs). The dosing regimen was based on patient weight (500 mg for \60 kg, 750 mg for 60–100 kg, and 1,000 mg for [100 kg). Abatacept was dissolved in 100 ml of normal saline, and the solution was administered as an intravenous infusion over a 30-min period at weeks 0, 2, and 4, and then every 4 weeks thereafter. Written informed consent for data collection was obtained from all patients according to the Declaration of Helsinki. Because this was a retrospective observational study, approval from an ethics review board was not deemed necessary.
Results Patient characteristics Fifty patients who started treatment with abatacept between November 2010 and September 2011 were enrolled in the study. Their characteristics are shown in Table 1. Mean age was 62.0 years, and most patients were women (84.0 %). Mean duration of illness was 10.0 years, and mean disease activity at baseline was 31.1 and 5.8 for SDAI and DAS28-ESR, respectively, indicating high disease activity. Mean HAQ-DI was 1.5, and mean mTSS was 60.1 (median 40.5; IQR 7.3–88.4). Mean DmTSS before
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Table 1 Patient characteristics at baseline Variables
Total (n = 50)
Age (years)
62.0 ± 14.2
Females [n (%)]
42 (84.0)
Disease duration (years)
10.0 ± 9.2
Stage (I/II/III/IV %)
(10.0/38.0/38.0/ 14.0)
Class (I/II/III/IV %)
(0.0/78.0/22.0/0.0)
Prior use of biologics [n (%)]
29 (58.0)
RF positive [n (%)] MTX use [n (%)]
40 (80.0) 37 (74.0)
MTX dose (mg/week)
9.6 ± 3.4
Fig. 1 Kaplan–Meier analysis of abatacept treatment retention
Oral steroid use [n (%)]
17 (34.0)
Oral steroid use (mg/daya)
3.1 ± 1.7
MMP-3 (ng/ml)
215.5 ± 166.0
Table 2 Reasons for discontinuation
SJC, 0–28
8.0 ± 4.6
Variables
All (n = 50)
TJC, 0–28
9.5 ± 6.0
ESR (mm/h)
53.1 ± 30.9
All discontinuations
10 (20 %)
CRP (mg/dl)
2.1 ± 2.1
PGA, VAS 0–100 mm
60.7 ± 23.4
SDAI
31.1 ± 12.3
CDAI
29.1 ± 11.7
DAS28-ESR
5.8 ± 1.2
HAQ-DI
1.5 ± 0.7
mTSS Median (IQR)
60.1 ± 67.8 40.5 (7.3–88.4)
Estimated yearly progression of mTSS (DmTSS)
7.1 ± 7.3
Median (IQR)
4.5 (2.2–8.4)
Values are mean ± standard deviation (SD) unless otherwise indicated RF rheumatoid factor, MTX methotrexate, MMP-3 matrix metalloproteinase 3, SJC swollen joint count, TJC tender joint count, ESR erythrocyte sedimentation rate, CRP C-reactive protein, PGA patient global assessment of disease activity, VAS visual analog scale, SDAI Simplified Disease Activity Index, CDAI Clinical Disease Activity Index, DAS Disease Activity Score, HAQ-DI Health Assessment Questionnaire Disability Index, mTSS modified total Sharp score, IQR interquartile range a
Prednisolone equivalent
the start of treatment was 7.1 (median 4.5; IQR 2.2–8.4). Of the 50 patients, 21 (42.0 %) were naı¨ve to biologics, and 29 (58.0 %) were previously treated with biologics. Concomitant medications included methotrexate (MTX) in 37 patients (74.0 %) and orally administered steroids in 17 (34.0 %) at mean doses of 9.6 mg/week and 3.1 mg/day (prednisolone equivalent), respectively. Other laboratory findings included rheumatoid factor (RF) positivity in 40 patients (80.0 %), with mean matrix metalloproteinase (MMP)-3, ESR, and C-reactive protein (CRP) levels of 215.5 ng/ml, 53.1 mm/h, and 2.1 mg/dl, respectively.
Lack of efficacy
9 (18 %)
Adverse events
1 (2 %)
Other reasons
0
Retention rate The retention rate is shown in Fig. 1. At week 24, 80 % of patients were still receiving abatacept treatment. The most common reason for discontinuation was inadequate effect (18 %) (Table 2); one patient (2 %) discontinued treatment because of an adverse event (frequent stomatitis) during abatacept treatment. No patient withdrew because of infection, such as bacterial pneumonia. Clinical efficacy The time course of SDAI recorded over 24 weeks is shown in Fig. 2a. Abatacept induced a significant improvement in SDAI from 31.1 ± 12.3 at baseline to 14.5 ± 13.9 at week 24. As shown, SDAI continued to improve over the 24 weeks of treatment. Changes in disease activity in patients stratified by SDAI (remission, SDAI B3.3; low, SDAI [3.3 to B11.0; moderate, SDAI [11.0 to B26.0; high, SDAI [ 26.0) are shown in Fig. 2b. At week 24, 20 % of patients achieved clinical remission. Overall, 50 % of patients achieved either remission or a low disease activity at the end of the study. Similar significant improvements in disease activity were also detected using the DAS28-ESR (Fig. 2c). The proportions of patients with remission or a low disease activity state were 16 % and 24 %, respectively, measured by the DAS28-ESR, and 20 % and 50 %, respectively, measured by the SDAI. Thus, these rates were higher when determined using the SDAI than with the DAS28-ESR
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Fig. 2 Effects of treatment with abatacept for 24 weeks on clinical outcomes. a Time course of SDAI. b Disease activity stratified according to SDAI. c Time course of DAS28-ESR. Values in a and c are for individual patients, whereas thick lines and error bar
represent means and standard deviations, respectively. SDAI Simplified Disease Activity Index, DAS28-ESR Disease Activity Score 28-Erythrocyte Sedimentation Rate
(Fig. 3a). In particular, the proportion of patients with a low disease activity state was significantly higher using SDAI than using DAS28-ESR. Changes in individual SDAI components are shown in Fig. 3b. The number of swollen joints (8.0 ± 4.6 to 3.0 ± 4.5), number of tender joints (9.5 ± 6.0 to 3.9 ± 6.2), patient global assessment of disease activity (6.1 ± 2.4 to 4.2 ± 2.8), evaluator global assessment of disease activity (5.5 ± 2.2 to 3.0 ± 2.5), and CRP (2.1 ± 2.1 to 0.9 ± 1.6 mg/dl) decreased significantly from baseline to week 24. The magnitude of change was greater for number of tender joints (5.6) and number of swollen joints (5.0) than the other three components. ESR (from 53.1 ± 30.9 to 43.0 ± 30.0 mm/h), MMP-3 (from 215.5 ± 166.0 to 152.1 ± 328.3 ng/ml), and RF (from 177.2 ± 355.5 to 121.0 ± 219.4 IU/ml) also improved significantly from baseline to week 24.
HAQ-DI Mean HAQ-DI improved moderately but significantly from 1.5 ± 0.7 to 1.3 ± 0.8 (Fig. 4a). Overall, 22 % of patients achieved functional remission at week 24, defined as HAQ-DI B 0.5 (Fig. 4b). Radiographic outcomes Mean DmTSS improved significantly from 7.1 ± 7.3 at baseline to 1.8 ± 5.7 at week 24 (Fig. 5a). This result indicates that abatacept inhibits joint damage. When mTSS was assessed separately as the erosion score (ES) and jointspace-narrowing score (JSN), significant improvements in the yearly progression rate were observed for both ES (from 3.8 ± 3.9 to 1.1 ± 3.7) and JSN (from 3.3 ± 3.7 to 0.7 ± 3.5) (Fig. 5b). Figure 5c shows a cumulative
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Fig. 3 a Proportions of patients who achieved remission or low disease activity defined according to SDAI, CDAI, and DAS28-ESR. b Values for individual components of the SDAI at baseline and at week 24. Values in b are means. Data were analyzed using the last observation carried forward (LOCF) method. SDAI Simplified Disease Activity Index, DAS28-ESR Disease Activity Score 28-Erythrocyte Sedimentation Rate, SJC swollen joint count, TJC tender joint count, PGA patient global assessment of disease activity, EGA evaluator global assessment of disease activity, CRP C-reactive protein
Fig. 4 Effects of treatment with abatacept for 24 weeks on: a time course of HAQ-DI, and b proportion of patients with HAQ-DI B 0.5. Values in a are for individual patients, whereas thick lines and error bar represent means and standard deviations, respectively. Data were analyzed using the last observation carried forward (LOCF) method. HAQ-DI Health Assessment Questionnaire Disability Index
scatterplot of DmTSS. At week 24, structural remission (defined as a change in DmTSS B 0.5) was achieved in 76.0 % of patients. However, rapid radiologic progression (DmTSS [ 5) was observed in six patients. We next performed subanalyses to identify factors associated with disease progression. Examination of prognostic factors at baseline contributing to DmTSS at week 24 revealed that CRP was an independent prognostic factor, whereas SDAI, MMP-3, and mTSS were not (Table 3).
Several other factors, including use of biologics or MTX, RF titer, and anticyclic citrullinated peptide (anti-CCP) antibody titer did not contribute to DmTSS. Based on these results, we determined the optimal cutoff value for baseline CRP using receiver operating characteristic (ROC) curve analysis. This analysis yielded a cutoff value of 1.5 mg/dl with a sensitivity and specificity of 75 % and 58 %, respectively, for DmTSS B 0.5 at week 24. Therefore, we performed subgroup analysis by stratifying patients
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Fig. 5 Abatacept inhibits radiographic progression: a Yearly progression in mTSS. b Yearly progression in ES and JSN. c Cumulative probability for a change in mTSS from baseline. Values in a and b are for individual patients, whereas thick lines and error bar represent means and standard deviations, respectively. Data were analyzed using the last observation carried forward (LOCF) method. mTSS modified total Sharp score, ES erosion score, JSN joint-space narrowing
according to CRP levels of 1.5 mg/dl. Abatacept inhibited progression of joint damage in both groups, with greater inhibitory effects in patients with baseline CRP \ 1.5 mg/ dl (Fig. 6a, b). A cumulative scatterplot of these data showed that structural remission was achieved in 64.0 % of patients with CRP C 1.5 mg/dl and in 88.0 % of patients with CRP \ 1.5 mg/dl (Fig. 6c). The cumulative scatterplot also revealed that the progression of joint damage was mild, even in patients with CRP \ 1.5 mg/dl and advanced joint damage.
We next determined the prognostic factors contributing to HAQ-DI at week 24. In this analysis, baseline HAQ-DI and baseline mTSS were identified as independent prognostic factors (Table 4), whereas the use of biologics or MTX, RF titer, and anti-CCP antibody titer, among others, did not. ROC curve analysis yielded an optimal cutoff mTSS value of 40.5. Therefore, we performed a subanalysis by stratifying patients according to mTSS of 40.5 (Fig. 6d, e). HAQ-DI improved significantly in patients with baseline mTSS \ 40.5 but not in patients with baseline mTSS C 40.5.
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Table 3 Independent predictors for progression of modified total Sharp score (DmTSS) at week 24 in multivariate analysis Variables
Standardized partial regression coefficient
P value
Age
–0.108
0.44
Sex (female)
–0.137
0.31
Disease duration Prior use of biologics
–0.009 0.009
0.95 0.95
MTX use
0.179
0.20
Oral steroid use
0.037
0.79
-0.100
0.47
0.064
0.64
RF titer (at baseline) Anti-CCP antibody titer (at baseline) MMP-3 (at baseline)
-0.14
0.41
CRP (at baseline)
0.372
0.01
SDAI (at baseline)
0.073
0.62
HAQ-DI (at baseline)
0.162
0.24
mTSS (at baseline)
0.223
0.99
MTX methotrexate, RF rheumatoid factor, CCP cyclic citrullinated peptide, MMP-3 matrix metalloproteinase 3, CRP C-reactive protein, SDAI Simplified Disease Activity Index, HAQ-DI Health Assessment Questionnaire Disability Index
Discussion The ALTAIR study was conducted to retrospectively examine the clinical efficacy and safety of abatacept in 50 patients with RA. Structural remission, corresponding to inhibition of joint damage progression, was achieved in approximately 75 % of patients treated with abatacept for 24 weeks. However, rapid radiologic progression (DmTSS [ 5) was observed in six patients (12 %). Therefore, we determined the prognostic factors for change in DmTSS at week 24 by multiple regression analysis. In this analysis, the only independent prognostic factor was CRP. Unexpectedly, SDAI and MMP-3 were not independently associated with the change in DmTSS at week 24. Notably, baseline disease activity and MMP-3, a marker for cartilage damage and the severity of joint damage, were not associated with joint damage in this study, whereas inflammatory activity at baseline was predictive of the progression of joint damage after 24 weeks of abatacept treatment. These results may be attributable to the biologic properties of abatacept, which do not directly block proinflammatory cytokine signaling, as observed with TNF and IL-6 receptor inhibitors, but instead inhibit T-cell activity. The stratified analysis according to the CRP cutoff value of 1.5 mg/dl, which was determined by ROC curve analysis, revealed that a very high proportion of patients with CRP \ 1.5 mg/dl (88 %) achieved structural remission and that patients with advanced joint damage experienced mild
progression. These results suggest that the production of proinflammatory cytokines by APCs is enhanced in patients with severe inflammatory activity, indicating that APCs play a major role in disease activity in these patients. By contrast, in patients with high disease activity but low inflammatory activity, lymphocytes rather than APCs may play a major role in disease activity, making these patients suitable targets for abatacept. In terms of clinical efficacy, we observed significant improvement in both SDAI and DAS28-ESR, with continual improvements in both scales over 24 weeks. The SDAI has a high sensitivity for joint damage and involves stringent criteria, and it has been used in many recent publications and in routine clinical practice. However, in this study, the proportion of patients in remission or with low disease activity was higher with the SDAI than with the DAS28-ESR. This may contribute to the inhibitory effects of abatacept on joint damage. Of note, among SDAI components, the greatest improvements were observed for the number of tender joints and the number of swollen joints. This suggests that the inhibitory effects of abatacept on joint damage are predominantly due to the faster improvement in subjective symptoms than of changes in laboratory findings. Significant improvements in functional assessment were also observed at week 24. Baseline severity of functional impairment and baseline mTSS were prognostic factors for functional improvement at week 24. These results indicate that patients with advanced joint damage at the start of abatacept treatment already have damagerelated physical disability (assessed by HAQ-DI) [19] and are less likely to achieve significant improvements in functional impairment. Although this outcome is common to all biologics and antirheumatic drugs, earlier initiation of appropriate therapy may facilitate functional remission in the future. Overall, 80 % of patients were still being treated with abatacept at week 24. This rate is similar to that reported for other biologics over 24 weeks of treatment with infliximab (n = 542/617, 88 %), etanercept (n = 299/349, 86 %), adalimumab (n = 194/229, 85 %), and tocilizumab (n = 178/207, 86 %) in routine clinical practice in our department. The retention rate is associated with drug efficacy and development of adverse events. In particular, the use of biologics greatly increases the risk of infections. However, no patient in this study discontinued treatment because of an infection. This result is consistent with those of previous studies in which the incidence of infection was lower in patients treated with abatacept compared with patients treated with other biologics [20, 21]. Several clinical trials have demonstrated that abatacept improves radiographic outcomes [7, 22, 23]. In the Abatacept in Patients with an Inadequate Response to
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Fig. 6 a, b Changes in DmTSS from baseline to week 24 (a) and cumulative probability of a change in DmTSS (b) in patients stratified by baseline CRP (\1.5 vs. C1.5 mg/dl). c Change in HAQ-DI in patients stratified by baseline mTSS (\40.5 vs. C40.5). Values in a and c are for individual patients, whereas thick lines and error bars represent means and standard deviations, respectively. Data were analyzed using the last observation carried forward (LOCF) method. DmTSS progression of modified total Sharp score, CRP C-reactive protein, HAQ-DI Health Assessment Questionnaire Disability Index
Methotrexate (AIM) study, inadequate responders to MTX received abatacept, and joint damage was inhibited in 46 % of patients 1 year later [22]. In the Abatacept Study to Gauge Remission and Joint Damage Progression in MTXnaı¨ve Patients with Early Erosive RA (AGREE) study, MTX-naı¨ve patients received either abatacept plus MTX or placebo plus MTX, and radiographic progression was inhibited in 61.2 % of patients in the former group versus 52.9 % in the latter group [23]. These clinical trials differ from our study in terms of patient characteristics and the scoring system used to evaluate joint damage (i.e., the Genant-modified Sharp scoring system). Whereas differences between the studies make it difficult to compare results of these earlier trials with those of our study, it is
notable that 76 % of patients in our study achieved structural remission in routine clinical practice, as opposed to the clinical trial setting in which patients with homogenous characteristics (e.g., age and disease activity) were enrolled. In our study, 74 % of patients received MTX in combination with abatacept. In the AGREE study, joint damage was inhibited in 52.9 % of patients treated with placebo plus MTX. However, MTX was not identified as a contributor to DmTSS in our study. Furthermore, joint damage progressed in just 1/13 patients on abatacept monotherapy. Of course, it is premature to evaluate the inhibitory effect of abatacept against joint damage with or without concomitant MTX, as scant data are available for patients
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Table 4 Independent predictors for HAQ-DI at week 24 in multivariate analysis Variables Age
Standardized partial regression coefficient
P value
0.096
0.28
-0.024
0.80
Disease duration Prior use of biologics
0.104 0.078
0.46 0.46
MTX use
0.002
0.99
Oral steroid use
0.121
0.20
RF titer (at baseline)
-0.077
0.42
Anti-CCP antibody titer (at baseline)
-0.119
0.22
0.013
0.89
CRP (at baseline)
-0.012
0.90
SDAI (at baseline)
-0.046
0.65
Sex (female)
MMP-3 (at baseline)
HAQ-DI (at baseline)
0.667
\0.001
mTSS (at baseline)
0.214
0.04
MTX methotrexate, RF rheumatoid factor, CCP cyclic citrullinated peptide, MMP-3 matrix metalloproteinase 3, CRP C-reactive protein, SDAI Simplified Disease Activity Index, HAQ-DI Health Assessment Questionnaire Disability Index, mTSS modified total Sharp score
treated without MTX. Nevertheless, MTX is accepted as the gold standard drug for treating RA, and its use should be strongly recommended in patients not contraindicated to MTX. Some limitations of this study warrant mention. First, results were obtained from a retrospective analysis of a small number of patients treated with abatacept for 24 weeks at a single center. Second, we did not include a control group of patients treated with other types of drugs. In conclusion, this study demonstrates that abatacept elicited functional improvement and inhibited progression of joint damage, with a good safety profile, in patients with RA treated within routine clinical practice. Subanalyses revealed that CRP at baseline was a prognostic factor for joint damage. Additionally, the incidence of infection during treatment with abatacept was low. Taken together, results of this study indicate that abatacept, which targets T cells rather than blocking proinflammatory cytokine signaling, enables personalized treatment according to the patient’s specific disease state. Individualized treatment is particularly important because of the heterogeneous features of RA. Acknowledgments The authors thank all medical staff in all institutions for providing the data. This work was supported in part by a Grant-In-Aid for Scientific Research from the Ministry of Health, Labour and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the University of Occupational and Environmental Health, Japan, through UOEH Grant for Advanced Research.
Conflicts of interest Y. Tanaka has received consulting fees, speaking fees, and/or honoraria from Mitsubishi-Tanabe Pharma Corporation, Abbott Japan Co., Ltd., Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Santen Pharmaceutical Co., Ltd., Pfizer Japan Inc., Astellas Pharma Inc., DaiichiSankyo Co., Ltd., GlaxoSmithKline K.K., Astra-Zeneca, Otsuka Pharmaceutical Co., Ltd., Actelion Pharmaceuticals Japan Ltd., Eli Lilly Japan K.K., Nippon Kayaku Co., Ltd., UCB Japan Co., Ltd., Quintiles Transnational Japan Co. Ltd., Ono Pharmaceutical Co., Ltd., and Novartis Pharma K.K. and has received research grants from Bristol-Myers Squibb, MSD K.K., Chugai Pharmaceutical Co., Ltd., Mitsubishi-Tanabe Pharma Corporation, Astellas Pharma Inc., Abbott Japan Co., Ltd., Eisai Co., Ltd. and Janssen Pharmaceutical K.K. K. Yamaoka has received consulting fees from Pfizer Japan Inc. All other authors have declared no conflicts of interest.
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