Evaluation of changes in magnetic resonance images following 24 and 52 weeks of treatment of rheumatoid arthritis with infliximab, tocilizumab, or abatacept.

Objectives. To compare MRI findings in rheumatoid arthritis (RA) patients treated with biologic disease-modifying anti-rheumatic drugs (DMARDs). Methods. The study subjects were 43 RA patients treated with biologic DMARDs (13 with infliximab, 15 with tocilizumab, and 15 with abatacept). They were evaluated using Simplified Disease Activity Index (SDAI) and low-field extremity MRI at baseline, and at 24 weeks and 52 weeks of treatment. Results. Synovitis scores were significantly lower by 24 weeks in all groups, compared with baseline (P < 0.05). Significant improvement in bone marrow edema (BME) scores were noted from baseline to 24 weeks in infliximab and abatacept groups (P < 0.05), but from 24 weeks to 52 weeks in tocilizumab group (P < 0.01). No significant change was found in erosion score. The synovitis score at baseline correlated significantly with SDAI at 24 weeks (P < 0.05), and the score at 24 weeks correlated significantly with SDAI at 52 weeks (P < 0.05). Conclusions. The results suggest that the inflammatory improvement by infliximab and abatacept may express earlier than those by tocilizumab, despite similar improvement in SDAI. MRI-detected synovitis could be a useful predictor of SDAI at 24 weeks of treatment. The MRI remains the best tool to detect and assess the effects of biologic DMARDs in RA.

cells, and improves the clinical symptoms of autoimmune diseases such as RA, juvenile idiopathic arthritis, and Castleman disease [11,12]. Abatacept (ABT) is a recombinant fusion protein comprising the extracellular domain of human . ABT binds to CD80 and CD86 on T cells, thereby inhibiting the binding of these molecules to CD28 and preventing T-cell activation [14]. Durez et al. [15] reported that treatment with the combination of IFX and methotrexate was superior to methotrexate alone for reducing magnetic resonance imaging (MRI)-detected synovitis and bone marrow edema (BME) in RA patients by 18 weeks. The ACT-RAY clinical trial of RA patients compared the effi cacy and safety of TCZ monotherapy with the TCZ -methotrexate dual therapy [16]. In the ACT-RAY MRI substudy, Conaghan et al. [17] reported signifi cant improvement in MRIdetected synovitis after 2 weeks of treatment. The ASSET clinical trial evaluated the eff ects of ABT on various MRI fi ndings, such as synovitis, BME, and bone erosion [18]. The present retrospective study compared the MRI fi ndings in RA patients treated with the biologic DMARDs; IFX, TCZ, and ABT during 52 weeks.

Introduction
Rheumatoid arthritis (RA) is a chronic systemic and progressive autoimmune disease [1]. Patients with RA develop signifi cant deformity, dysfunction, and destruction of the aff ected joints and, if left untreated, are at increased risk of morbidity and mortality [2]. Persistent infl ammation or synovitis leads to pannus formation and, ultimately, to bone destruction [3].
The management of RA rests primarily on the use of disease-modifying anti-rheumatic drugs (DMARDs). Since the end of the last decade of the 20th century, biologic DMARDs therapy raised the standards of medical treatment by preventing the progression of joint destruction [4,5] and by providing symptom relief and improving employment opportunities [6,7]. Infl iximab (IFX) is a chimeric antibody that binds with high affi nity to human tumor necrosis factor alpha (TNF α ) [8]. The ASPIRE clinical trial reported little radiographic progression in patients treated with IFX and methotrexate combination therapy compared with those treated with methotrexate alone [9]. Tocilizumab (TCZ) is a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor [10]. Treatment with TCZ blocks IL-6 signaling within infl ammatory and immune Mod Rheumatol, 2016;26(1): 29-35 Simplifi ed Disease Activity Index (SDAI). Therapeutic response was measured in accordance with the European League against Rheumatism (EULAR) response criteria, and clinical remission was defi ned as SDAI score Ͻ 3.3. All patients of this study were diagnosed with RA based on the American College of Rheumatology (ACR) criteria [19], had received monotherapy with IFX, TCZ, or ABT.

Treatment with biologic DMARDs
IFX was prescribed at a dose of 3 mg/kg body weight (KBW) in 12 patients and 5 mg/KBW in 1 patient. It was administered at 0, 2, and 6 weeks, and every 8 weeks thereafter till week 52. TCZ was administered at a dose of 8 mg/KBW, every 4 weeks in all patients. ABT was dosed according to body weight (500 mg for Ͻ 60 kg, 750 mg for 60 -100 kg, and 1000 mg for Ͼ 100 kg). It was administered by intravenous infusion at 0, 2, and 4 weeks, and every 4 weeks thereafter till week 52.

Image analysis
Synovitis, BME, and bone erosion were evaluated using the compact MRI score (cMRIS) [20]. cMRIS was developed because the OMERACT-RAMRIS scoring system [21] is not available for PIP joints, which can be detected by CompacTscan imaging. Moreover, cMRIS is an easier system to use than RAMRIS for evaluating bone erosion. Images were scored by two independent readers.

Statistical analysis
Data related to patient characteristics were expressed as mean Ϯ standard deviation or percentage values. The Wilcoxon signed-rank test was used to compare the diff erence in RA activity and MRI scores from baseline to 24 weeks, and to 52 weeks. Dunnett ' s multiple comparison test was used for comparison of ⊿ SDAI (change from baseline to 24 weeks, and to 52 weeks) and ⊿ MRI fi nding scores among the three treatment groups. The Spearman ' s rank correlation coeffi cient was performed to estimate the correlation between SDAI and MRI fi nding scores. Probability values less than 0.05 were considered signifi cant. All analyses were conducted using IBM SPSS Statistics software, version 22.0 (IBM SPSS, Chicago, IL, USA).

Patient characteristics
In this study, 13 patients were treated with IFX, 15 with TCZ, and another 15 patients with ABT. The baseline demographic and clinical data of these patients were similar (Table 1). There were no statistically signifi cant diff erences of SDAI score and CRP at baseline among the three groups. None of the patients treated with IFX had been previously treated with another anti-TNF biologic. Six patients of TCZ group had been previously treated with anti-TNF biologics. Four patients of ABT group had been previously treated with anti-TNF or anti-IL-6R biologics.

Discussion
In the 2013 EULAR recommendations for the management of RA, biologic DMARDs, including IFX, TCZ, and ABT, were equally recommended as fi rst-line therapy for those patients with poor response to methotrexate and/or other conventional synthetic DMARD strategies [22]. Furthermore, Durez et al. [15] reported that the combination of IFX and methotrexate was superior to methotrexate alone in reducing MRI-detected synovitis and BME by 18 weeks [15]. The ACT-RAY MRI substudy reported early improvement of synovitis of RA patients after initiation of treatment with TCZ [17]. The ASSET trial evaluated the clinical effi cacy and safety of ABT as well as the eff ect of treatment on MRI fi ndings [18]. To our knowledge, the present study is the fi rst to compare MRI fi ndings in RA patients treated with these three biologics.
In the present study, it was interesting that both BME score and synovitis score improved signifi cantly at the early phase (0 -24 weeks) of treatment with IFX and ABT; on the other hand, only synovitis score improved signifi cantly at the early was noted among all groups despite the diff erence in ⊿ BME ( Figure 2C).

Associations between clinical and MRI assessment
There were no signifi cant correlations between ⊿ SDAI and ⊿ total cMRI score (the sum of ⊿ synovitis, ⊿ BME, and ⊿ erosion scores) in all three groups ( Figure 4A). Similarly, no significant correlation was found between ⊿ SDAI and components of the ⊿ total cMRI score (i.e., ⊿ synovitis, ⊿ BME, and ⊿ erosion score; Supplementary Figure 1 to be found online at http://informahealthcare.com/doi/abs/ 10.3109/14397595.2015.1069471). However, the synovitis score at baseline correlated signifi cantly with SDAI at 24 weeks (IFX: R ϭ 0.58, P ϭ 0.04; TCZ: R ϭ 0.60, P ϭ 0.02; ABT: R ϭ 0.57, P ϭ 0.04; Figure 4B). A similar tendency was found between synovitis scores at 24 weeks and SDAI at 52 weeks (IFX: R ϭ 0.58, P ϭ 0.03; TCZ: R ϭ 0.63, P ϭ 0.01; ABT: R ϭ 0.62, P ϭ 0.01; Figure 4C). However, there were no signifi cant correlations between the BME or erosion scores and SDAI.   Figure 2. Changes in (A) synovitis, (B) BME, and (C) erosion scores from baseline to 24 weeks and 52 weeks. Synovitis scores were signifi cantly lower at 24 weeks relative to baseline in all groups. Signifi cant improvement in BME scores was noted from baseline to 24 weeks in the infl iximab and abatacept groups, and from 24 weeks to 52 weeks in the tocilizumab group. No signifi cant changes were found in the erosion scores. * BME bone marrow edema.
phase and BME score improved at the late phase (24 -52 week) with TCZ. We speculated that the reason may depend on the diff erence of sensitivity between sensitivity of MRI-detected synovitis and BME. In this study, the sensitivity of synovitis might be inferior to that of BME all the more because the MR images were obtained without contrast. Actually, Freeston et al. reported that low-fi eld MRI without contrast was less sensitive at detecting synovitis than ultrasound [23]. Although MRI-detected synovitis might not detect the slight diff erence in infl ammatory improvement.
In addition, the BME scores improved signifi cantly at the early phase (0 -24 weeks) of treatment with IFX and ABT, but at the late phase (24 -52 week) with TCZ. A similar pattern was observed in ⊿ BME scores. Although the reason for the diff erence in the improvement phase among the above three biologics is unknown, we speculate the following two possibilities. One is the diff erence in administration schedule of each biological DMARD. In IFX and ABT, the fi rst interval of loading administration was shortened. In contrast, TCZ was administrated every 1 month without shortening the initial interval. Although not refl ected in SDAI, this shortening could result in faster improvement of MRI fi ndings, especially BME, in RA patients treated with IFX and ABT. Another reason could be related to diff erences in inhibition of the infl ammatory cytokine cascade by the diff erent biologic DMARDs. In other words, IFX and ABT inhibit the upstream of the cascade of infl ammatory cytokine compared with TCZ [24]. IFX inhibits TNF-α , which is located upstream of the cascade, compared with IL-6 [24]. ABT inhibits activation of naive T cells, which activate macrophages and synovial fi broblasts to produce TNF-α [13]. Further analysis of the relationship between changes in serum cytokines and MRI changes is necessary.
In RA patients treated with biologic DMARDs, there were no signifi cant correlations between ⊿ SDAI and ⊿ total cMRI score. Similarly, no signifi cant correlation was found between ⊿ SDAI and each component of ⊿ total cMRI score (i.e., ⊿ synovitis, ⊿ BME, and ⊿ erosion score). On the other hand, synovitis score at baseline correlated signifi cantly with SDAI at 24 weeks. A similar correlation was found between synovitis score at 24 weeks and SDAI at 52 weeks. These results suggest that MRI-detected synovitis may predict SDAI after 24 weeks.
In the 2013 EULAR recommendations for the use of imaging in the clinical management of RA, it was suggested that MRI or ultrasound are superior to clinical examination in the detection of joint infl ammation [25]. Actually, some patients still showed residual synovitis or BME despite achieving clinical remission in this study. The CIMESTRA study explained that baseline BME score was an independent predictor of radiographic progression [26]. Therefore, MRI can be useful in identifying the true activity of RA.
Several limitations must also be considered in the interpretation of these data presented in this study. In the present study, we included only RA patients who could continue treatment with the same biologic DMARDs for 52 weeks. In fact, some patients treated at our facility did not show adequate response or developed adverse eff ects and their treatment was switched to other drugs or discontinued before 52 weeks, and these patients were not included in the present study. However, for the patients treated with these biologic DMARDs at our hospital between 2010 and 2013, the retention rate up to 52 weeks was not signifi cantly diff erent (IFX: 85.4%, TCZ: 87.0, and ABT: 80.8%) ( Table 2).
In conclusion, MRI-detected BME in RA patients treated with IFX and ABT improved signifi cantly at the early phase of treatment (0 -24 weeks), whereas BME in those treated with TCZ only decreased at the late phase (24 -52 weeks). These results suggest that the therapeutic eff ects of IFX and ABT may appear more rapidly compared with those of TCZ despite similar improvement in SDAI. In addition, the synovitis scores at baseline and 24 weeks could be potentially useful to predict the clinical response to treatment at 24 weeks and 52 weeks. The MRI remains the best tool to detect and assess the eff ects of biologic DMARDs in RA. Figure 3. Comparison of (A) ⊿ synovitis score, (B) ⊿ BME score, and (C) ⊿ erosion score from baseline to 24 weeks and to 52 weeks. ⊿ Synovitis scores decreased signifi cantly form baseline to 24 weeks in all groups. Signifi cant diff erence in the ⊿ BME scores was noted in the infl iximab and abatacept groups from baseline to 24 weeks, and in the tocilizumab group from 24 weeks to 52 weeks. No signifi cant change in the bone erosion scores was noted. For all MRI fi ndings at 24 weeks and 52 weeks, there were no signifi cant diff erences among the three groups. Data are mean Ϯ SD. † 1. All groups did or did not show signifi cant changes. † 2. No signifi cant diff erence was noted among the three groups. † 3. Signifi cant changes were noted in the infl iximab and abatacept groups but not the tocilizumab group. † 4. Signifi cant changes were noted in the tocilizumab group but not the other two groups. * BME bone marrow edema.  Correlation between SDAI and ⊿ total cMRI scores from baseline to 52 weeks. No signifi cant correlation was found. (B) Correlation between synovitis scores at baseline and SDAI at 24 weeks. The SDAI at 24 weeks correlated signifi cantly with synovitis scores at baseline. (C) Correlation between synovitis scores at 24 weeks and SDAI at 52 weeks. The SDAI at 52 weeks correlated signifi cantly with synovitis scores at 24 weeks.