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Values of intravoxel incoherent motion diffusion weighted imaging and dynamic contrast-enhanced MRI in evaluating the activity of sacroiliitis in ankylosing spondylitis of rat model
Magnetic Resonance Imaging 68 (2020) 30–35
Contents lists available at ScienceDirect
Magnetic Resonance Imaging journal homepage: www.elsevier.com/locate/mri
Original contribution
Values of intravoxel incoherent motion diffusion weighted imaging and dynamic contrast-enhanced MRI in evaluating the activity of sacroiliitis in ankylosing spondylitis of rat model
T
Jian Qin, Jiang Li1, Hui Yang1, Mingsheng Jia, Xiaoqian Li, Qianqian Yao, Yue Zhang, ⁎ Jianzhong Zhu, Changqin Li Department of Radiology, The Second Affiliated Hospital of Shandong First Medical University, Tai'an, Shandong 271000, China
ARTICLE INFO
ABSTRACT
Keywords: MRI Intravoxel incoherent motion Dynamic contract enhance Ankylosing spondylitis Animal model
Objective: To prospectively evaluate the ability of IVIM-DWI and DCE-MRI in detecting early activity of sacroiliitis in rat model of ankylosing spondylitis by comparing with pathological results. Methods: 20 wistar male rats were induced by bovine proteoglycan combined with complete/incomplete Freund's adjuvant as model group, and 20 healthy male rats were used as the control group. The parameters of IVIM-DWI and DCE-MRI in synovial regions of SIJ were measured respectively at 7th, 12th, 17th, and 22th weeks after the last induction, and the pathological features of SIJ were taken also, further studying the pathological characteristics of sacroiliac region. Independent sample t-test and one-way ANOVA were used for statistical analysis. The prediction parameters and diagnostic efficiency were compared by ROC curve. Results: There was no significant difference of image parameters between the model and control groups at the 7th, 12th weeks after the last induction, and there were no positive findings in histopathological examination at the same time. At the 17th week after induction, the f and Fenh%, Senh% between the model and the control groups were statistically significant. At the 22th week, there was a statistically significant increase all the values in model group than those in control group (P < 0.05). Histologic examination confirmed inflmmtorycell infiitrtion at the 17th week and pannus forming of synovium on the surface of cartilage at the 22th week in the model groups. The Fenh%, Senh%, Dslow and f had the moderate diagnostic efficiency and the areas under the curve were 0.77, 0.75, 0.77 and 0.82 respectively. The Senh% demonstrated the highest sensitivity (71.4%) and f demonstrated the highest specificity (95.0%). Conclusion: IVIM-DWI and DCE-MRI can be used as the sensitive imaging methods to detect and accurate diagnosis the early activity of sacroiliitis in AS.
1. Introduction Ankylosing spondylitis (AS) and related spondyloarthropathies (SpA)are among the most common inflammatory rheumatic diseases, occurring most commonly in early adulthood and late adolescence with a strong genetic predisposition and poor understanding of the etiology and the pathogenesis. Due to the lack of specific diagnostic methods in the early stage, the delay of AS between onset of symptoms and accurate diagnosis can reach up to 5–7 years on average, incurring significant disability and economic cost [1], which seriously affected the quality of life for patients. Therefore, how to improve the cognition of
early microscopic pathological changes of AS, ulteriorly diagnose and treat timely are the challenge which we need to face. Recent studies have shown that commercial bovine cartilage-derived proteoglycans can be used for the induction of AS with high success [2], which can provide convenience for studying the local pathological changes of AS in the early stage. Intravoxel incoherent motion imaging (IVIM- MRI) was proposed by Le Bihan et al. [3] to acknowledge that diffusion MR imaging was sensitive not only to molecular diffusion in tissues, but also to random flow of blood in capillaries. Dynamic contract enhance MRI (DCE-MRI) quantitative analysis is to explore the regularity of concentration of contrast agent in tissue with time going on and the
Corresponding author at: Department of Radiology, The Second Affiliated Hospital of Shandong First Medical University, No.366 Taishan Street, Tai'an City, Shandong Province, China. E-mail address: [email protected] (C. Li). 1 These authors have contributed equally. ⁎
https://doi.org/10.1016/j.mri.2020.01.007 Received 3 July 2019; Received in revised form 22 November 2019; Accepted 19 January 2020 0730-725X/ © 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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exchange process of contrast agent inside and outside the vessels on the molecular level by pharmacokinetic model, and then quantitatively describe hemodynamic information of tissue micro-angiogenesis and permeability [4]. Several studies have investigated AS by using IVIMDWI and DCE-MRI for patients [5–6]. However, using these two analysis and comparing with pathology of early AS in animal models has not been investigated. This current study aims to explore the characteristics of early AS from the molecular level using functional magnetic resonance quantitative imaging technique and comparing with pathological changes, whether the quantitative functional magnetic resonance IVIM-DWI and DCE-MRI could provide the early information for clinical diagnosis in AS.
Table 1 IVIM-DWI and DCE-MRI parameters.
2. Materials and methods
Forty male wistar rats were obtained from Experimental Animal breeding Co., Ltd. The rats were 6 weeks old and weighed 170–200 g, comparison of weight at different weeks between model group and control group were not statistically significant (p > 0.05). All rats were acclimatized in a SPF environment for one week before the experiment and randomly divided into model group (n = 20) and control group (n = 20).The rats were injected intraperitoneally with 100μg of proteoglycan protein(1 mg/m1) and an equal volume of Freund's complete adjuvant(FCA). Then the rats were reinjected with the antigen and Freund's incomplete adjuvant (FIA) after 2 week and 4 weeks. Control rats were injected in the same way, but the proteoglycan was not added, instead of same amount of saline. At 7, 12, 17, 22 weeks after induction, 5 rats in the model group and 5 rats in the control group were randomly selected for MRI examination and then killed and acquired pathology. The study was approved by the Institutional Animal Care and Use Committee and was performed in accordance with the National Institutes of Health guidelines for the use of laboratory animals.
IVIM-DWI
OAx T2 fs
OCor fs T1 FSE
Flip angle(°) TE(ms) TR(ms) Thickness(mm) Spacing(mm) Reconstruction diameter(cm) Matrix NEX Freq.FOV Total time
12 2.0 5.7 2.0 −1.0 12 × 12
90 67.0 4000 2.9 −1.9 14 × 11.2
111 96.1 3000 0.8 0.1 6×6
111 13.5 500 0.8 0.0 6×6
128 × 128 0.70 12.0 04:38
64 × 64 2.00 24 03:18
192 × 192 4.0 6.0 02:30
192 × 192 4.0 6.0 02:10
2.3.2. Analysis of DCE MR parameters For DCE MR parameters analysis, all data were quantitatively analyzed using image processing software, calculated by manually drawing different regions of interest (ROIs) from time signal in tensity curve (TIC).
Fenh (%) = (SImax
SI0 ) × 100%/SI0 ;
Senh(%s 1) = (SImax
SI0) 100/(SI0 × Tmax );
where SI0 is the baseline SI measured before contrast injection, approaches the maximum signal intensity (SImax) exponentially in the characteristic time. SImax is determined as the maximum SI during the phases and Tmax were defined as the time point of SImax. 2.3.3. Data analysis The original image was processed using the Advantage Workstation (ADW 4.6 version, GE, US) and post-processed by Functool workstation. Two observers with 15 years and 10 years of experience in MRI were blinded to the information and individually measured the resulting parameter maps. Disagreement of both radiologists was resolved in consensus. All data were measured for 3 times and the average of 3 times is taken to reduce the bias caused by measurement error. The region of interest (ROI) was selected in the anterior and posterior synovial areas of the bilateral sacroiliac joint space with ranges were 2 or 3 mm2, total of four ROIs for each layer and then the average values were taken(Figs. 1, 2).
2.2. MR imaging techniques All MR imaging was performed using a 3.0-T MR (GE company) and utilizing a single-channel animal coil (GE company). Four standard sequences MR imaging was performed: (A) OAx T2-weighted with fatsaturated [echo time (TE)/repetition time (TR),96.1 ms/3000 ms; echo train length,16];(B) OCor fs T1 FSE(TE/TR,13.5 ms/500 ms; echo train length,3);(C)the fat-saturated contrast enhanced T1-weighted images with LAVA sequence,1 ml gadopentetate dimeglumine contrast agent (BeiLu Pharmaceutical Co., Ltd., Beijing, China) was administered intravenously at a rate of 0.1 ml/s, followed by a 2 ml saline flush by hand after the acquisition of seven baseline dynamic scans, each 16slice set was collected at 80 time points for approximately 5 min of scanning, and (D) diffusion weighted MR imaging, a total of 12 b-values were used: 10, 20, 30, 50,80,100, 200, 300, 600, 800, 1000, 1500 s/ mm2. The parameters of the four standard sequences were shown at Table 1.
2.4. Histologic assessment After MR examnation, the rats were killed, sacroiliaca were removed, fixed in 10% formalin for one-two day, acid-decalcified with 10% methanoic acid for one week, embedded in paraffin and cutted after dehydration, stained with hematoxylin and eosin.The pathological changes of SIJ were observed under microscope (MODEL BX53F) finally. The abnormal microscopic features of the following were recorded: (1) Synovitis, pannus formation; (2) Cartilage or subchondral bone changes: cartilage surface and subchondral bone inflammatory cell infiltration,cartilage destruction;(3) osteomyelitis and so on.
2.3. Image analysis 2.3.1. Analysis of IVIM parameters The DWI signal follows the biexponential model to calculate the signal attenuation IVIM, as [3]:
f ) exp( bD ) + f exp.[ b × (D
DCE-MRI
consecutively calculated in which D was gained by a simplified linear regression algorithm (Sb = S0 × exp-bD) using b values > 200 s/mm2. This was based on the assumption that D* was significantly larger than D and the effects of D* on the signal decay at large b values (> 200 s/ mm2) can be neglected. D* and f were calculated by using a non-linear regression algorithm for all b values.
2.1. Research objects
S (b)/ S0 = (1
Parameter
+ D)]
where Sb is the signal intensity in the pixel with diffusion gradient b, S0 is the signal intensity without diffusion gradient, D is the true diffusion, f is the perfusion fraction related to microcirculation and D* is the pseudo-diffusion coefficient which represented perfusion-related diffusion or incoherent microcirculation. The three parameters were
2.5. Statistical analysis SPSS Statistics version 16.0 and Med Calc 15.8 were used for statistical analysis. The normality and homoscedasticity of data were 31
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Fig. 1. MRI of control group rat at week 12. (a) Axial T2-weighted with fat-saturated;(b–c) DCE-MRI and TIC curves;(d–g) Display of DWI, Dfast, Dslow, f values.
tested using the Kolmogorove Smirnov test and Levene's tests, respectively. All the parameter values were compared by two independent samples t-test or one-way ANOVA. The measured parameters were expressed as means ± standard deviation (SD). According to the pathological results, the experimental data were divided into positive AS group and negative normal group and the parameters were selected for receiver operating characteristic (ROC) curve analysis to assess the diagnostic performance. The sensitivity and specificity of these parameters were calculated by the ROC curve. P values of < 0.05 were considered as statistically significant.
no statistically significant difference in appearance (including paw, hair, tail, spine, etc.) between the model group and control group. 3.2. Comparisons of the parameters derived from IVIM-DWI and DCE-MRI between model group and normal control group There were no positive signal changes with conventional MRI sequences in no matter the control group or model group from week 7 to week 22. At 7 weeks, the Fenh%, Senh% and Dfast, f values in the model group were slightly lower than those in control group, excepting for the value of Dslow, which was relatively higher in model group, but all the differences were not statistically significant (p > 0.05). At 12 weeks, the Fenh% value in model group was slightly higher than that in control group, excepting for the values of Senh%, Dslow, Dfast and f, which inversely decreased in model group, but all the differences between two groups also were not statistically significant (p > 0.05) (Fig. 1). At 17 weeks, a increase in Fenh%, Senh%, Dslow, Dfast and f values were
3. Results 3.1. Performance of Wistar rats The changes of weight in the two groups of Wistar rats with different weeks were no difference.Over the entire study period, there was
Fig. 2. MRI of model group rat at week 17. (a) Axial T2-weighted with fat-saturated;(b–c) DCE-MRI and TIC curves;(d–g) Display of DWI, Dfast, Dslow, f values. 32
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3.3. Histopathologic changes
Table 2 Comparison between model group and normal control group at week 17.
Fenh% Senh%(s−1) Dslow(×10−4 mm2/s) Dfast(×10−4 mm2/s) f
Model group
Control group
t
p
212.49 ± 29.39 3.12 ± 0.68 6.47 ± 0.32 62.90 ± 7.89 24.92 ± 3.24
192.97 ± 30.66 2.64 ± 0.63 6.27 ± 0.29 61.16 ± 18.30 19.65 ± 5.45
2.056 −2.290 1.604 0.307 2.974
0.040 0.028 0.121 0.763 0.009
Positive histologic evidence of inflammation was entirely lacking from week 7 to 12 in synovium, cartilage, subchondral bone and bone marrow of SIJ in model group. At week 17, inflmmtorycell infiitrtion within the synovial joints were observed in model subjects initially, next pannus forming of synovium and exudation or hemorrhage on the surface of cartilage could be seen of SIJ joints at week 22 in model wistar rats group (Fig. 4).
Data are expressed as the mean ± standard deviation.
3.4. Area under ROC curve of parameter values with diagnostic value
Table 3 Comparison between model group and normal control group at week 22.
Fenh% Senh%(s−1) Dslow(×10−4 mm2/s) Dfast(×10−4 mm2/s) f
Model group
Control group
t
p
236.88 ± 37.78 3.22 ± 0.56 6.74 ± 0.30 69.73 ± 6.59 32.76 ± 2.02
193.42 ± 28.47 2.62 ± 0.49 6.26 ± 0.25 62.90 ± 5.85 21.66 ± 3.26
9.162 0.293 3.781 2.476 8.76
0.000 0.000 0.001 0.021 0.000
According to histopathologic changes, a total of 10 wistar mice at 17 and 22 weeks in model group were taken for positive AS group and 20 wistar mice in control group were taken for negative normal group. The parameters were selected for ROC curve analysis to assess the diagnostic performance. The Fenh%, Senh%, Dslow and f had the moderate diagnostic efficiency. The areas under the curve were 0.77, 0.75, 0.77 and 0.82 respectively (Table 5). The ROC curves shown f had the maximum AUC with sensitivity (61.6%) and specificity (95.0%),and Dfast had the minimum AUC with sensitivity (53.9%) and specificity (75.0%) (Fig. 5) by using only one parameter. The Senh% demonstrated the highest sensitivity (71.4%) and f demonstrated the highest specificity (95.0%).
Data are expressed as the mean ± standard deviation.
observed in model group comparing with control group. These changes, however, only Fenh%, Senh%, and f values were statistically significant (Table 2,Fig. 2). At 22 weeks, there was a statistically significant increase in Fenh%, Senh%, Dslow, Dfast and f values in model group than those in control group (p < 0.05) (Table 3,Fig. 3). Univariate anova was performed for comparing the differences between the 12, 17 and 22 weeks (Table 4) in model group. With the increase of weeks, Fenh% and Senh% also increased gradually. In model group, there was no significant change in the Fenh% value between the 12 and 17 weeks (P > 0.05), but statistical significance between the 12 and 22 weeks, 17 and 22 weeks (P < 0.05). There was no significant change in Senh% value between the 17 and 22 weeks (P > 0.05), inversely statistical significance between 12 and 17 weeks, 12 and 22 weeks (P < 0.05).The differences in Dslow and Dfast values between12 and 22 weeks, 17 and 22 weeks were statistically significant (P < 0.05), excepting for the changes between 12 and 17 weeks (P > 0.05).Pairwise comparisons of f value at 12, 17 and 22 weeks were all statistically significant (P < 0.05).
4. Discussion Ankylosing spondylitis (AS) is a chronic progressive rheumatic disorder that affects the sacroiliac joint (SIJ) firstly and there have been severely hampered by a lack of understanding of the early microscopic changes in previous investigations of AS, because the joint tissue involved is not readily accessible for examination. Due to the difficult access for pathology, authentic animal models have special value, and would be of great benefit for investigative purposes. Our study has induced the rat model successfully by using bovine proteoglycan combined with complete/incomplete Freund's adjuvant with no peripheral arthritis explicit occurrence, which provide insight into the pathogenesis of AS and opportunities to investigate their pathology in relationship to human disease. The previous investigations claim that enthesitis is of key importance pathological basis and later studies have recorded that synovitis and subchondral bone marrow inflammation hold the key to understanding the early characteristic joint changes in AS. Francois's [7] research have found that the subsynoviocytic, areolar connective tissue
Fig. 3. MRI of model group rat at week 22. (a) Axial T2-weighted with fat-saturated;(b–c) DCE-MRI and TIC curves;(d–g) Display of DWI, Dfast, Dslow, f values. 33
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Table 4 Comparison between different weeks in model group.
Fenh% Senh%(s−1) Dslow(×10−4 mm2/s) Dfast(×10−4 mm2/s) f
12 weeks
17 weeks
22 weeks
F
p
199.52 ± 36.95 2.36 ± 0.60 6.26 ± 0.30 60.01 ± 12.65 18.56 ± 3.45
212.49 ± 29.39 3.12 ± 0.68 6.47 ± 0.32 62.90 ± 7.89 24.92 ± 3.24
236.15 ± 37.78 3.22 ± 0.56 6.74 ± 0.30 69.73 ± 6.59 32.76 ± 2.02
9.988 20.259 9.240 4.495 57.738
0.000 0.000 0.000 0.017 0.000
Data are expressed as the mean ± standard deviation.
early SIJ changes in AS were investigated from the molecular level using functional magnetic resonance technique, and whether the quantitative functional magnetic resonance IVIM-DWI and semi-quantitative DCE-MRI could provide the early information for diagnosis in animal models was explored in this study. As we all know, apparent diffusion coefficient (ADC) is the most commonly used metric in the mono-exponential model (MEM) of DWI, which does not consider the influence of the microcirculation of blood in capillaries, leading to inaccurate description of the diffusion [11]. In fact, there are two main aspects that affect the measured diffusion signals in living tissues, one is the motion of water molecules and another is the perfusion of blood microcirculation with low b values < 200 s/mm2 which may lead to inaccurate estimation of the diffusion. In 1986, Le Bihan et al. [3] by using multi-b-value DWI with a bi-exponential curve fitting firstly described a new imaging technique named IVIM, which is sensitive not only to molecular diffusion in tissues, but also to random flow of blood in capillaries, providing related analytical parameters represented by diffusion-related parameters Dslow (pure molecular diffusion) and perfusion-related parameters including Dfast (pseudo-diffusion coefficient) and f(perfusion fraction). Semiquantitative dynamic contrast-enhanced MRI using a generalised kinetic model allows for estimation of tissue perfusion and permeability,which necessarily involves not only exchange dynamics of intra- and extravascular but also some other factors, such as the pattern of blood delivery,blood vessel density, vascular permeability, and distribution of contrast agent in lesions [12]. so far, Many studies have demonstrated its efficiency of IVIMDWI and DCE-MRI parameters in prostate cancer [13], breast cancer [14] and liver fibrosis [15].The previous studies have shown that the IVIM and DCE parameters might play a critical role in detecting the progression of AS of patients [16]and moreover predict response to the therapy by antitumour necrosis factor-α (TNF- α) in AS [17,18]. In this study, there was no significant difference between the model group and control group of IVIM and DCE-MRI parameters assessing in the synovial area from week 7 to 12 after induction, consistented with the pathological results, which showed no obvious positive features. At week 17, increase in f value was observed statistically significant in model group comparing with control group. Combined with the analysis of pathological results, the subsynoviocytic, areolar connective tissue was locally infiltrated by inflammatory cell in the early stage, ledding to the increase of vascular permeability and accelerated diffusion of water molecules. Although pannus formation was not observed in the early stage of pathological process, the f value reflecting the volume of vascular and extracellular space had been significantly increased, indicating that the blood flow in the synovial area has increased at this time. At week 22, there was a statistically significant increase in Dslow, Dfast and f values of IVIM-DWI parameters in model group than those in control group. This could be explained by the increasing number of capillaries and limition of the diffusion movement of water molecules in synovium, so as to the increase of blood flow and proportion of blood perfusion, which was presented with pannus formation of histopathologic changes. At 17 and 22 weeks, there was a statistically significant increase in Fenh%, Senh% values in model group, which suggest that when inflammatory cells infiltrate and pannus forms in the synovial area, blood flow was abundant, because the amount of blood and serum of capillary transported to the marrow cavity was increased. Additionally, the results of the ROC of diffusion parameters used to
Fig. 4. Pathological images ①Negative histologic evidence of inflammation of SI joints at week 12 of normal group; ②Infiltration of inflammatory cells in the synovium at week 17 of model group; ③Pannus formation in the synovium in the SIJ area of model group at week 22; ④Exudation and hemorrhage on the surface of the lateral iliac cartilage at week 22 of model group. Table 5 ROC related parameters of DCE-MRI and IVIM-DWI. Area under the curve
Cut-off value
Sensitivity(%)
Specificity(%)
Fenh% Senh%(s−1) Dslow(×10−4 mm2/s) Dfast(×10−4 mm2/s) f
0.77 0.75 0.77 0.65 0.82
220.9 2.80 6.48 65.2 26.4
60.7 71.4 65.4 53.9 61.6
87.5 72.5 85.0 75.0 95.0
Data are expressed as the mean ± standard deviation.
was locally infiltrated by small numbers of lymphocytes and plasmacytes, and by larger numbers of macrophages in early disease basing on a systematic histologic study of SIJ, which was consistent with our finding of synovitis in early SIJ changes in animal models. The assessment in SpondyloArthritis international Society (ASAS) [8] provides insight in available and newly developed criteria for classifying spondyloarthritis (SpA) and it exemplifies response criteria as well as recent achievements in measuring disease activity, which points that bone marrow oedema (osteitis), capsulitis, synovitis and enthesitis are the characteristic changes in active inflammatory lesions of SIJ. Recent studies [9] have found that bone marrow edema has the lowest specificity among all MRI positive manifestations with a high false positive rate. It has been suggested in the previous investigations that combing bone marrow edema with signal changes in SIJ on MRI can improve the specificity of diagnosis [10]. How to diagnose the early changes of AS accurately is the challenge which the imaging examination needs to face. The application of new MRI technologies gradually makes up the shortcomings of conventional MRI sequences. The characteristics of 34
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Fig. 5. Comparison of ROC curves of related parameters.
distinguish from the activity of sacroiliitis in AS than normal control group were analyzed in our study. Using ROC analysis, the Fenh%, Senh %, Dslow and f had the moderate diagnostic efficiency. The areas under the curve were 0.77, 0.75, 0.77 and 0.82 respectively. The ROC curves shown f had the maximum AUC with sensitivity (61.6%) and specificity (95.0%), and Dfast had the minimum AUC with sensitivity (53.9%) and specificity (75.0%) by using only one parameter. The Senh% demonstrated the highest sensitivity (71.4%) and f demonstrated the highest specificity (95.0%). In conclusion, we have demonstrated that IVIM-DWI and DCE-MRI have potential in the quantitative analysis of early activity of sacroiliitis in a rat model of AS by comparing with pathological results, which can be highlighted as a novel and effective technique to detect the early progression of AS and provide reliable imaging evidence for early clinical diagnosis.
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CRediT authorship contribution statement Jian Qin:Conceptualization, Writing - review & editing.Jiang Li:Data curation, Resources.Hui Yang:Methodology, Writing - original draft.Mingsheng Jia:Visualization, Formal analysis. Xiaoqian Li:Visualization, Investigation.Qianqian Yao:Data curation, Software.Yue Zhang:Software, Formal analysis. Jianzhong Zhu:Supervision, Project administration.Changqin Li:Conceptualization, Supervision, Project administration. Declaration of competing interest The authors declare no conflict of interest. Acknowledgements The present study was supported by grants from the Shandong Provincial Natural Science Foundation, China (No.ZR2017MH105) and Academic promotion programme of Shandong First Medical University (No.2019QL017). We thank by Xinli Wang for assistance of histologic assessment and Qiuling Zhang of animal experiments. References [1] Reed MD, Dharmage S, Boers A, et al. Ankylosing spondylitis: an Australian
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Contents lists available at ScienceDirect
Magnetic Resonance Imaging journal homepage: www.elsevier.com/locate/mri
Original contribution
Values of intravoxel incoherent motion diffusion weighted imaging and dynamic contrast-enhanced MRI in evaluating the activity of sacroiliitis in ankylosing spondylitis of rat model
T
Jian Qin, Jiang Li1, Hui Yang1, Mingsheng Jia, Xiaoqian Li, Qianqian Yao, Yue Zhang, ⁎ Jianzhong Zhu, Changqin Li Department of Radiology, The Second Affiliated Hospital of Shandong First Medical University, Tai'an, Shandong 271000, China
ARTICLE INFO
ABSTRACT
Keywords: MRI Intravoxel incoherent motion Dynamic contract enhance Ankylosing spondylitis Animal model
Objective: To prospectively evaluate the ability of IVIM-DWI and DCE-MRI in detecting early activity of sacroiliitis in rat model of ankylosing spondylitis by comparing with pathological results. Methods: 20 wistar male rats were induced by bovine proteoglycan combined with complete/incomplete Freund's adjuvant as model group, and 20 healthy male rats were used as the control group. The parameters of IVIM-DWI and DCE-MRI in synovial regions of SIJ were measured respectively at 7th, 12th, 17th, and 22th weeks after the last induction, and the pathological features of SIJ were taken also, further studying the pathological characteristics of sacroiliac region. Independent sample t-test and one-way ANOVA were used for statistical analysis. The prediction parameters and diagnostic efficiency were compared by ROC curve. Results: There was no significant difference of image parameters between the model and control groups at the 7th, 12th weeks after the last induction, and there were no positive findings in histopathological examination at the same time. At the 17th week after induction, the f and Fenh%, Senh% between the model and the control groups were statistically significant. At the 22th week, there was a statistically significant increase all the values in model group than those in control group (P < 0.05). Histologic examination confirmed inflmmtorycell infiitrtion at the 17th week and pannus forming of synovium on the surface of cartilage at the 22th week in the model groups. The Fenh%, Senh%, Dslow and f had the moderate diagnostic efficiency and the areas under the curve were 0.77, 0.75, 0.77 and 0.82 respectively. The Senh% demonstrated the highest sensitivity (71.4%) and f demonstrated the highest specificity (95.0%). Conclusion: IVIM-DWI and DCE-MRI can be used as the sensitive imaging methods to detect and accurate diagnosis the early activity of sacroiliitis in AS.
1. Introduction Ankylosing spondylitis (AS) and related spondyloarthropathies (SpA)are among the most common inflammatory rheumatic diseases, occurring most commonly in early adulthood and late adolescence with a strong genetic predisposition and poor understanding of the etiology and the pathogenesis. Due to the lack of specific diagnostic methods in the early stage, the delay of AS between onset of symptoms and accurate diagnosis can reach up to 5–7 years on average, incurring significant disability and economic cost [1], which seriously affected the quality of life for patients. Therefore, how to improve the cognition of
early microscopic pathological changes of AS, ulteriorly diagnose and treat timely are the challenge which we need to face. Recent studies have shown that commercial bovine cartilage-derived proteoglycans can be used for the induction of AS with high success [2], which can provide convenience for studying the local pathological changes of AS in the early stage. Intravoxel incoherent motion imaging (IVIM- MRI) was proposed by Le Bihan et al. [3] to acknowledge that diffusion MR imaging was sensitive not only to molecular diffusion in tissues, but also to random flow of blood in capillaries. Dynamic contract enhance MRI (DCE-MRI) quantitative analysis is to explore the regularity of concentration of contrast agent in tissue with time going on and the
Corresponding author at: Department of Radiology, The Second Affiliated Hospital of Shandong First Medical University, No.366 Taishan Street, Tai'an City, Shandong Province, China. E-mail address: [email protected] (C. Li). 1 These authors have contributed equally. ⁎
https://doi.org/10.1016/j.mri.2020.01.007 Received 3 July 2019; Received in revised form 22 November 2019; Accepted 19 January 2020 0730-725X/ © 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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exchange process of contrast agent inside and outside the vessels on the molecular level by pharmacokinetic model, and then quantitatively describe hemodynamic information of tissue micro-angiogenesis and permeability [4]. Several studies have investigated AS by using IVIMDWI and DCE-MRI for patients [5–6]. However, using these two analysis and comparing with pathology of early AS in animal models has not been investigated. This current study aims to explore the characteristics of early AS from the molecular level using functional magnetic resonance quantitative imaging technique and comparing with pathological changes, whether the quantitative functional magnetic resonance IVIM-DWI and DCE-MRI could provide the early information for clinical diagnosis in AS.
Table 1 IVIM-DWI and DCE-MRI parameters.
2. Materials and methods
Forty male wistar rats were obtained from Experimental Animal breeding Co., Ltd. The rats were 6 weeks old and weighed 170–200 g, comparison of weight at different weeks between model group and control group were not statistically significant (p > 0.05). All rats were acclimatized in a SPF environment for one week before the experiment and randomly divided into model group (n = 20) and control group (n = 20).The rats were injected intraperitoneally with 100μg of proteoglycan protein(1 mg/m1) and an equal volume of Freund's complete adjuvant(FCA). Then the rats were reinjected with the antigen and Freund's incomplete adjuvant (FIA) after 2 week and 4 weeks. Control rats were injected in the same way, but the proteoglycan was not added, instead of same amount of saline. At 7, 12, 17, 22 weeks after induction, 5 rats in the model group and 5 rats in the control group were randomly selected for MRI examination and then killed and acquired pathology. The study was approved by the Institutional Animal Care and Use Committee and was performed in accordance with the National Institutes of Health guidelines for the use of laboratory animals.
IVIM-DWI
OAx T2 fs
OCor fs T1 FSE
Flip angle(°) TE(ms) TR(ms) Thickness(mm) Spacing(mm) Reconstruction diameter(cm) Matrix NEX Freq.FOV Total time
12 2.0 5.7 2.0 −1.0 12 × 12
90 67.0 4000 2.9 −1.9 14 × 11.2
111 96.1 3000 0.8 0.1 6×6
111 13.5 500 0.8 0.0 6×6
128 × 128 0.70 12.0 04:38
64 × 64 2.00 24 03:18
192 × 192 4.0 6.0 02:30
192 × 192 4.0 6.0 02:10
2.3.2. Analysis of DCE MR parameters For DCE MR parameters analysis, all data were quantitatively analyzed using image processing software, calculated by manually drawing different regions of interest (ROIs) from time signal in tensity curve (TIC).
Fenh (%) = (SImax
SI0 ) × 100%/SI0 ;
Senh(%s 1) = (SImax
SI0) 100/(SI0 × Tmax );
where SI0 is the baseline SI measured before contrast injection, approaches the maximum signal intensity (SImax) exponentially in the characteristic time. SImax is determined as the maximum SI during the phases and Tmax were defined as the time point of SImax. 2.3.3. Data analysis The original image was processed using the Advantage Workstation (ADW 4.6 version, GE, US) and post-processed by Functool workstation. Two observers with 15 years and 10 years of experience in MRI were blinded to the information and individually measured the resulting parameter maps. Disagreement of both radiologists was resolved in consensus. All data were measured for 3 times and the average of 3 times is taken to reduce the bias caused by measurement error. The region of interest (ROI) was selected in the anterior and posterior synovial areas of the bilateral sacroiliac joint space with ranges were 2 or 3 mm2, total of four ROIs for each layer and then the average values were taken(Figs. 1, 2).
2.2. MR imaging techniques All MR imaging was performed using a 3.0-T MR (GE company) and utilizing a single-channel animal coil (GE company). Four standard sequences MR imaging was performed: (A) OAx T2-weighted with fatsaturated [echo time (TE)/repetition time (TR),96.1 ms/3000 ms; echo train length,16];(B) OCor fs T1 FSE(TE/TR,13.5 ms/500 ms; echo train length,3);(C)the fat-saturated contrast enhanced T1-weighted images with LAVA sequence,1 ml gadopentetate dimeglumine contrast agent (BeiLu Pharmaceutical Co., Ltd., Beijing, China) was administered intravenously at a rate of 0.1 ml/s, followed by a 2 ml saline flush by hand after the acquisition of seven baseline dynamic scans, each 16slice set was collected at 80 time points for approximately 5 min of scanning, and (D) diffusion weighted MR imaging, a total of 12 b-values were used: 10, 20, 30, 50,80,100, 200, 300, 600, 800, 1000, 1500 s/ mm2. The parameters of the four standard sequences were shown at Table 1.
2.4. Histologic assessment After MR examnation, the rats were killed, sacroiliaca were removed, fixed in 10% formalin for one-two day, acid-decalcified with 10% methanoic acid for one week, embedded in paraffin and cutted after dehydration, stained with hematoxylin and eosin.The pathological changes of SIJ were observed under microscope (MODEL BX53F) finally. The abnormal microscopic features of the following were recorded: (1) Synovitis, pannus formation; (2) Cartilage or subchondral bone changes: cartilage surface and subchondral bone inflammatory cell infiltration,cartilage destruction;(3) osteomyelitis and so on.
2.3. Image analysis 2.3.1. Analysis of IVIM parameters The DWI signal follows the biexponential model to calculate the signal attenuation IVIM, as [3]:
f ) exp( bD ) + f exp.[ b × (D
DCE-MRI
consecutively calculated in which D was gained by a simplified linear regression algorithm (Sb = S0 × exp-bD) using b values > 200 s/mm2. This was based on the assumption that D* was significantly larger than D and the effects of D* on the signal decay at large b values (> 200 s/ mm2) can be neglected. D* and f were calculated by using a non-linear regression algorithm for all b values.
2.1. Research objects
S (b)/ S0 = (1
Parameter
+ D)]
where Sb is the signal intensity in the pixel with diffusion gradient b, S0 is the signal intensity without diffusion gradient, D is the true diffusion, f is the perfusion fraction related to microcirculation and D* is the pseudo-diffusion coefficient which represented perfusion-related diffusion or incoherent microcirculation. The three parameters were
2.5. Statistical analysis SPSS Statistics version 16.0 and Med Calc 15.8 were used for statistical analysis. The normality and homoscedasticity of data were 31
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Fig. 1. MRI of control group rat at week 12. (a) Axial T2-weighted with fat-saturated;(b–c) DCE-MRI and TIC curves;(d–g) Display of DWI, Dfast, Dslow, f values.
tested using the Kolmogorove Smirnov test and Levene's tests, respectively. All the parameter values were compared by two independent samples t-test or one-way ANOVA. The measured parameters were expressed as means ± standard deviation (SD). According to the pathological results, the experimental data were divided into positive AS group and negative normal group and the parameters were selected for receiver operating characteristic (ROC) curve analysis to assess the diagnostic performance. The sensitivity and specificity of these parameters were calculated by the ROC curve. P values of < 0.05 were considered as statistically significant.
no statistically significant difference in appearance (including paw, hair, tail, spine, etc.) between the model group and control group. 3.2. Comparisons of the parameters derived from IVIM-DWI and DCE-MRI between model group and normal control group There were no positive signal changes with conventional MRI sequences in no matter the control group or model group from week 7 to week 22. At 7 weeks, the Fenh%, Senh% and Dfast, f values in the model group were slightly lower than those in control group, excepting for the value of Dslow, which was relatively higher in model group, but all the differences were not statistically significant (p > 0.05). At 12 weeks, the Fenh% value in model group was slightly higher than that in control group, excepting for the values of Senh%, Dslow, Dfast and f, which inversely decreased in model group, but all the differences between two groups also were not statistically significant (p > 0.05) (Fig. 1). At 17 weeks, a increase in Fenh%, Senh%, Dslow, Dfast and f values were
3. Results 3.1. Performance of Wistar rats The changes of weight in the two groups of Wistar rats with different weeks were no difference.Over the entire study period, there was
Fig. 2. MRI of model group rat at week 17. (a) Axial T2-weighted with fat-saturated;(b–c) DCE-MRI and TIC curves;(d–g) Display of DWI, Dfast, Dslow, f values. 32
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3.3. Histopathologic changes
Table 2 Comparison between model group and normal control group at week 17.
Fenh% Senh%(s−1) Dslow(×10−4 mm2/s) Dfast(×10−4 mm2/s) f
Model group
Control group
t
p
212.49 ± 29.39 3.12 ± 0.68 6.47 ± 0.32 62.90 ± 7.89 24.92 ± 3.24
192.97 ± 30.66 2.64 ± 0.63 6.27 ± 0.29 61.16 ± 18.30 19.65 ± 5.45
2.056 −2.290 1.604 0.307 2.974
0.040 0.028 0.121 0.763 0.009
Positive histologic evidence of inflammation was entirely lacking from week 7 to 12 in synovium, cartilage, subchondral bone and bone marrow of SIJ in model group. At week 17, inflmmtorycell infiitrtion within the synovial joints were observed in model subjects initially, next pannus forming of synovium and exudation or hemorrhage on the surface of cartilage could be seen of SIJ joints at week 22 in model wistar rats group (Fig. 4).
Data are expressed as the mean ± standard deviation.
3.4. Area under ROC curve of parameter values with diagnostic value
Table 3 Comparison between model group and normal control group at week 22.
Fenh% Senh%(s−1) Dslow(×10−4 mm2/s) Dfast(×10−4 mm2/s) f
Model group
Control group
t
p
236.88 ± 37.78 3.22 ± 0.56 6.74 ± 0.30 69.73 ± 6.59 32.76 ± 2.02
193.42 ± 28.47 2.62 ± 0.49 6.26 ± 0.25 62.90 ± 5.85 21.66 ± 3.26
9.162 0.293 3.781 2.476 8.76
0.000 0.000 0.001 0.021 0.000
According to histopathologic changes, a total of 10 wistar mice at 17 and 22 weeks in model group were taken for positive AS group and 20 wistar mice in control group were taken for negative normal group. The parameters were selected for ROC curve analysis to assess the diagnostic performance. The Fenh%, Senh%, Dslow and f had the moderate diagnostic efficiency. The areas under the curve were 0.77, 0.75, 0.77 and 0.82 respectively (Table 5). The ROC curves shown f had the maximum AUC with sensitivity (61.6%) and specificity (95.0%),and Dfast had the minimum AUC with sensitivity (53.9%) and specificity (75.0%) (Fig. 5) by using only one parameter. The Senh% demonstrated the highest sensitivity (71.4%) and f demonstrated the highest specificity (95.0%).
Data are expressed as the mean ± standard deviation.
observed in model group comparing with control group. These changes, however, only Fenh%, Senh%, and f values were statistically significant (Table 2,Fig. 2). At 22 weeks, there was a statistically significant increase in Fenh%, Senh%, Dslow, Dfast and f values in model group than those in control group (p < 0.05) (Table 3,Fig. 3). Univariate anova was performed for comparing the differences between the 12, 17 and 22 weeks (Table 4) in model group. With the increase of weeks, Fenh% and Senh% also increased gradually. In model group, there was no significant change in the Fenh% value between the 12 and 17 weeks (P > 0.05), but statistical significance between the 12 and 22 weeks, 17 and 22 weeks (P < 0.05). There was no significant change in Senh% value between the 17 and 22 weeks (P > 0.05), inversely statistical significance between 12 and 17 weeks, 12 and 22 weeks (P < 0.05).The differences in Dslow and Dfast values between12 and 22 weeks, 17 and 22 weeks were statistically significant (P < 0.05), excepting for the changes between 12 and 17 weeks (P > 0.05).Pairwise comparisons of f value at 12, 17 and 22 weeks were all statistically significant (P < 0.05).
4. Discussion Ankylosing spondylitis (AS) is a chronic progressive rheumatic disorder that affects the sacroiliac joint (SIJ) firstly and there have been severely hampered by a lack of understanding of the early microscopic changes in previous investigations of AS, because the joint tissue involved is not readily accessible for examination. Due to the difficult access for pathology, authentic animal models have special value, and would be of great benefit for investigative purposes. Our study has induced the rat model successfully by using bovine proteoglycan combined with complete/incomplete Freund's adjuvant with no peripheral arthritis explicit occurrence, which provide insight into the pathogenesis of AS and opportunities to investigate their pathology in relationship to human disease. The previous investigations claim that enthesitis is of key importance pathological basis and later studies have recorded that synovitis and subchondral bone marrow inflammation hold the key to understanding the early characteristic joint changes in AS. Francois's [7] research have found that the subsynoviocytic, areolar connective tissue
Fig. 3. MRI of model group rat at week 22. (a) Axial T2-weighted with fat-saturated;(b–c) DCE-MRI and TIC curves;(d–g) Display of DWI, Dfast, Dslow, f values. 33
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Table 4 Comparison between different weeks in model group.
Fenh% Senh%(s−1) Dslow(×10−4 mm2/s) Dfast(×10−4 mm2/s) f
12 weeks
17 weeks
22 weeks
F
p
199.52 ± 36.95 2.36 ± 0.60 6.26 ± 0.30 60.01 ± 12.65 18.56 ± 3.45
212.49 ± 29.39 3.12 ± 0.68 6.47 ± 0.32 62.90 ± 7.89 24.92 ± 3.24
236.15 ± 37.78 3.22 ± 0.56 6.74 ± 0.30 69.73 ± 6.59 32.76 ± 2.02
9.988 20.259 9.240 4.495 57.738
0.000 0.000 0.000 0.017 0.000
Data are expressed as the mean ± standard deviation.
early SIJ changes in AS were investigated from the molecular level using functional magnetic resonance technique, and whether the quantitative functional magnetic resonance IVIM-DWI and semi-quantitative DCE-MRI could provide the early information for diagnosis in animal models was explored in this study. As we all know, apparent diffusion coefficient (ADC) is the most commonly used metric in the mono-exponential model (MEM) of DWI, which does not consider the influence of the microcirculation of blood in capillaries, leading to inaccurate description of the diffusion [11]. In fact, there are two main aspects that affect the measured diffusion signals in living tissues, one is the motion of water molecules and another is the perfusion of blood microcirculation with low b values < 200 s/mm2 which may lead to inaccurate estimation of the diffusion. In 1986, Le Bihan et al. [3] by using multi-b-value DWI with a bi-exponential curve fitting firstly described a new imaging technique named IVIM, which is sensitive not only to molecular diffusion in tissues, but also to random flow of blood in capillaries, providing related analytical parameters represented by diffusion-related parameters Dslow (pure molecular diffusion) and perfusion-related parameters including Dfast (pseudo-diffusion coefficient) and f(perfusion fraction). Semiquantitative dynamic contrast-enhanced MRI using a generalised kinetic model allows for estimation of tissue perfusion and permeability,which necessarily involves not only exchange dynamics of intra- and extravascular but also some other factors, such as the pattern of blood delivery,blood vessel density, vascular permeability, and distribution of contrast agent in lesions [12]. so far, Many studies have demonstrated its efficiency of IVIMDWI and DCE-MRI parameters in prostate cancer [13], breast cancer [14] and liver fibrosis [15].The previous studies have shown that the IVIM and DCE parameters might play a critical role in detecting the progression of AS of patients [16]and moreover predict response to the therapy by antitumour necrosis factor-α (TNF- α) in AS [17,18]. In this study, there was no significant difference between the model group and control group of IVIM and DCE-MRI parameters assessing in the synovial area from week 7 to 12 after induction, consistented with the pathological results, which showed no obvious positive features. At week 17, increase in f value was observed statistically significant in model group comparing with control group. Combined with the analysis of pathological results, the subsynoviocytic, areolar connective tissue was locally infiltrated by inflammatory cell in the early stage, ledding to the increase of vascular permeability and accelerated diffusion of water molecules. Although pannus formation was not observed in the early stage of pathological process, the f value reflecting the volume of vascular and extracellular space had been significantly increased, indicating that the blood flow in the synovial area has increased at this time. At week 22, there was a statistically significant increase in Dslow, Dfast and f values of IVIM-DWI parameters in model group than those in control group. This could be explained by the increasing number of capillaries and limition of the diffusion movement of water molecules in synovium, so as to the increase of blood flow and proportion of blood perfusion, which was presented with pannus formation of histopathologic changes. At 17 and 22 weeks, there was a statistically significant increase in Fenh%, Senh% values in model group, which suggest that when inflammatory cells infiltrate and pannus forms in the synovial area, blood flow was abundant, because the amount of blood and serum of capillary transported to the marrow cavity was increased. Additionally, the results of the ROC of diffusion parameters used to
Fig. 4. Pathological images ①Negative histologic evidence of inflammation of SI joints at week 12 of normal group; ②Infiltration of inflammatory cells in the synovium at week 17 of model group; ③Pannus formation in the synovium in the SIJ area of model group at week 22; ④Exudation and hemorrhage on the surface of the lateral iliac cartilage at week 22 of model group. Table 5 ROC related parameters of DCE-MRI and IVIM-DWI. Area under the curve
Cut-off value
Sensitivity(%)
Specificity(%)
Fenh% Senh%(s−1) Dslow(×10−4 mm2/s) Dfast(×10−4 mm2/s) f
0.77 0.75 0.77 0.65 0.82
220.9 2.80 6.48 65.2 26.4
60.7 71.4 65.4 53.9 61.6
87.5 72.5 85.0 75.0 95.0
Data are expressed as the mean ± standard deviation.
was locally infiltrated by small numbers of lymphocytes and plasmacytes, and by larger numbers of macrophages in early disease basing on a systematic histologic study of SIJ, which was consistent with our finding of synovitis in early SIJ changes in animal models. The assessment in SpondyloArthritis international Society (ASAS) [8] provides insight in available and newly developed criteria for classifying spondyloarthritis (SpA) and it exemplifies response criteria as well as recent achievements in measuring disease activity, which points that bone marrow oedema (osteitis), capsulitis, synovitis and enthesitis are the characteristic changes in active inflammatory lesions of SIJ. Recent studies [9] have found that bone marrow edema has the lowest specificity among all MRI positive manifestations with a high false positive rate. It has been suggested in the previous investigations that combing bone marrow edema with signal changes in SIJ on MRI can improve the specificity of diagnosis [10]. How to diagnose the early changes of AS accurately is the challenge which the imaging examination needs to face. The application of new MRI technologies gradually makes up the shortcomings of conventional MRI sequences. The characteristics of 34
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Fig. 5. Comparison of ROC curves of related parameters.
distinguish from the activity of sacroiliitis in AS than normal control group were analyzed in our study. Using ROC analysis, the Fenh%, Senh %, Dslow and f had the moderate diagnostic efficiency. The areas under the curve were 0.77, 0.75, 0.77 and 0.82 respectively. The ROC curves shown f had the maximum AUC with sensitivity (61.6%) and specificity (95.0%), and Dfast had the minimum AUC with sensitivity (53.9%) and specificity (75.0%) by using only one parameter. The Senh% demonstrated the highest sensitivity (71.4%) and f demonstrated the highest specificity (95.0%). In conclusion, we have demonstrated that IVIM-DWI and DCE-MRI have potential in the quantitative analysis of early activity of sacroiliitis in a rat model of AS by comparing with pathological results, which can be highlighted as a novel and effective technique to detect the early progression of AS and provide reliable imaging evidence for early clinical diagnosis.
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CRediT authorship contribution statement Jian Qin:Conceptualization, Writing - review & editing.Jiang Li:Data curation, Resources.Hui Yang:Methodology, Writing - original draft.Mingsheng Jia:Visualization, Formal analysis. Xiaoqian Li:Visualization, Investigation.Qianqian Yao:Data curation, Software.Yue Zhang:Software, Formal analysis. Jianzhong Zhu:Supervision, Project administration.Changqin Li:Conceptualization, Supervision, Project administration. Declaration of competing interest The authors declare no conflict of interest. Acknowledgements The present study was supported by grants from the Shandong Provincial Natural Science Foundation, China (No.ZR2017MH105) and Academic promotion programme of Shandong First Medical University (No.2019QL017). We thank by Xinli Wang for assistance of histologic assessment and Qiuling Zhang of animal experiments. References [1] Reed MD, Dharmage S, Boers A, et al. Ankylosing spondylitis: an Australian
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