| [L1] - The Effect of Golimumab on Structural Spinal Changes in Ankylosing Spondylitis: Magnetic Resonance Imaging Results of the Randomized, Placebo-Controlled Go-Raise Study.
Juergen Braun, MD1,Xenofon Baraliakos, MD2,Kay-Geert Hermann3,Desiree M Van Der Heijde, MD, PhD,Robert D Inman4,Atul A Deodhar, MD, MRCP5,Anna M Baratelle, BSRT6,Stephen Xu7,Weichun Xu7,Benjamin L Hsu, MD, PhD8. 1Rheumazentrum Ruhrgebiet, Herne,2Rheumatology, Rheumazentrum Ruhrgebiet, Herne, Germany, Bochum,3Charité Hospital, Berlin, Germany,4,5Dept of Medicine/Rheumatology, Toronto Western Hospital, Toronto, ON,6Division of Arthritis & Rheumatology, OR Health & Science University, Portland, OR,7Centocor R&D, Inc., Malvern, United States, Springfield, PA,8Centocor R&D, Inc., Malvern, United States,9Centocor R&D, Inc., Malvern, United States, Wynnewood, PA
Purpose: Despite reducing inflammation, TNF-blockers do not seem to inhibit the progression to syndesmophyte formation and bony fusion in pts with ankylosing spondylitis(AS). One of several hypotheses proposes stepwise pathologic changes in the spine beginning with active inflammation, and then fatty degeneration(FD) before syndesmophyte formation. This implies that TNF-blockers may reduce spinal inflammation without affecting new bone formation. Here we describe the effects of anti-TNF therapy with golimumab(GLM) on structural spinal changes in AS pts who had serial MRI scans as part of GO-RAISE.
Methods: 356 pts with definite AS, BASDAI >4, and back pain score >4 were randomized to SC GLM 50mg, 100mg, or PBO q4wks. Most, but not all of these pts had active spinal MRIs at baseline(BL). At wk16, PBO or GLM 50mg pts with<20% improvement in total back pain and morning stiffness were to enter early escape to GLM 50 and 100mg q4wks, respectively (double-blind). At wk24, pts receiving PBO crossed over to blinded GLM 50mg SC q4wks. At MRI substudy sites, serial spine MRI scans in the sagittal plane were acquired using 1.5T scanners with T1 and short tau inversion recovery (STIR) sequences at BL, wk14, and wk104. Two MRI readers blinded to tx and image order independently evaluated structural changes by MRI using the modified ASspiMRI-c scoring method to assess structural damage using a 0-6 scale (0=normal,no lesions; 1=minor FD; 2=much FD; 3=1-2 syndesmophytes; 4=>2 syndesmophytes, 5=vertebral bridging, 6=vertebral fusion). Of note, “F” denoting FD is added to scores 3-6 when fat is present in each of the 23 vertebral units (VU) (total score, 138). Change from BL to wk14 and 104 were assessed using an ANOVA on van der Waerden normal scores.
Results: Most of the 91 pts in the substudy had structural changes by spinal MRI before tx. Increase in the ASspiMRI-c after 14wks(4 SC injections) was significantly greater in the combined GLM grp vs those in the PBO grp with further increases seen at wk104, when all pts had received ≥18 months of GLM. The increase in the ASspiMRI-c score observed at wk14 in the GLM-tx'd pts was due to the occurrence of more FD in several VUs, whereas there was no apparent shift toward more FD at wk14 in the PBO grp. Percentages of VUs with a ASspiMRI-c score of 0 at BL that shifted to a score of 1-2 at wk14: [Reader #1] 2.5% and 5.0% of PBO-and GLM-tx'd pts, respectively, and [Reader #2] 1.5% and 2.4%, respectively. For VUs that had decreases in MRI activity score from BL to wk14, a greater proportion developed changes corresponding to FD in the GLM tx grps combined vs PBO grp (Table). 
Conclusion: Pts who received GLM showed an increase in modified ASspiMRI-c score in the spine largely due to increases in FD. Our findings support the hypothesis that when active inflammation lessens or is decreased by a TNF blocker, it can convert to focal areas of FD in the vertebral bodies. This may contribute to the relative lack of inhibition of structural damage by TNF-blockers.
| Golimumab对AS脊柱结构改变的作用：随机、安慰剂对照Go-Raise研究的MRI结果 Braun J, et al. ACR 2010. Present No: L1. 目的：尽管TNF拮抗剂能减轻炎症，但不能抑制AS患者的韧带骨赘形成和骨性融合。有假说认为脊柱的病理变化先为活动性炎症，然后脂肪变性（FD），最后形成韧带骨赘。TNF拮抗剂虽然可以减轻脊柱炎症，但不能阻止新骨形成。在此，我们报告GO-RAISE试验中Golimumab（GLM）对AS脊柱结构改变的作用。 方法：356例BASDAI>4、背痛评分>4的AS患者随机使用GLM皮下注射50mg、100mg或安慰剂（PBO），每4周一次。大部分（并非所有）患者在基线期有MRI活动性脊柱病变。在第16周，背痛和晨僵改善<20%的PBO或GLM 50mg组患者分别早期(逃逸)进入GLM 50mg和100mg组（双盲）。在第24周，PBO组患者进入GLM 50mg组。在基线期、第14周和第104周，采用1.5T扫描仪进行脊柱MRI扫描（T1和STIR）。2名阅片者采用修订的ASspiMRI-c评分法，独立、盲态对结构损害进行0-6评分（0=正常，没有病变；1=轻度FD；2=很多FD；3=1-2个韧带骨赘；4=2个以上韧带骨赘；5=脊柱骨桥；6=脊柱融合）。当23个椎体单位（VU）均有脂肪时，可在3-6分后加上F（总分138）。从基线期到第14周和第104周的变化采用van der Waerde正态计分的方差分析。 结果：91例患者中大部分在基线期有结构损害。14周后（注射4次），与PBO组相比，GLM组ASspiMRI-c升高更为显著，第104周升高更为明显（所有患者均使用GLM≥18个月）。第14周GLM组ASspiMRI-c评分升高是因为数个VU出现更多FD，而PBO组没有出现更多FD。1号阅片者认为，基线期ASspiMRI-c评分为0、第14周为1-2的VU百分比在PBO组为2.5%，GLM组为5.0%；2号阅片者认为分别为1.5%和2.4%。对于从基线期到第14周MRI活动度评分下降的VU，GLM组发生FD的比例高于PBO组（见表）。 结论：接受GLM治疗的患者脊柱ASspiMRI-c评分升高的原因主要是因为FD增多。本研究结果支持前述假说，即使用TNF拮抗剂后，椎体的活动性炎症减轻，而转化为灶性FD。这可能是TNF拮抗剂不能阻止结构损害的原因。 |
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