新证据: NSAID对AS放射学进展的影响

Sieper J, et al. EULAR 2015. Present ID: OP0145.

背景: 既往有研究显示持续给予NSAID相较于按需给药能在2年间减缓强直性脊柱炎(AS)患者的放射学进展[1]。在另一个前瞻性队列中也观察到类似的效果[2]。

目的: 在本研究中, 我们将试图通过另一个随机对照试验来确认NSAIDs的这一效果。

方法: AS患者被随机分组接受持续给予双氯芬酸(剂量至少为最大剂量即150mg的一半)或按需给予双氯芬酸钠, 治疗2年如果疗效欠佳或不耐受, 患者可转用另一种NSAID。在整个研究期间不允许使用TNF-α拮抗剂。主要观察终点是脊柱放射学进展。放射学评估通过2名对治疗分组和随访点完全不知情的阅片师对脊柱X线摄片进行mSASSS评分。

结果: 持续给药组的85例患者中有62例完成2年观察, 平均年龄42岁, BASDAI均值4.2, CRP均值8.4mg/L, 平均病程12.2年, 74％为男性, mSASSS评分11.3, HLA-B27阳性率为83.5％。按需给药组的82例患者有60例完成观察, 平均年龄44岁, BASDAI均值4.5, CRP 均值12.9mg/L, 平均病程15.2年, 68％为男性, mSASSS评分14.0, HLA-B27阳性率为84％。令人惊讶的是, 与按需组相比, 持续给药组mSASSS进展的数值较高(1.28, 95％CI: 0.68-1.92 vs 0.79, 95％CI: 0.17-1.38; 以上为完成试验者分析所得结果), 尽管这种差异未达统计学显著意义(如图)。如果仅分析基线CRP升高者(持续给药组54％, 按需组58%), 或者基线有韧带骨赘者(持续组55％, 按需组57％), 这两个是放射学进展相关的已知危险因素, 同样又是持续组放射学进展的数值高于按需组(仅分析CRP增高: 1.68 vs 0.83, 仅分析基线有韧带骨赘: 2.1 vs 0.89)。我们 采用ASAS NSAIDs指数(0-100)来量化2年间患者服用的NSAID, 持续给药组为75(均值), 按需组为44(均值)。随访满2年时, 有73％的患者仍在用双氯芬酸, 而并未转换为其它NSAID。

两个治疗组在药物安全性方面没有显著差异。两组各有19例次严重不良事件(SAE)。

结论: 在本研究中, 持续服用以及按需服用双氯芬酸均未能阻止AS患者的脊柱放射学进展。这不太可能是由于样本量偏小所致, 因为我们所发现的按需组放射学进展较少在亚组分析中也呈现较为一致的趋势。由于73％的患者在观察结束时仍在用双氯芬酸, 所以我们不知道是否其它NSAIDs例如如塞来昔布[1]是否对我们的患者的影像学进展有不同的效果。

该图标题: 采用完成试验者分析所得两组的脊柱放射学进展(持续给药组62例, 按需组60例)。纵坐标: mSASSS变化值;横坐标累积概率%; 蓝色实心圆点代表持续给药组, 天青色实心三角代表按需给药组。

原文链接或参见以下信息。

OP0145 Continuous Versus on Demand Treatment of Ankylosing Spondylitis with Diclofenac Over 2 Years Does not Prevent Radiographic Progression of the Spine – Results from a Randomized Prospective Multi-Center Trial (Enradas)

1. J. Sieper¹,
2. J. Listing²,
3. D. Poddubnyy¹,
4. I.-H. Song¹,
5. K.-G. Hermann¹,
6. J. Callhoff²,
7. J. Braun³,
8. M. Rudwaleit¹
9. on behalf of ENRADAS investigators

-Author Affiliations

1. ¹Charité Universitätsmedizin Berlin
   
2. ²German Rheumatism Research Centre, Berlin
3. ³Rheumazentrum Ruhrgebiet, Herne, Germany
   

Objectives In the current study we tested whether such an effect of NSAIDs could be confirmed in another prospective randomized trial.

Methods AS patients were randomized to be treated with either continuous (at least 50% per day of the maximum dose of 150 mg) or on demand diclofenac for 2 years. Switching to another NSAID was possible in case of side effects or inefficacy. TNF-blockers were not allowed during the whole study period. Primary outcome was the difference in radiographic spinal progression measured by the mSASSS, scored by two readers blinded to treatment arm and time point.

Results 62 of 85 patients enrolled in the continuous arm (mean age 42 years, BASDAI 4.2, CRP 8.4 mg/l, disease duration 12.2 y, 74% male, mSASSS 11.3, HLA-B27 positivity 83.5%) and 60 of 82 enrolled in the on demand arm (mean age 44 years, BASDAI 4.5, CRP 12.9 mg/l, disease duration 15.2 y, 68% male, mSASSS 14.0, HLA-B27 84%) completed the study. Surprisingly, the mSASSS progression was numerically higher in the continuous group compared to the on demand group (1.28; 95%CI 0.68-1.92 vs 0.79; 95%CI 0.17-1.38 in the completer population), although this difference was not statistically significant (figure). When only patients were analysed who were CRP positive at baseline (54% cont., 58% demand) or had syndesmophytes at baseline (55% cont., 57% on demand), both known risk factors for radiographic progression, again there was numerically a higher radiographic progression in the continuous vs the on demand group: 1.68 vs 0.83 and 2.1 vs 0.89, respectively. We used the ASAS NSAIDs index (0-100) to quantify NSAIDs intake over the 2 years, which was 75 (mean) for the continuous and 44 (mean) for the on demand group. At the end of year 2, 73% of the patients were still on diclofenac and had not switched to another NSAID.

There were no differences between the 2 treatment groups regarding side effects: 19 serious adverse event (SAEs) occurred in the continuous group vs 19 in the on demand group.

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Conclusions In our study continuous vs on demand treatment with diclofenac over 2 years did not prevent radiographic progression in AS. It is highly unlikely that the results would have been different with a higher number of patients because we found even a trend for less progression in the on demand group. Since 73% of patients were still on diclofenac at the end of the study we do not know whether other NSAIDs such as Celecoxib [1] would have had a different effect on radiographic progression in our patients.

References

1. Wanders et al, Arthritis Rheum 2005;52:1756-65.

2. Poddubnyy et al, Ann Rheum Dis 2012;71:1616-22.

Acknowledgements This study was supported by a grant (FKZ 01KG0801) from the German Ministry for Education and Research. The drug diclofenac was provided by Novartis which did not have any influence on design, conduct or analysis of the study.

Disclosure of Interest None declared