初始TNF抑制剂治疗RA失败后宜考虑利妥昔单抗

一项开放前瞻性研究显示，对于初始肿瘤坏死因子(TNF)抑制剂治疗失败的类风湿性关节炎(RA)患者，改用利妥昔单抗可能比改用其他抗TNF药物好得多。

在SWITCH-RA试验中，研究者招募了405例在初始TNF抑制剂治疗无应答或不耐受之后改用抗CD20 B细胞耗竭药物利妥昔单抗(Rituxan)的RA患者，以及323例在同样情况下改用另一种TNF抑制剂的RA患者(Ann. Rheum. Dis. 2014 Jan. 17 [doi:10.1136/annrheumdis-2013-203993])。

6个月后，采用红细胞沉降率计算并校正基线特征和疾病活动性，利妥昔单抗组患者的10分制28关节RA疾病活动度评分(DAS28-3–ESR)平均改善1.5分。

改用第二种TNF抑制剂的患者，DAS28-3–ESR平均改善1.1分(P=0.007)。接受利妥昔单抗治疗的患者在基线时情况更差(平均DAS28-3–ESR评分为5.2分 vs. 4.8分)。研究者未介绍患者改用的第二种TNF抑制剂的名称。

英国利兹大学的Paul Emery医生指出，上述结果“提供了来自真实世界临床实践的证据”，表明患者接受利妥昔单抗而非另一种TNF抑制剂作为二线生物治疗可获得明显更佳的6个月临床应答。

上述结果支持目前美国食品药品管理局(FDA)已批准的利妥昔单抗RA适应证，即与甲氨蝶呤联用于TNF抑制剂应答不佳的成年患者。

在一项亚组分析中，利妥昔单抗仅在用于血清阳性患者时保持其统计边缘，这类患者大约占研究人群的80%。尽管血清阴性患者在6个月时显示出改善，但“在利妥昔单抗组和更换TNF抑制剂组之间无显著差异”。由于血清阴性患者数量较少，该研究没有足够效能去发现较小的差异，但上述结果与“近期研究报告的血清阳性患者对利妥昔单抗临床应答较强”相符合。

在一项二次亚组分析中，利妥昔单抗仅在因初始TNF抑制剂治疗无效而停药的患者中保持统计边缘，而在不能耐受初始TNF抑制剂治疗的患者中则不然。

上述结果的意义在于，当初始TNF抑制剂治疗无效时，患者很可能并未患TNF-α介导性疾病。其效能随时间流逝而减弱，最可能的解释是，患者产生了对该药的抗体。在这两种情况下，改用具有不同作用机制的生物制剂——例如利妥昔单抗——很可能是最佳选择。

该研究的受试者来自欧洲、南美和加拿大。多数受试者为中年女性，有大约8年的RA病史，使用第一种TNF抑制剂大约2年时间。

改用利妥昔单抗组和改用另一种TNF抑制剂组分别有0.7%和0.2%的患者被诊断为肺炎，分别有0.7%和0例患者被诊断为泌尿系感染。改用另一种TNF抑制剂组有1例患者的结核检查结果为阳性，但预防性治疗结果理想。

改用另一种TNF抑制剂组有2例患者被诊断为新发鳞状细胞癌。改用利妥昔单抗组发生了1例前列腺癌和1例原发性巨球蛋白血症。

罗氏公司生产利妥昔单抗并资助第三方撰写了上述结果。Emery医生为罗氏和其他销售RA治疗药物的公司提供咨询或参与其研究。在另外14名研究者中有3名为罗氏公司的雇员，其余研究者多数与罗氏公司有利益关系。

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By: M. ALEXANDER OTTO, Internal Medicine News Digital Network

Rheumatoid arthritis patients who fail initial tumor necrosis factor–inhibitor treatment may do a bit better when switched to rituximab instead of another anti-tumor necrosis factor agent, according to findings from an open-label, prospective study.

In the SWITCH-RA trial, investigators enrolled 405 rheumatoid arthritis (RA) patients who switched to the anti-CD20 B-cell-depleting drug rituximab (Rituxan) after they didn’t respond to or couldn’t tolerate their first tumor necrosis factor inhibitor (TNFi) and 323 RA patients in the same situation who switched instead to a second TNFi (Ann. Rheum. Dis. 2014 Jan. 17 [doi:10.1136/annrheumdis-2013-203993]).

After 6 months, the rituximab group had a mean improvement of –1.5 points on the 10-point and 28-joint RA Disease Activity Score, calculated with erythrocyte sedimentation rate (DAS28-3–ESR), after controlling for baseline characteristics and disease activity.

The group that switched to a second TNFi improved by a mean of –1.1 points (P = .007). The patients who received rituximab were sicker at baseline than those who started a second TNFi (mean DAS28-3–ESR of 5.2 vs. 4.8 points, respectively). The investigators didn’t name the TNFi agents to which patients were switched.

The results "provide evidence from real-world practice" that patients "achieve significantly better clinical responses over 6 months if they receive rituximab rather than an alternative TNF inhibitor as their second biological therapy," said Dr. Paul Emery of the University of Leeds (England) and his associates.

The findings support rituximab’s current Food and Drug Administration RA indication for use with methotrexate in adults who don’t do well on TNF inhibitors.

In a subanalysis of the data, rituximab kept its statistical edge only when used in seropositive subjects, who made up about 80% of the study population. Although seronegative patients showed improvements at 6 months, "there was no significant difference between the rituximab and alternative TNF inhibitor groups." Due to the low number of seronegative patients, the project was "underpowered to detect small differences," but the findings also jibe with "recent studies reporting enhancement of clinical responsiveness to rituximab in seropositive" patients, the investigators said.

In a second subanalysis, rituximab kept its edge only in those who quit initial TNFi therapy because it didn’t work and not in those who couldn’t tolerate it.

That makes sense because, when the first TNFi doesn’t work, it’s probably because patients don’t have TNF-alpha–mediated disease. When its power fades over time, most likely it means that patients have developed antibodies to it. In both situations, a biologic with a different mechanism of action, like rituximab, is probably the best choice, Dr. Emery and his associates said.

Study subjects were from Europe, South America, and Canada. Most were middle-aged women with RA for about 8 years who had been on their first TNFi for about 2 years.

Pneumonia was diagnosed in 0.7% of rituximab and 0.2% of second-TNFi patients. Urinary tract infections were diagnosed in 0.7% of rituximab patients but no second-TNFi patients. One TNFi patient tested positive for tuberculosis but did fine with prophylactic treatment, they noted.

Two TNFi patients were diagnosed with new-onset squamous cell carcinomas. One rituximab patient developed prostate cancer and another Waldenstrom’s macroglobulinemia.

Hoffmann-La Roche makes rituximab and paid a third party to write up the results. Dr. Emery advises and runs studies for Roche and other companies marketing drugs for RA. Three of the other 14 investigators are Roche employees, and most of the rest have financial ties to the company.