B-Lymphocyte Depletion in Myalgic Encephalopathy/Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment
B-Lymphocyte Depletion in Myalgic Encephalopathy/Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment
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DOI：
10.1371/journal.pone.0129898
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发表时间：
2015-07-01
期刊：
影响因子：
3.7
通讯作者：
Mella, Olav
中科院分区：
文献类型：
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作者：
Fluge, Oystein;Risa, Kristin;Mella, Olav
肌痛性脑病/慢性疲劳综合征（ME/CFS）是一种病因不明的疾病。我们先前报道了一个试点病例系列，随后进行了一项小型，随机，安慰剂对照的II期研究，表明使用单克隆抗CD 20抗体利妥昔单抗进行B细胞耗竭可以在ME/CFS中产生临床获益。（NCT 01156909），29例患者入选接受利妥昔单抗治疗（500 mg/m2）两次输注，间隔两周，随后在3、6、10和15个月后维持利妥昔单抗输注，并随访36个月。结果主要或中度反应，预先定义为自我报告的疲劳评分的持续改善，在29例患者中有18例（意向治疗）。在接受利妥昔单抗维持治疗的28例患者中，有18例（64%）出现临床显著反应。对于这18例患者，14例主要缓解者在156周研究期间的平均缓解持续时间为105周，4例中度缓解者为69周。在随访结束时（36个月），18例缓解患者中有11例仍处于持续临床缓解状态。对于主要应答者，从首次利妥昔单抗输注至开始临床应答的平均滞后时间为23周（范围8-66）。在先前的随机研究中，安慰剂组的9名患者在盐水输注后12个月随访期间没有显著改善，其中6名患者在本研究中利妥昔单抗维持输注后12个月前达到临床应答。两名患者对利妥昔单抗有过敏反应，两名患者发生了无并发症的迟发性中性粒细胞减少症。8例患者在利妥昔单抗输注后出现一次或多次一过性症状发作。有没有意想不到的toxicity.ConclusionIn ME/CFS患者的一个亚组，长期B细胞耗竭与利妥昔单抗维持输注与持续的临床反应。观察到B细胞耗竭和再生后的延迟反应和复发模式，女性的疾病患病率是男性的三倍，以及先前证明的老年ME/CFS患者B细胞淋巴瘤风险增加，表明ME/CFS可能是自身免疫性疾病的变体。
BackgroundMyalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS.MethodsIn this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m(2)) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months.FindingsMajor or moderate responses, predefined as lasting improvements in self-reported Fatigue score, were detected in 18 out of 29 patients (intention to treat). Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment. For these 18 patients, the mean response durations within the 156 weeks study period were 105 weeks in 14 major responders, and 69 weeks in four moderate responders. At end of follow-up (36 months), 11 out of 18 responding patients were still in ongoing clinical remission. For major responders, the mean lag time from first rituximab infusion until start of clinical response was 23 weeks (range 8-66). Among the nine patients from the placebo group in the previous randomized study with no significant improvement during 12 months follow-up after saline infusions, six achieved a clinical response before 12 months after rituximab maintenance infusions in the present study. Two patients had an allergic reaction to rituximab and two had an episode of uncomplicated late-onset neutropenia. Eight patients experienced one or more transient symptom flares after rituximab infusions. There was no unexpected toxicity.ConclusionIn a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed patterns of delayed responses and relapse after B-cell depletion and regeneration, a three times higher disease prevalence in women than in men, and a previously demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease.