Chapurlat Roland, Gensburger Deborah, Trolliet Cédric, Rouanet Stéphanie, Mehsen-Cetre Nadia, Orcel Philippe
INSERM UMR 1033, Université Claude Bernard-Lyon 1, Hôpital E Herriot, 69437 Lyon cedex 03, France.
INSERM UMR 1033, Université Claude Bernard-Lyon 1, Hôpital E Herriot, 69437 Lyon cedex 03, France.
Bone. 2022 Apr;157:116343. doi: 10.1016/j.bone.2022.116343. Epub 2022 Jan 29.
Increased interleukin-6 (IL-6) has been observed in the bone tissue of fibrous dysplasia of bone/McCune-Albright syndrome (FD/MAS) and is possibly involved in the increased bone destruction and bone pain characterizing this disease. The TOCIDYS trial was a randomized, placebo-controlled, 1 year, cross-over, proof-of-concept trial, conducted in patients not responding to bisphosphonates, using monthly intra-venous tocilizumab (a monoclonal antibody to the IL-6 receptor) at 8 mg/kg or a matching placebo for 6 months. Over the following 6 months, they received tocilizumab if they first had placebo, and vice-versa. We measured change in serum CTX after 6 months of treatment, compared with baseline (primary endpoint). Other endpoints were the change in bone pain, change in P1NP, bone alkaline phosphatase, osteocalcin and ICTP, and variation of quality of life. The analysis relied on ANOVA, with sequence of treatment, period and treatment as factors and accounting for a potential carry-over effect. We have randomized 8 patients with FD/MAS in each sequence who all completed the first 6 months treatment period. During the second 6 months period, 3 patients stopped therapy, so the efficacy analysis set included 13 patients. We observed no significant change in serum CTX and other biochemical markers of bone turnover between the tocilizumab and placebo groups. There was no significant change in the level of bone pain on tocilizumab, although 3 patients had a sharp decrease in pain while on active drug, with progressive relapse on placebo for 2 of them, but with some degree of improvement in a few patients while on placebo. The SF-36 quality of life scale was not significantly changed. We conclude that tocilizumab does not decrease bone turnover in FD/MAS when administered in patients who fail to respond to bisphosphonates. Tocilizumab does not reduce bone pain in most patients, but a substantial effect in a subset cannot be ruled out in this trial powered for markers but not for pain.
在骨纤维发育不良/麦库恩-奥尔布赖特综合征（FD/MAS）的骨组织中已观察到白细胞介素-6（IL-6）水平升高，其可能与该疾病特征性的骨破坏增加和骨痛有关。TOCIDYS试验是一项为期1年的随机、安慰剂对照、交叉概念验证试验，在对双膦酸盐无反应的患者中进行，每月静脉注射8mg/kg的托珠单抗（一种IL-6受体单克隆抗体）或匹配的安慰剂，为期6个月。在接下来的6个月里，如果他们最初接受的是安慰剂，则改为接受托珠单抗，反之亦然。我们测量了治疗6个月后血清CTX相对于基线的变化（主要终点）。其他终点包括骨痛变化、骨特异性I型前胶原氨基端前肽（P1NP）、骨碱性磷酸酶、骨钙素和I型胶原交联羧基末端肽（ICTP）的变化以及生活质量的变化。分析采用方差分析，将治疗顺序、治疗期和治疗作为因素，并考虑潜在的残留效应。我们在每个序列中随机分配了8例FD/MAS患者，他们均完成了前6个月的治疗期。在第二个6个月期间，3例患者停止治疗，因此疗效分析集包括13例患者。我们观察到托珠单抗组和安慰剂组之间血清CTX及其他骨转换生化标志物无显著变化。使用托珠单抗时骨痛水平无显著变化，尽管3例患者在使用活性药物时疼痛急剧减轻，其中2例在使用安慰剂时疼痛逐渐复发，但也有少数患者在使用安慰剂时疼痛有一定程度改善。SF-36生活质量量表无显著变化。我们得出结论，在对双膦酸盐无反应的患者中使用托珠单抗时，其不会降低FD/MAS患者的骨转换。托珠单抗在大多数患者中不会减轻骨痛，但在这项以标志物而非疼痛为指标的试验中，不能排除在一部分患者中有显著效果。
