Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
J Am Acad Dermatol. 2012 Mar;66(3):e89-96. doi: 10.1016/j.jaad.2010.11.033. Epub 2011 May 14.
In a multicenter clinical trial in North America and Europe that tested the cathepsin K (catK) inhibitor balicatib for the treatment of osteoporosis, several patients developed hardening of the skin.
We sought to characterize these observed adverse events.
Patients with skin hardening were examined by a local dermatologist. All of those patients except one had at least one biopsy specimen taken from affected skin, which was read by local and two central dermatopathologists. Workup was directed for consideration of systemic scleroderma.
Nine patients of 709 treated with balicatib developed skin hardening and were given a diagnosis of morphea-like skin changes. No such events were observed in patients taking placebo or the lowest balicatib dose. After discontinuation of balicatib, skin changes resolved completely in 8 and partially in one patient.
Each patient was seen by a different dermatologist in 6 different countries.
These observations are likely dose-related adverse effects of balicatib. Although catK was originally thought to be expressed only in osteoclasts, it has more recently also been found in lung and dermal fibroblasts and been implicated in the degradation of the extracellular matrix in the lung and the skin. It is therefore plausible that the observed dermal fibrosis in balicatib-treated patients is a result of impaired degradation of extracellular matrix proteins and may represent a class effect of catK inhibitors. We recommend that further exploration of catK inhibition for the treatment of osteoporosis or cancer should include monitoring for similar adverse effects.
在一项针对北美和欧洲的多中心临床试验中，测试了组织蛋白酶 K（catK）抑制剂巴利昔替尼治疗骨质疏松症，一些患者出现了皮肤硬化。
我们试图描述这些观察到的不良事件。
由当地皮肤科医生对有皮肤硬化的患者进行检查。除 1 名患者外，所有患者均至少从受影响的皮肤取 1 个活检标本，由当地和 2 个中心皮肤科病理学家进行解读。检查方向是考虑系统性硬皮病。
709 名接受巴利昔替尼治疗的患者中有 9 名出现皮肤硬化，并被诊断为硬皮病样皮肤改变。服用安慰剂或最低剂量巴利昔替尼的患者均未观察到此类事件。停用巴利昔替尼后，8 名患者的皮肤改变完全缓解，1 名患者部分缓解。
每位患者均在 6 个不同国家由不同的皮肤科医生进行检查。
这些观察结果可能是巴利昔替尼的剂量相关不良事件。虽然最初认为 catK 仅在破骨细胞中表达，但最近也在肺和真皮成纤维细胞中发现了它，并与肺和皮肤中细胞外基质的降解有关。因此，巴利昔替尼治疗患者的皮肤纤维化可能是细胞外基质蛋白降解受损的结果，可能代表 catK 抑制剂的一类作用。我们建议，进一步探索 catK 抑制治疗骨质疏松症或癌症时，应包括监测类似的不良事件。
