Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib - 18/02/12
, Silvano Adami, MD b, Claude-Laurent Benhamou, MD c, Edward Czerwiński, MD d, Jordi Farrerons, MD e, David L. Kendler, MD f, Linda Mindeholm, MD g, Giuseppe Realdi, MD h, Christian Roux, MD i, Vanessa Smith, MD j
Reprint requests: Thomas M. Rünger, MD, Department of Dermatology, Boston University School of Medicine, 609 Albany St, Boston, MA 02118.Abstract |
Background |
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.
Objective |
We sought to characterize these observed adverse events.
Methods |
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.
Results |
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.
Limitations |
Each patient was seen by a different dermatologist in 6 different countries.
Conclusions |
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.
Le texte complet de cet article est disponible en PDF.Key words : balicatib, cathepsin K, collagen degradation, drug-induced morphea, osteoporosis treatment, scleroderma
Abbreviations used : ANA, catK, ECM
Plan
| The osteoporosis and osteoarthritis trials with balicatib were funded by Novartis Pharma AG, which also financed one publication meeting to prepare this report on the cutaneous adverse events of morphea-like skin reactions. |
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| Disclosure: Dr Rünger served on the independent data safety monitoring board that monitored the clinical trial in which the described observations were made. For that service, he received compensation from Novartis Pharma AG. Dr Kendler reports consultancies with honoraria for Merck, Eli Lilly, Novartis, Servier, and Amgen. He received grants from Merck, Eli Lilly, Novartis, Servier, Amgen, GSK, Pfizer, Wyeth, Roch, Biosante, Johnson & Johnson, and Proctor & Gamble. He has served on advisory boards for Merck, Eli Lilly, Novartis, Servier, and Amgen. Dr Mindeholm is an employee of Novartis Pharma AG. Dr Roux reports honoraria from Novartis and MSD and served on advisory boards for Novartis, MSD, Sanofi, Servier, Roche, Amgen, and Eli Lilly. All authors, except Drs Rünger and Mindeholm, were clinical investigators in the described clinical trial. |
Vol 66 - N° 3
P. e89-e96 - mars 2012 Retour au numéro
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