Collagenase clostridium histolyticum: a novel nonoperative treatment for Dupuytren’s disease

Dupuytren’s disease is a progressive disease of the palmar and digital fascial structures of the hand characterized by abnormal collagen deposition, nodular thickening of the palmar aponeurosis and subsequent joint contracture. Contracture occurs primarily at the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joint levels (Figure 1). Although pathologically benign, Dupuytren’s contracture results in sig‐ nificant functional debility of the hand with a strong propensity toward disease progression and recurrence. The incidence of Dupuytren’s disease varies from 2 to 42%, depending on the population under investigation, with a higher incidence found among populations of northern European descent [1]. Inheritance is generally considered to be autosomal dominant with variable pen‐ etrance; however, complex inheritance patterns have been suggested. Disease expression typi‐ cally becomes apparent with advancing age, with men typically demonstrating initial signs of the disease in the 5th decade of life, and women in the 6th. A notable exception to this trend is in patients with a Dupuytren’s diathesis character‐ ized by early onset, typically severe and often bilateral disease. Although Dupuytren’s disease has been for‐ mally recognized and clinically treated for over two centuries, it has only been over the past 30 years that surgeons and scientists have begun to unravel the cellular mechanisms that contrib‐ ute to the development of Dupuytren’s disease. Histopathologic studies have revealed nodular condensations of fibroblasts surrounded by dense collagen within the palmar and digital fascia, and molecular ana lysis reveals a preponderance of type III collagen within the Dupuytren’s cords. Type III collagen is a hallmark of the disease as it is not typically observed within the mature palmar fascia of patients unaffected by Dupuytren’s disease [2,3]. Luck described the pathogenesis of Dupuytren’s contracture in pathologic terms con‐ sisting of proliferative, involutional and residual phases [4]. This description has provided a frame‐ work within which molecular advances may be analyzed as well as a foundation for clinicians’ understanding of disease progression. The pro‐ liferative phase is characterized by nodule forma‐ tion within the palmar fascia and biochemically by increased fibrinolytic activity. At this stage, fibroblasts differentiate into myofibroblasts and comprise the majority of nodular architecture. Myofibroblasts are fibroblastic in origin; however, they contain an actin microfilamentous struc‐ ture analogous to that found in smooth muscle cells. These actin microfilaments are arranged in bundles oriented along the long axis of the cell and communicate with the extracellular matrix fibronectin, thereby allowing transmission of intracellular contractile forces to the extracel‐ lular tissues. Marked nodular thickening and signs of early joint contracture characterize the involutional phase. Throughout the involutional phase, type III collagen is synthesized and the myofibroblasts reorient along the lines of ten‐ sion within the palm. Type III collagen depo‐ sition continues and is gradually replaced with type I collagen throughout the residual phase. Collagenase clostridium histolyticum has demonstrated safety and efficacy in the treatment of metacarpophalangeal and proximal interphalangeal joint contractures in Dupuytren’s disease as a 0.58‐mg dose delivered via direct injection into the Dupuytren’s cord. Extension is achieved via manual manipulation 24 h following injection. Commercially available collagenase clostridium histolyticum is a combination of class I and class II collagenases that act in concert to degrade the type I and type III collagen content of pathologic Dupuytren’s cords and is available to practitioners who have completed focused training in injection technique. This article reviews collagenase clostridium histolyticum pharmacodynamics as well as the basic science and clinical studies resulting in US FDA and EMA approval for the treatment of Dupuytren’s disease. Clinical indications, technique and an ana lysis of future indications are reviewed.