Sophie D. Curie, MBA

Introduction: Dupuytren’s disease (DD) is an irreversible progressive fibroproliferative disorder of the hand manifesting as function-limiting nodules and cords surrounding phalangeal tendons, primarily affecting older males of northern European descent.¹ DD fibrosis is characterized histologically by mesenchymal cells, immune cells, and ECM proteins and is treated by chemical or mechanical degradation, or in severe cases, complete tissue excision. All available treatment options have high 5-yr recurrence rates.^2,3 While previously postulated that fibroblasts (FB) and myofibroblasts (mFB) are involved in the development of DD, their exact contribution is not known.⁴ The current understanding of DD etiology is not well-defined, but a number of recent studies have shown increasing evidence of a genetic and immunological origin triggered by continuous long-term exposure to stimuli such as vibration.³      Methods: A literature review was conducted to gauge current understanding of patho-mechanics underlying Dupuytren’s disease. Once determined, this proto-pathway was cross-referenced with normal wound healing as well as patho-mechanisms underlying other fibrotic diseases to further resolve the proposed role of implicated chemokines and cytokines. Components of the predicted development pathway of DD suggested that anti-inflammatory drugs may be used off-label for prevention and treatment of DD and a query into supporting data was conducted. Results: Early histologic analysis of late-stage cords revealed relatively acellular material primarily composed of type III collagen secreted by mFBs activated from FBs.⁴ Layton et al.⁵ conducted a cellular census of diseased patient tissue and found that fibroblasts enriched in immune pathways (IL-6, IL-8, CXCL14, C1R, PLA2G2A) were predominant in early-stage proliferation, while myofibroblasts enriched in contractile pathways (ACTA2, TPM2, POSTN) were found in late-stage proliferation. The presence of these immune chemokines suggests FBs play an important role in a feedback mechanism which ultimately upregulates fibrosis, corresponding to dysregulation of the normal wound healing process.^6,7 Previous studies also found upregulation of chemokines TGF-β^8-10 and TNF-α,^11,12 both of which could induce the FB-to-mFB conversion. Although canonically considered to play opposing roles in the matrix remodeling process, TNF-α has been shown to promote TGF-β expression in diseases such as pulmonary fibrosis.¹³ Ex vivo investigations into TGF-β^8-10 and TNF-α^11,12 inhibitors have yielded positive results, with anti-TNF-α adalimumab in phase 2b clinical trials for hindering progression of early disease. Conclusions: The immunogenic basis for Dupuytren’s disease warrants a re-investigation into current treatment options. Drug intervention in early disease and postoperative anti-inflammatory adjunct in late disease could provide curative treatment for patients suffering from Dupuytren’s disease.

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