Explore the vast range of titles available.

IntroductionDupuytren’s contracture (DC) is a chronic fibroproliferative disorder of the palmar fascia which leads to flexion contracture in one or more fingers. There is no definitive cure for DC, and treatment aims at relieving symptoms by releasing the contracture using percutaneous or operative techniques.Methods and analysisWe planned a prospective, randomised, controlled, outcome assessor-blinded, three-armed parallel 1:1:1, multicentre trial comparing the effectiveness and cost of (1) collagenase clostridium histolyticum injection followed by limited fasciectomy in non-responsive cases, (2) percutaneous needle fasciotomy followed by limited fasciectomy in non-responsive cases and (3) primary limited fasciectomy during short-term and long-term follow-up for Tubiana I–III stages DC. We will recruit participants from seven national centres in Finland. Primary outcome is the rate of success in the treatment arm at 5 years after recruitment. Success is a composite outcome comprising (1) at least 50% contracture release from the date of recruitment and (2) participants in a patient-accepted symptom state (PASS). Secondary outcomes are (1) angle of contracture, (2) quick disabilities of the arm, a shoulder and hand outcome measure (QuickDASH), (3) perceived hand function, (4) EQ-5D-3L, (5) rate of major adverse events, (6) patient’s trust of the treatment, (7) global rating, (8) rate of PASS, (9) rate of minimal clinically important improvement, (10) expenses, (11) progression of disease, (12) progression-free survival, (13) favoured treatment modality, (14) patients achieving full contracture release and >50% improvement and (15) patient satisfaction with the treatment effect. Predictive factors for achieving the PASS will also be analysed.Ethics and disseminationThe protocol was approved by the Tampere University Hospital Institutional Review Board and Finnish Medicine Agency. The study will be performed according to the principles of good clinical practice. The results of the trial will be disseminated as published articles in peer-reviewed journals.Trial registration number NCT03192020; Pre-results.

While Dupuytren's disease can cause disabling contractures requiring open surgery, a less-invasive option using Clostridium Histolyticum collagenase (CHC) via percutaneous injection was recently reported. A recent prospective, randomized trial demonstrated few complications during 90 days follow-up, however did not assess any longer term follow-up for these patients. Long-term outcomes in this setting have not been adequately reported, and the current manuscript aims to identify late complications from the clinical use of percutaneous CHC. The current manuscript reports an extended 12-month follow-up for a cohort of twelve of patients enrolled in the original prospective, randomized trial, treated at a single institution. An analysis of complications requiring surgical intervention was undertaken. Two of twelve patients reported debilitating pain and triggering requiring surgical intervention. Extensive deep-tissue scarring and adhesions were identified, providing the first visual and qualitative analysis of the pathologic effects of CHC. Late complications from CHC use can and have occurred, outside the follow-up period of the initial phase III trials. Longer term follow-up of such patients is thus essential, and further investigation and characterization of the late effects of CHC use is warranted.

Dupuytren’s disease (DD) is a chronic fibroproliferative disorder of the palmar fascia, leading to disabling digital contractures and high recurrence after surgery. This narrative review highlights DD as a multifactorial condition in which genetic predisposition and cytogenetic instability converge with extracellular matrix remodeling, aberrant transforming growth factor β (TGF-β) and Wnt/β-catenin signaling, cytoskeletal stabilization and immune-inflammatory amplification. Epigenetic dysregulation further locks fibroblasts into a persistent myofibroblast state. Discrepancies between studies are largely explained by disease stage and experimental anti-inflammatory, antifibrotic and epigenetic strategies to achieve durable disease modification.

One of the major determinants of Dupyutren disease (DD) treatment efficacy is recurrence of the contracture. Unfortunately, lack of agreement in the literature on what constitutes recurrence makes it nearly impossible to compare the multiple treatments alternatives available today. The aim of this study is to bring an unbiased pool of experts to agree upon what would be considered a recurrence of DD after treatment; and from that consensus establish a much-needed definition for DD recurrence. To reach an expert consensus on the definition of recurrence we used the Delphi method and invited 43 Dupuytren's research and treatment experts from 10 countries to participate by answering a series of questionnaire rounds. After each round the answers were analyzed and the experts received a feedback report with another questionnaire round to further hone in of the definition. We defined consensus when at least 70% of the experts agreed on a topic. Twenty-one experts agreed to participate in this study. After four consensus rounds, we agreed that DD recurrence should be defined as \"more than 20 degrees of contracture recurrence in any treated joint at one year post-treatment compared to six weeks post-treatment\". In addition, \"recurrence should be reported individually for every treated joint\" and afterwards measurements should be repeated and reported yearly. This study provides the most comprehensive to date definition of what should be considered recurrence of DD. These standardized criteria should allow us to better evaluate the many treatment alternatives.

Fibrotic disorders are some of the most devastating and poorly treated conditions in developed nations, yet effective therapeutics are not identified for many of them. A major barrier for the identification of targets and successful clinical translation is a limited understanding of the human fibrotic microenvironment. Here, we construct a stromal cell atlas of human fibrosis at single cell resolution from patients with Dupuytren’s disease, a localized fibrotic condition of the hand. A molecular taxonomy of the fibrotic milieu characterises functionally distinct stromal cell types and states, including a subset of immune regulatory ICAM1 + fibroblasts. In developing fibrosis, myofibroblasts exist along an activation continuum of phenotypically distinct populations. We also show that the tetraspanin CD82 regulates cell cycle progression and can be used as a cell surface marker of myofibroblasts. These findings have important implications for targeting core pathogenic drivers of human fibrosis. New anti-fibrotics aided by a better understanding of fibrotic cell subsets and their functions are needed. Here the authors perform single-cell RNA-seq and CyTOF on nodules from patients with Dupuytren’s disease to map subsets and the state of mesenchymal cells during pathogenic fibrogenesis.

Fibrosis is characterized by excessive matrix protein accumulation and contributes to significant morbidity and mortality in the Western world. The relative lack of effective antifibrotic therapeutics for the majority of these conditions reflects the difficulty in identifying targets for human fibrosis. Animal models fail to recapitulate all of the facets of human disease, and the limited clinical samples from patients with fibrosis of visceral organs are usually of late-stage disease [J. Nanchahal, B. Hinz, Proc. Natl. Acad. Sci. U.S.A. 113, 7291–7293 (2016)]. Here, we use Dupuytren’s disease (DD), a localized fibrotic condition of the hand, as a model to profile the vasculature niche of human fibrosis at single-cell resolution. Our spatially resolved molecular taxonomy of fibrotic blood vessels identifies distinct endothelial and pericyte populations and demonstrates a complex topological organization in the fibrotic microenvironment. In developing fibrosis, we show that the endothelium acts to promote immune regulatory fibroblast phenotype through platelet-derived growth factor (PDGF) signaling, thereby sustaining an immune cell–enriched perivascular niche. Moreover, we highlight pericytes as “housing” a putative myofibroblast precursor in DD. Overall, our results elucidate a tightly coupled vasculature niche in fibrosis that instructs the differentiation of functionally distinct stromal cells. These findings provide an important translational resource and highlight the therapeutic potential of targeting blood vessel signaling in human fibrosis.

Dupuytren's disease is a very common progressive fibrosis of the palm leading to flexion deformities of the digits that impair hand function. The cell responsible for development of the disease is the myofibroblast. There is currently no treatment for early disease or for preventing recurrence following surgical excision of affected tissue in advanced disease. Therefore, we sought to unravel the signaling pathways leading to the development of myofibroblasts in Dupuytren's disease. We characterized the cells present in Dupuytren's tissue and found significant numbers of immune cells, including classically activated macrophages. High levels of proinflammatory cytokines were also detected in tissue from Dupuytren's patients. We compared the effects of these cytokines on contraction and profibrotic signaling pathways in fibroblasts from the palmar and nonpalmar dermis of Dupuytren's patients and palmar fibroblasts from non-Dupuytren's patients. Exogenous addition of TNF, but not other cytokines, including IL-6 and IL-1β, promoted differentiation into specifically of palmar dermal fibroblasts from Dupuytren's patients in to myofibroblasts. We also demonstrated that TNF acts via the Wnt signaling pathway to drive contraction and profibrotic signaling in these cells. Finally, we examined the effects of targeted cytokine inhibition. Neutralizing antibodies to TNF inhibited the contractile activity of myofibroblasts derived from Dupuytren's patients, reduced their expression of α-smooth muscle actin, and mediated disassembly of the contractile apparatus. Therefore, we showed that localized inflammation in Dupuytren's disease contributes to the development and progression of this fibroproliferative disorder and identified TNF as a therapeutic target to down-regulate myofibroblast differentiation and activity.

Dupuytren’s contracture belongs to a group of fibrotic diseases that have similar mechanisms but lack effective treatment and prevention options. The excessive accumulation of connective tissue in Dupuytren’s disease leads to palmar fibrosis that results in contracture deformities. The present study aimed to investigate how the tissue microenvironment in Dupuytren’s contracture affects the phenotypic differentiation of macrophages, which leads to an inflammatory response and the development of chronicity in fibrotic disease. We utilized a decellularization-based method combined with proteomic analysis to identify shifts in extracellular matrix composition and the surrounding tissue microenvironment. We found that the expression of several matricellular proteins, such as MFAP4, EFEMP1 (fibulin-3), and ANGPTL2, was elevated in Dupuytren’s tissue. We show that, in response to the changes in the extracellular matrix of Dupuytren’s contracture, macrophages regulate the fibrotic process by cytokine production, promote myofibroblast differentiation, and increase the fibroblast migration rate. Moreover, we found that the extracellular matrix of Dupuytren’s contracture directly supports the macrophage-to-myofibroblast transition, which could be another contributor to Dupuytren’s disease pathogenesis. Our results suggest that interactions between macrophages and the extracellular matrix should be considered as targets for novel fibrotic disease treatment and prevention strategies in the future.

Abstract Palmar and plantar fibromatosis are benign proliferative processes which present as a diffuse thickening or nodules of the hands and/or feet and may lead to flexion contractures, pain, and functional impairment known as Dupuytren and Ledderhose diseases, respectively. Current treatments are noncurative and associated with significant morbidity. Here, we report on the outcomes of 5 patients with advanced disease, no longer surgical candidates, treated with sorafenib. Sorafenib exhibited an expected safety profile. All 5 patients demonstrated objective responses as evaluated by a decrease in tumor size and/or tumor cellularity from baseline and all 5 patients reported subjective pain relief and/or functional improvement. Mechanistically, immunohistochemistry revealed patchy positivity for PDGFRβ, a known target of sorafenib. The outcomes of these 5 patients suggest the safety and efficacy of a relatively well-tolerated oral agent in the treatment of Dupuytren and Ledderhose diseases and suggest the need for future controlled studies. Palmar and plantar fibromatosis are benign proliferative processes that present as a diffuse thickening or nodules of the hands and/or feet and may lead to Dupuytren or Ledderhose disease. This article describes outcomes of five patients with advanced disease who were treated with sorafenib.

Dupuytren’s disease, a chronic and progressive fibroproliferative lesion of the hand, which affects the palmar fascia, has a recurrence rate after selective aponeurotomy of 20–40% at 5 years. This study focused, for the first time, on the microanatomical and histopathological characteristics of the longitudinal and vertical fibres (usually spared during surgery) in the aponeurosis with Dupuytren’s disease, in different stages of the Tubiana’s classification. Twelve human samples were collected and analysed by immunostaining, Total Collagen Assay, ELISA Immunoassay, and immunoblotting for the Von Willebrand factor, α-Sma, D2-40, CD-68, Total Collagen, Collagen-I and III, IL1β, TNF-α to analyse the blood and lymphatic vascularization, the amount and distribution of collagen, and the inflammation. The results show a progressive increase in the arterial vascularization in the vertical fibres (from 8.8/mm2 in the early stage to 21.4/mm2 in stage 3/4), and a parallel progressive decrease in the lymphatic drainage (from 6.2/mm2 to 2.8/mm2), correlated with a local inflammatory context (increase in IL-1β and TNF-α until the stage 2) in both the longitudinal and vertical fibres. The acute inflammation after stage 2 decreased, in favour of a fibrotic action, with the clear synthesis of new collagen (up to ~83 µg/mg), especially Collagen-I. These results clearly demonstrate the involvement of the septa of Legueu and Juvara in the disease pathology and the modifications with the disease’s progression. A greater understanding of the pathology becomes fundamental for staging and the adequate therapeutic timing, to obtain the best morpho-functional result and the lowest risk of complications.