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Corresponding author: Alex G. Lambi, MD, PhD, Department of Orthopedics & Rehabilitation, University of New Mexico School of Medicine, MSC08 4720 1 UNM, Albuquerque, NM 87131.
Department of Orthopaedic Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PADepartment of Biomedical Education and Data Science, Lewis Katz School of Medicine at Temple University, Philadelphia, PA
Department of Biomedical Education and Data Science, Lewis Katz School of Medicine at Temple University, Philadelphia, PACenter for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA
Dupuytren disease is a benign, progressive fibroproliferative disorder of the hands. To date, only one pharmacotherapy (clostridial collagenase) has been approved for use in Dupuytren disease. There is a great need for additional nonsurgical methods that can be used to either avoid the risks of invasive treatments or help minimize recurrence rates following treatment. A number of nonsurgical modalities have been discussed in the past and continue to appear in discussions among hand surgeons, despite highly variable and often poor or no long-term clinical data. This article reviews many of the pharmacotherapies discussed in the treatment of Dupuytren disease and novel therapies used in inflammation and fibrosis that offer potential treatment options.
Our understanding of the mechanisms behind fibroproliferative disorders continues to expand. As a result, newer potential pharmacotherapies in treating diseases such as idiopathic pulmonary fibrosis, scleroderma, Peyronie disease, and Dupuytren disease (DD) are being identified. There has also been renewed interest in repurposing medications already approved by the US Food and Drug Administration (FDA) for the treatment of fibrotic disorders.
Despite this, the mainstay of treatment for patients with DD is largely surgical. The two most common nonsurgical treatments are local collagenase injections, for enzymatic degradation, and local corticosteroid injections, to reduce inflammatory processes. There is a need for additional pharmacotherapeutic options that are directed toward halting early disease progression or following treatment to prevent recurrence.
The purpose of this article is to provide a summary of currently used and potential new pharmacotherapies in DD. A brief description of the pathophysiology, key signaling cascades, and natural history of the disease are included to set the stage for the need for additional nonsurgical treatments. This article covers many of the medications that have been considered for a repurposed use in DD over the years. Several newer monoclonal antibodies already in use are discussed for their potential antifibrotic and anti-inflammatory role.
Natural History
The typical patient presenting for symptomatic DD demonstrates contracture of the ulnar digits of the hand, with the long and ring fingers most often affected. The Hueston table-top test, considered positive when a patient can no longer place their hand and fingers flat on a table, can serve as an indication for intervention. Specific degrees of flexion contraction of 30° at the MCP joint and 15° at the PIP joint also serve as thresholds for the provision of an intervention.
As contractures progress, impairment of hand function ensues, with 53° of MCP joint contracture and 77° of PIP joint contracture indicative of critical impairments in hand function.
Current interventional strategies include fasciectomy, percutaneous needle fasciotomy (PNF), and enzymatic digestion. Fasciectomy techniques, including limited fasciectomy and dermatofasciectomy, remain the gold standard, since they have demonstrated high clinical efficacy and low recurrence rates.
Nevertheless, because of their high complication rate as a consequence of their invasiveness, attention has been paid to minimally invasive techniques, such as PNF and enzymatic digestion.
Pathophysiology
DD is a benign fibroproliferative disorder that affects the palmar fascia of the hand and digits. Its clinical course can involve progressive and symptomatic contractures of the hand and digits, leading to decreased hand function and diminishing quality of life.
Stage I, the proliferative phase, is classically characterized by nodule formation within the palmar fascia as well as increased fibroblast activity. Myofibroblasts comprise the majority of cells in the nodule in this phase. Stage II, the involutional phase, is noted by marked nodular thickening and an increase in underlying type III collagen synthesis that becomes oriented along the lines of tension within the palm. Early joint contracture can be seen during this phase. Stage III, the residual phase, is characterized by a large disappearance of myofibroblasts and the replacement of type III collagen with type I collagen (Fig. 1).
Figure 1Pathophysiology of Dupuytren contracture. Dupuytren disease progression exists on histologic, cellular, and clinical levels. Resting tissue of the unaffected hand contains quiescent fibroblasts. Upon tissue injury or stress, fibroblasts are activated, proliferate, and differentiate into mature myofibroblasts (proliferative stage). With continued TGF-β stimulation and Dupuytren risk factors, disease progresses. Nodule formation occurs as myofibroblasts differentiate and produce extracellular matrix (ECM), with collagen III:I ratio predominating (Involutional stage). The ECM collagen ratio changes to I:III, increased collagen crosslinking occurs, and cellularity decreases as cords form and contraction ensues (residual stage). TGF, transforming growth factor.
Disease progression varies between individuals and can be influenced by established risk factors, such as alcohol intake, smoking, manual labor, diabetes, anticonvulsant drugs, metabolic factors, and genetic predisposition.
Despite significant research, the underlying genesis of DD has not been clearly elucidated. DD nodules are thought to originate from or near the palmar fascia via mechanisms that include trauma to the palmar fascia, altered immune responses, and/or the presence of oxygen-free radicals.
Additionally, the amount and composition of subcutaneous palmar fat may play a role in the progression and recurrence of DD, as lower levels of subcutaneous fat tissue have been noted in individuals with DD.
Although the specific mechanisms and triggers for DD development are still yet to be fully elucidated, it is well established that the cell type responsible for DD progression is the myofibroblast. Derived from fibroblasts, the myofibroblast is characterized by the co-expression of high levels of α-smooth muscle actin (α-SMA) and platelet-derived growth factor (PDGF).
The clinical contractures seen in DD most likely occur on a cellular level through a contractile apparatus of the myofibroblast containing bundles of actin microfilaments and associated contractile proteins (eg, nonmuscle myosin). Intracellular actin bundles terminate on the myofibroblast surface in the fibronexus, an adhesion complex that incorporates transmembrane integrin proteins to link the actin with extracellular matrix proteins, such as fibronectin fibrils, and adjacent myofibroblasts.
In vivo co-distribution of fibronectin and actin fibers in granulation tissue: immunofluorescence and electron microscope studies of the fibronexus at the myofibroblast surface.
Extensive research has been performed to better understand the modulators of fibroblasts and myofibroblasts in DD development. Transforming growth factor-β (TGF-β) signaling has been highlighted as critical in DD development.
Concurrent inhibition of TGF-beta and mitogen driven signaling cascades in Dupuytren’s disease - non-surgical treatment strategies from a signaling point of view.
Its specific role in myofibroblast function, DD progression, and potential in treatment is discussed below.
Transforming Growth Factor-Signaling In Dupuytren Disease Development
Transforming growth factor-β has been implicated in DD development and progression. Three mammalian isoforms of TGF-β exist: TGF-β1, TGF-β2, and TGF-β3. All 3 isoforms have been identified in DD disease nodules, palmar fascia, and cord tissue.
TGF beta and bFGF synthesis and localization in Dupuytren’s disease (nodular palmar fibromatosis) relative to cellular activity, myofibroblast phenotype and oncofetal variants of fibronectin.
TGF-β signaling is upregulated in DD and has been shown to be expressed in fibroblasts and myofibroblasts in all 3 histologic stages of DD progression.
TGF beta and bFGF synthesis and localization in Dupuytren’s disease (nodular palmar fibromatosis) relative to cellular activity, myofibroblast phenotype and oncofetal variants of fibronectin.
The different characteristics of Dupuytren’s disease fibroblasts derived from either nodule or cord: expression of alpha-smooth muscle actin and the response to stimulation by TGF-beta1.
In fibroblasts derived from either DD affected or unaffected tissues, TGF-β upregulates α-SMA expression and induces differentiation of a quiescent fibroblast to a contracting myofibroblast.
The different characteristics of Dupuytren’s disease fibroblasts derived from either nodule or cord: expression of alpha-smooth muscle actin and the response to stimulation by TGF-beta1.
Furthermore, when TGF-β signaling is blocked in DD cells in vitro, a dose-dependent decrease in contractility with concomitant decreases in α-SMA and Col1 gene expression and α-SMA protein level are seen.
Therefore, the ability to block the profibrotic effects of TGF-β signaling in DD is an area ripe for research and clinical potential. Several therapeutic options discussed later in this article target the TGF-β pathway.
Challenges In Studying New Therapies In Dupuytren Disease
To date no single, reliable animal model has been created to study the pathophysiology of DD or the disease response to therapeutics. As a result, researchers have had to rely on a few ways to study the potential efficacy of therapeutics. The first is through in vitro studies using fibroblasts isolated from Dupuytren nodules or cords in comparison to fascia overlying the carpal tunnel or the transverse carpal ligament.
Key limitations to this approach include the fact that the palmar fascia overlying the carpal tunnel is rarely involved in DD, and the transverse carpal ligament never.
Fibroblasts from phenotypically normal palmar fascia exhibit molecular profiles highly similar to fibroblasts from active disease in Dupuytren’s contracture.
Furthermore, because of the paucity of cells isolated from tissue, many experiments expand their cell population through passage 5 prior to performing experiments. However, prior work has shown that by this passage the phenotypes and normal human dermal fibroblasts and mature myofibroblasts tend to converge.
The other challenge in studying DD at the clinical level is our reliance on only clinical findings to measure therapeutic efficacy. A noninvasive test to measure the therapeutic effect on Dupuytren tissues in real time is sorely needed. Imaging modalities for monitoring other fibrotic disorders, chiefly idiopathic pulmonary fibrosis, are well described.
Challenges in pulmonary fibrosis. 1: Use of high resolution CT scanning of the lung for the evaluation of patients with idiopathic interstitial pneumonias.
Noninvasive tests that could be used to study DD are being investigated for other musculoskeletal fibroses. These include modalities such as nuclear magnetic resonance, to assess thickened tissue layers, and ultrasound shear-wave elastography, to assess tissue stiffness.
Current Pharmacotherapies Used In Dupuytren Disease Treatment
Enzymatic digestion with collagenase
To date, the only approved pharmacologic therapy that has shown sustained efficacy in treating DD is clostridial collagenase. The underlying mechanism by which Clostridium histolyticum collagenases produce their effect is through the degradation of the collagen found in DD contracture. In 2010, the US FDA approved C. histolyticum for injectable use under the name Xiaflex (Auxilium Pharmaceuticals, Inc.).
Xiaflex constitutes 2 purified collagenases (AUX-I and AUX-II) that preferentially degrade collagen types I and III found in DD cords, while sparing collagen types IV and VI that are predominant in vascular basement membranes and perineurium.
Treatment takes place over 2 stages, with the first including injection of the diseased DD cord and the second consisting of cord rupture via manual manipulation. Success has been seen in the treatment of MCP and PIP joint contracture, with higher success rates seen in reducing contracture of MCP joints (to within 5° of full extension) than for PIP joints. However, limited data exist for the use of collagenase in early DD as the safety and efficacy data included in the original submission to the FDA for approval were for flexion deformities >20°, in either MCP or PIP joints.
Published recurrence rates following collagenase treatment vary widely, with the most cited rate as 35% when defined as a worsening of previously treated contracture >20°.
With respect to recurrence rates, enzymatic treatment performs similarly to PNF when used in PIP joints and potentially outperforms PNF when used in MCP joints.
Injectable collagenase versus percutaneous needle fasciotomy for Dupuytren contracture in proximal interphalangeal joints: A randomized controlled trial.
To our knowledge, no clinical studies have been performed examining the effect of triamcinolone as part of treatment with collagenase. It has been shown that short-term improvements in flexion deformity occur when triamcinolone injection is used in combination with PNF.
However, long-term studies are needed to examine whether these effects result in significant long-term recurrence reduction.
Repurposed Pharmacotherapies Proposed For Dupuytren Disease
To date, several other pharmacotherapies have been proposed for off-label use in treating DD (Table 1). None have demonstrated either decreased severity or recurrence in long-term clinical trials.
N-acetyl-L-cysteine suppresses TGF-beta signaling at distinct molecular steps: the biochemical and biological efficacy of a multifunctional, antifibrotic drug.
N-acetyl-L-cysteine suppresses TGF-beta signaling at distinct molecular steps: the biochemical and biological efficacy of a multifunctional, antifibrotic drug.
Inhibition of TGF-beta induced lung fibroblast to myofibroblast conversion by phosphodiesterase inhibiting drugs and activators of soluble guanylyl cyclase.
Inhibition of TGF-beta induced lung fibroblast to myofibroblast conversion by phosphodiesterase inhibiting drugs and activators of soluble guanylyl cyclase.
High-dosage tamoxifen as neoadjuvant treatment in minimally invasive surgery for Dupuytren disease in patients with a strong predisposition toward fibrosis: a randomized controlled trial.
High-dosage tamoxifen as neoadjuvant treatment in minimally invasive surgery for Dupuytren disease in patients with a strong predisposition toward fibrosis: a randomized controlled trial.
Multiple classes of anti-inflammatory and antimitotic medications, in addition to corticosteroids, have been proposed for DD. The nonsteroidal anti-inflammatory (NSAID) celecoxib is being investigated for a role in patients with a high risk of recurrence, while naproxen may have a benefit in reducing postoperative swelling following fasciectomy in patients with DD, although data thus far have been limited and not shown to effect a significant clinical difference.
However, no further studies appear in the literature to expand this work. 5-Fluorouracil (5-FU) demonstrated inhibitory effects on Dupuytren myofibroblasts in vitro,
Systemic colchicine has been reported to improve the severity of penile contractures in Peyronie disease, although without improving concomitant DD contractures.
The anti-oxidants vitamin E and N-acetyl-L-cysteine (NAC) have been investigated for potential roles in DD owing to their ability to abrogate fibrogenesis in vitro.
N-acetyl-L-cysteine suppresses TGF-beta signaling at distinct molecular steps: the biochemical and biological efficacy of a multifunctional, antifibrotic drug.
Various antihypertensive and vasoactive medications have been described for DD. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists were proposed owing to their effect in decreasing fibrotic responses in vitro and in animal models.
Calcium-channel blockers (eg, verapamil) have been described owing to potential effects on myofibroblast-mediated contracture and the potential to decrease scarring in patients with burns.
Phosphodiesterase inhibitors (eg, sildenafil) have been proposed as they improve fibrosis via plaque development in animal models with Peyronie disease, another localized fibrotic process.
Inhibition of TGF-beta induced lung fibroblast to myofibroblast conversion by phosphodiesterase inhibiting drugs and activators of soluble guanylyl cyclase.
Nitric oxide donors (eg, molsidomine) decrease lung fibrosis and Peyronie disease progression in animal models, likely due to the inhibitory effect nitric oxide has on myofibroblast differentiation and function.
It also results in short-term improvements in patients with DD undergoing limited fasciectomy. However, the gain is lost by two years after treatment and the side effect profile was poorly tolerated.
High-dosage tamoxifen as neoadjuvant treatment in minimally invasive surgery for Dupuytren disease in patients with a strong predisposition toward fibrosis: a randomized controlled trial.
While these results were shown using fibroblasts isolated from samples of patients with DD, no clinical trials demonstrating an effect of metformin in DD have been performed.
Currently Approved Therapies Targeting Inflammation And Fibrosis
Several pharmacotherapies with current approval for their anti-inflammatory or antifibrotic effects are under investigation for use in DD (Table 2). The rationale for their use and results to date are discussed below.
Table 2Currently Approved Pharmacotherapies in Fibrosis and Inflammation
Medication
Basic Mechanism of Drug
Proposed Mechanism in DD
In Vitro Results in DD model
In Vivo Results in Patients with DD
Ref.
TNF inhibitors (eg, adalimumab)
•
Monoclonal antibody targeting and inactivating TNF-α
•
Decrease TNF-driven fibroblast differentiation and contraction
Study protocol: A multi-centre, double blind, randomised, placebo-controlled, parallel group, phase II trial (RIDD) to determine the efficacy of intra-nodular injection of anti-TNF to control disease progression in early Dupuytren’s disease, with an embedded dose response study.
Study protocol: A multi-centre, double blind, randomised, placebo-controlled, parallel group, phase II trial (RIDD) to determine the efficacy of intra-nodular injection of anti-TNF to control disease progression in early Dupuytren’s disease, with an embedded dose response study.
Tumor necrosis factor (TNF) is known to play a role in the development and maintenance of the myofibroblast phenotype in DD nodules (Table 2). This has been demonstrated in vitro where the addition of TNF, but not other known proinflammatory cytokines (interleukin [IL]-6 and IL-1β), to fibroblasts from samples of patients with DD promoted their differentiation into myofibroblasts.
TNF blockade has been performed on DD cells in vitro using the FDA-approved anti-TNF agents, adalimumab and golimumab. Both agents effectively inhibit myofibroblast contraction.
These studies have since been corroborated in a proof-of-concept clinical trial. TNF blockade was performed by injection of adalimumab into DD nodules, followed by surgical excision and evaluation. Nodules demonstrated down regulation of the myofibroblast phenotype.
Study protocol: A multi-centre, double blind, randomised, placebo-controlled, parallel group, phase II trial (RIDD) to determine the efficacy of intra-nodular injection of anti-TNF to control disease progression in early Dupuytren’s disease, with an embedded dose response study.
Further studies are necessary to assess the long-term utility of TNF blockade in the treatment of DD.
Nintedanib
Nintedanib is one of the two currently used treatments for idiopathic pulmonary fibrosis. Approved for use in the United States in 2014, and in Europe in 2015, Nintedanib is a tyrosine kinase inhibitor with known effects on signaling receptors involved in fibrogenesis, chiefly vascular endothelial growth factor, fibroblast growth factor (FGF), and PDGF.
Concurrent inhibition of TGF-beta and mitogen driven signaling cascades in Dupuytren’s disease - non-surgical treatment strategies from a signaling point of view.
which as discussed earlier, plays a role in DD development. Yet, no studies examining the use of Nintedanib for DD have been performed to date. It could be a potential target in DD. However, since Nintedanib does not directly affect TGF-β-mediated fibrogenesis, it may ultimately have limited clinical utility.
Pirfenidone
Pirfenidone (PFD; 5-methyl-1-phenyl-2(1H)-pyridone) is the second most used treatment for idiopathic pulmonary fibrosis. Approved for use in Europe in 2011 and in the United States in 2014, PFD has an inhibitory effect on TGF-β production and TGF-β-mediated fibroblast function and differentiation.
PFD has been tested in DD fibroblasts in vitro and shown to abrogate TGF-β effects including fibroblast proliferation, myofibroblast development, and matrix formation.
It is worth mentioning two additional therapies currently used in cancer and inflammation, and with proposed effects in fibrosis–tocilizumab and rituximab. Tocilizumab is a monoclonal antibody targeting the IL-6 receptor and preventing the binding of IL-6. Although not currently approved for the treatment of fibrosis, it has been suggested based on the known effect of IL-6 on myofibroblast development.
Despite the upregulation of IL-6 in cells from DD tissue, neither the addition of IL-6 nor its blockade has shown significant effects on DD cells in vitro.
Rituximab is a monoclonal antibody targeting the B-cell surface protein CD20, leading to downregulation of B-cell differentiation and antibody formation.
a definitive link with CD20-positive cells has not been made.
Conclusion
Dupuytren disease remains a challenging clinical entity to treat. While historically accepted and proven therapies such as fasciectomy procedures demonstrate good efficacy of treatment, their risk profile has led to a search for minimally invasive techniques. Enzymatic digestion and treatment with collagenase have become a staple in DD treatment for over a decade. Despite the addition and broad acceptance of this pharmacotherapy, there is a need of a primary (or adjuvant) therapy modality that can either stop progression in the 30% to 50% of patients in early stages at risk or prevent disease recurrence following treatment.
As fibroproliferation underscores the etiology of DD, it is important to take an antifibrogenic approach to find new pharmacotherapies. This review highlights the pathophysiologic basis of the fibrotic response seen in DD, chiefly through TGF-β signaling. The 2 most used pharmacotherapies in DD today, collagenase for enzymatic digestion of diseased cords as well as corticosteroids for the anti-inflammatory effects, are described. For the sake of providing historical background, many of the medications that have been discussed in articles over years for a repurposed use in DD are covered. Lastly, the article presents several medications with current approval for anti-inflammatory or antifibrotic effects that either are being used or may be considered for use in DD.
Acknowledgments
All authors contributed to the preparation of the manuscript, including design and figure preparation. This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Grant 5R01AR056019-13 to senior author (MFB). Figure 1 was created with BioRender.com.
In vivo co-distribution of fibronectin and actin fibers in granulation tissue: immunofluorescence and electron microscope studies of the fibronexus at the myofibroblast surface.
Concurrent inhibition of TGF-beta and mitogen driven signaling cascades in Dupuytren’s disease - non-surgical treatment strategies from a signaling point of view.
TGF beta and bFGF synthesis and localization in Dupuytren’s disease (nodular palmar fibromatosis) relative to cellular activity, myofibroblast phenotype and oncofetal variants of fibronectin.
The different characteristics of Dupuytren’s disease fibroblasts derived from either nodule or cord: expression of alpha-smooth muscle actin and the response to stimulation by TGF-beta1.
Fibroblasts from phenotypically normal palmar fascia exhibit molecular profiles highly similar to fibroblasts from active disease in Dupuytren’s contracture.
Challenges in pulmonary fibrosis. 1: Use of high resolution CT scanning of the lung for the evaluation of patients with idiopathic interstitial pneumonias.
Injectable collagenase versus percutaneous needle fasciotomy for Dupuytren contracture in proximal interphalangeal joints: A randomized controlled trial.
N-acetyl-L-cysteine suppresses TGF-beta signaling at distinct molecular steps: the biochemical and biological efficacy of a multifunctional, antifibrotic drug.
Inhibition of TGF-beta induced lung fibroblast to myofibroblast conversion by phosphodiesterase inhibiting drugs and activators of soluble guanylyl cyclase.
High-dosage tamoxifen as neoadjuvant treatment in minimally invasive surgery for Dupuytren disease in patients with a strong predisposition toward fibrosis: a randomized controlled trial.
Study protocol: A multi-centre, double blind, randomised, placebo-controlled, parallel group, phase II trial (RIDD) to determine the efficacy of intra-nodular injection of anti-TNF to control disease progression in early Dupuytren’s disease, with an embedded dose response study.
Dr. Benhaim is a speaker for Endo Pharmaceuticals. No benefits in any form have been received or will be received related directly or indirectly to the subject of this article. All remaining authors of this journal-based CME activity have no relevant conflicts of interest to disclose.
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