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SN Comprehensive Clinical Medicine

, Volume 1, Issue 11, pp 938–943 | Cite as

Prevention of Recurrences in Dupuytren’s Contracture: Are We in the Right Side?

  • Rafael Sanjuan-Cerveró
Surgery
  • 122 Downloads
Part of the following topical collections:
  1. Topical Collection on Surgery

Abstract

Dupuytren contracture is a fibroproliferative disorder affecting the palm of the hand causing a sustained flexion of the fingers due to fibrous cord contracture. Collagenase clostridium histolyticum, as pharmacological treatment, achieves the selective degradation of a portion of the cord, thus enabling the affected finger’s functionality. Our hypothesis is based on a literary review looking for associations based on collagenase for the treatment of the Dupuytren’s disease. Current treatment options for Dupuytren’s are symptomatic and aim at removing part of the affected tissue to restore hand functionality. Recurrence remains the greatest challenge for achieving long-term successful treatment. The association of a hydrogel with the collagenase increases the action time of the latter. The association to a collagenase-hydrogel complex with a third drug (anti-TGFß) acting at the unstructured extracellular matrix in the proliferative phase of the response of wound healing that takes place after the administration of collagenase for direct action on the transformation of fibroblast into myofibroblast, thus resembling as far as possible the actions drugs have on cell cultures. However, in Dupuytren’s contracture, the breakage and degradation of the cord that occur with current treatment make this increase in local action time unnecessary. Combining actual treatment options in Dupuytren’s disease with a hydrogel acting as a vehicle can provide an alternative to destroy the extracellular matrix and act directly against the myofibroblast.

Keywords

Dupuytren’s disease Fibroproliferative Hydrogel Collagenase Extracellular matrix Myofibroblast 

Introduction

Dupuytren’s contracture (DC) is a fibroproliferative disorder affecting the palm of the hand. It is a benign process characterized by the initial appearance of nodes that evolve into fibrous cords which cause a progressive contracture in flexion of the fingers. These cords are made up of collagen types I and III, mainly produced by myofibroblasts. Treatment is based on action on the affected fascia. Currently, the most frequently used treatment is partial fasciectomy (FSC), which consists of the resection of the affected fascia using surgical techniques. Non-surgical or pharmacological treatment with collagenase clostridium histolyticum (CCH) is being used more and more, with mid-term clinical outcomes similar to those after surgery [1] based on the degradation of the cord’s collagen.

However, there is yet no complete cure in sight for DC. Currently, the condition is not curable and it affects not just the area where there is clinical manifestation, but possibly the entire palm [1]. This can be seen, for example, in the occurrence of recurrences that, to a greater or lesser extent, end up affecting most patients. Although various etiological factors play a role, the basic or fundamental etiology of the pathology remains unknown [2]. The factors influencing the development of recurrences even after adequate treatment also remain unclear. Despite the efforts of several groups such as the Dupuytren Foundation [3] to improve early diagnosis, current treatment options aim to alleviate the clinical manifestations of the disease. The methods used produce a gap in the pathological tissue that enables normal mobility of the finger by creating a sort of “firewall” of non-pathological scar tissue with no cord [4].

DC, unlike other fibroproliferative disorders, does not endanger the patient’s life nor is it clinically incapacitating in the initial stages. In fact, many DC patients reject aggressive treatment, particularly in the initial or moderate phases of the disease, because they are still able to perform most of their professional and leisure activities with minimal discomfort. Hence, conservative and minimally invasive options are preferred by these patients [5]. Based on this, pharmacological treatment for DC should meet a series of requirements. Local action is fundamental; the administration of treatment options that have troublesome adverse effects is not workable with benign disease. Adverse events should be local and minor, as much as possible. And the goal should be to greatly reduce or even eliminate recurrences. This is in accordance with the statements by patients who say what they are seeking are treatment options offering low rates of recurrence, complete finger extension, and minimal convalescence [6].

What patients are looking for most is a treatment option that will prevent recurrences. However, many of the proposed options have turned out to be unsuccessful in practice. Our hypothesis is based on the optimal moment of action for the medications used with the objective of preventing recurrences. The possibility of using vehicles for initial treatment with CCH associated with another drug that will act before the development of a recurrent cord is an idea that has not been considered until now, and which might produce good results in the long term (Fig. 1). Moving in this direction requires an analysis of both current problems in the administration of treatment options for DC in order to then assess ways to make improvements and available medications for the application of our hypothesis.
Fig. 1

Combination of an effective drug (anti-TGFβ) with CCH (raspberry icon) inside a matrix (hydrogel) in a empiric purpose to sequential action at ECM (collagen) and myofibroblast levels

Problems with DC Research

Studies on DC use samples of the disease in the nodular phase (cellular) or in the regressive phase (fibrous). But the mechanisms triggering the disease are unknown. A recent study [7] has succeeded in reproducing DC in animal models, but such progress is far from being ready for clinical application.

Regarding in vitro treatment options, many of them take place objectifying the action of a medication on the fibroblasts/myofibroblasts on collagen lattices [8]. The problem presented by these studies is that they completely obviate the rest of the extracellular matrix (ECM) involved in the process. Collagen lattices are optimal for assessing the evolution of isolated cellularity and the effects of factors that are soluble in them [9], but they do not comprise a “real” comparative field for DC. Alterations in the ECM of DC have been observed, for example, in dermatan sulfate [10] or in the increase of biglycan deposits [11]. Spatial reorganization of the ECM is a crucial turning point for fibroblast activity [12]. This is one of the reasons why certain clinical assays (e.g., tamoxifen) did not produce the expected results [13] after in vitro assays provided promising outcomes [14].

Medical Treatment Options

CCH has sparked a revolution in DC treatment [15]. It allows replacing a surgical option with a local and minimally invasive alternative. The application of the mixture of the two collagenases enables collagen degradation until the formation of oligomers, which are easily digested by inflammatory cells in the organism, which “clean” the area [16]. Thus, the inflammatory reaction following the CCH administration is almost constant in all subjects [17]. This degradation and destructuring of the collagen with the CCH and of the rest of the ECM from the inflammation gives us a chance to act during the scarring process, just when normal scarring ceases to be normal and abnormal structuring of the ECM predisposes the formation of CD recurrence.

The end of this first step is collagen degradation. Bromelain [18], with both proteolytic and immunomodulatory activity, could be an alternative to CCH since it theoretically removes the inflammatory problems that CCH presents. Other collagenases, such as those produced by Vibrio algynoliticum [19], could be used, although they should be clinically tested first.

Vehicle

Recently, a patent [20] for a hydrogel that admits CCH, thus extending its effect in the lesion area where it is administered, has been granted. Hydrogel admits approximately 70–80% of CCH, leaving the rest for immediate action. This patent’s design has probably been developed with other objectives rather than DC in mind, such as in action on residual fibrosis secondary to siliconitis [21], where a uniform and progressive degradation of the fibrous capsule is required. In the case of DC, the extension of the medication effect will initially be useless since the objective of breaking the cord is already achieved with the application as currently used.

However, the administration of CCH with a matrix allows us to consider administering it in conjunction with another medication that acts slowly enough to interrupt the new structuring of pathological ECM. The aim of using such a matrix would be the complete disappearance of the vehicle once the action of the transported drugs has ended, allowing for extended delivery of the medication. On the other hand, not reabsorbing the hydrogel would not be harmful. It could both act as a means of transport for the two drugs and as spacer at the lesion, creating a gap in the area where the disease would not reproduce. This last option is not new: Acellular dermal matrix has already been used as a spacer [22].

Another possible option would be introducing both drugs using a biodegradable sponge [23]. Although this method has not been specifically tested for CCH, and it will probably be more difficult to adequate such a method to CCH administration, it offers multiple possibilities, acting in the first step as a hemostatic. This would decrease the inflammatory secondary effects observed with the administration of CCH.

There are several options for CCH vehicles. But multiple problems need to be resolved to accomplish this hypothesis: putting two medications in the vehicle, controlling the action times in order to improve the sequential effect of both drugs, passing the liquid combination of the drugs through the syringe, the polymerization at body temperature within the lesion, and the dose or the total volume of liquid to be injected (CCH injection under current practices inside the CD cord meets great resistance).

Association and Action Time

DC is known to be a disease caused by an alteration in the scarring process, sharing characteristics with scar pathologies such as keloids or hypertrophic scars. Different alterations, both at an intracellular and extracellular level, have been described in patients with DC. As previously indicated, the initial mechanism triggering the whole sequence of processes remains unknown. But the administration of CCH with the selective degradation of collagen and ECM destructuring are ways of restoring the affected area to what it was prior to the pathological tissue creation. The problem lies in assessing at which precise moment to act in order to interrupt the formation of an abnormal collagen deposit without altering the normal scarring process.

In our scheme, the actuation of a second drug could take place at different moments, considering normal scarring times. The basic concept of this idea would be acting in the same way as when isolation methods are used in cell cultures: Collagen digestion allows for leaving the cells “floating” in the destructurated ECM, thus making it possible for the drugs to act directly on them (Fig. 2). In this way, treatments could act just as they do in cell cultures. The most appropriate action time would comprise a period of 3 days to 2 weeks, a time span that covers the proliferative phase of the wound’s healing process [24]. During this phase, different things could be done at different levels:
  • Partial inhibition of fibronectin: Fibronectin acts as a guide for the fibroblasts for the invasion of the wound bed together with the hyaluronic acid. Aya [25] indicates that hyaluronic acid is mitogenic for fibroblasts and is activated by TGFß-1. Thus, the inhibition of any of these two substances will reduce the number of fibroblasts. Furthermore, it should be noted that DC involves a huge quantity of TGFß-1 in an inactive form of the ECM [26] bond to decorin, a proteoglycan. The action of a TGFß inhibitor at this moment could provide good results.

  • Collagen formation: In initial stages of the scarring process, the predominant collagen is type III, which is subsequently replaced by type I, corresponding to the mature forms of the scar. Collagen III predominates in DC. The selective action of a collagenase selectively affecting collagen III from the second week would be a possible solution. Zhang [27] managed to create peptide-conjugated polymeric micelles that contain metalloproteinase (MMP) 2 and 9. Thus, MMP action would be achieved at the specific site and with a time delay. This option would be similar to perpetuating CCH action in a selective way since MMP basically acts as collagenolytic and gelatinolytic agents [28]. However, local MMP action could extend the inflammatory process since it would be stimulated by collagen’s degradation products [16]. Alterations in the ratio of MMP and its inhibitors (TIMP) present in DC [29] should be taken into account.

  • From fibroblast to myofibroblast: The interruption of this process might be the specific moment to prevent the development of recurrences. Myofibroblasts are the characteristic DC cells that cause cord contraction through actin filaments [30]. It has already been described that therapies preventing the contraction of myofibroblasts could prevent the contraction and subsequent continuous remodeling of ECM [31]. Pirfenidone [32] acts at this level, inhibiting the functions mediated by TGFß-1 in the cells. 5-fluorouracil has also been tested in DC at this level, reducing the fibroblast and myofibroblast differentiation ratios and their contractility [33]. In this step, the activation of transformation by TGFß is fundamental.

  • Other options, not specifically tested for DC, could also be considered, such as halofuginone [34], an alkaloid with activity on Smad-3 phosphorylation and anti-fibrotic and anti-inflammatory effects, and Avotermin [35], a selective human recombinant TGFß3 used in the reduction of hypertrophic scars and keloids, as well as several treatment options under investigation for other fibroproliferative disorders.

Fig. 2

Sequence of the process. (A) Schematic representation of the microscopic view of the DC with collagen and myofibroblasts. (B) CCH degrades the collagen leaving the cells “floating” without the ECM “shield”. (C) Direct action of the acting drug at the myofibroblast level and secondary inflammatory process

Discussion

Our hypothesis has already been partially developed. In a clinical assay, the oral administration of tamoxifen controlled the recurrence rate until the end of the treatment [13] after performing the fasciectomy. Other substances have been postulated for DC treatment and they could be successful under these conditions. Among them, we note, especially, relaxin [36], IGF-II [37], anti-TNFα [38], or imiquimod [39].

Anti-TGFß would be the ideal candidate for the concomitant administration of this preparation. The application of TGFß antibodies into the wound healing moment involves the reduction of TGFß native levels, prevents the auto-induction of TGFßmRNA, and limits the infiltration of macrophages and the subsequent release of TGFß [37]. One of the administration paths for these antibodies is in the form of decorin [38]. Anti-TGFß can be administered in different ways: RNA-based technologies, monoclonal antibodies acting at the αvß6 integrin level preventing the activation of latent TGFß, small molecules and drugs that have demonstrated an anti-TGFß effect, such as tramilast, losartan, glitazone, imatinib mesylate, or pirfenidone [40]. Another advantage of acting on the TGFß level is the blockage of the main activation pathways for myofibroblasts since TGFß participates in the signaling pathways of ß-catenin, thrombospondin, protein kinase, or Smad [40]. Blocking these pathways at the cytoplasm or membrane levels would prevent the transformation of fibroblasts into myofibroblasts. Anti-TGFß needs to bind to the matrix for its delayed action. The formation of a lipogel for the skin application of the P144© peptide, similar to biglycan interacting with decorin, has been used in scleroderma models in mice [41, 42]. This could constitute a means of adaptation to the matrix. Another example is the anti-TGFβ2 nanosynthesized together with polyethylenimine forming complexes inside poly(lactide-co-glycolide) microspheres for the post-surgical treatment in glaucoma surgery tested on mice [43].

The proposed current perspectives are various and varied. Apart from the cited drugs, additional examples include selective blockage of cell signaling pathways, genetic therapy at a growth factors level, or the selective action on integrins. This hypothesis needs to be tested first for the effectiveness of CCH-hydrogel association and then with anti-TGFß incorporation. In cases treated with surgery, the preparation could consist of only the vehicle and the associated drug after cord resection. In cases with multiple affected radii, this option would allow for the sequential and progressive treatment of the different radii according to affectation, letting patients program their treatment to minimize the effects on their daily lives.

Under this hypothesis, one of the CCH administration contraindications might disappear: direct administration on the nodules. The concomitant use of imaging techniques, such as echography or MR, already applied in DC, would allow for the objectivation of the incipient nodules’ presence and the administration of the compound to prevent subsequent contractures in the flexion. The application of the CCH-hydrogel-anti-TGFß compound, in this case, would dissolve the ECM and let the anti-TGFß act directly on the fibroblast, preventing its transformation into myofibroblast and therefore, cord development.

Our hypothesis states that the administration of CCH using a vehicle (hydrogel) associated with another pharmacological treatment (anti-TGFß) could prevent recurrence in DC. The destructuration of ECM after collagenolysis with CCH action would let the associated drug act at the moment just prior to new local creation of pathological fibrous tissue and with few adverse events.

Notes

Compliance with Ethical Standards

Conflict of Interest

The author declares that there is no conflict of interest.

Ethical Approval

Not necessary. Review with no patients (no clinical study).

Informed Consent

No patients are included in the study.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Orthopedics and Traumatology SurgeryHospital de DeniaDeniaSpain
  2. 2.University of GranadaGranadaSpain

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