Abstract

INTRODUCTION

Dupuytren’s disease is a benign connective tissue disorder affecting the palmar fascia; it limits hand function and may disable the hand (Figure 1). It was first described by Felix Plater, a Swiss physician, in 1614 and later (1831) attributed to a French physician, Guillaume Dupuytren ¹ , ² , ³.

Figure 1. A patient with a right small finger metacarpophalangeal and proximal interphalangeal joint contracture.

Dupuytren’s Disease leads to progressive hand contractures: mediated by myofibroblasts, pathologic cords form and lead to progressive flexion deformity of the fingers, involving the metacarpophalangeal and proximal interphalangeal joint (Figures 2, 3, 4); deformity may become severe enough to interfere with daily living activities, cause embarrassment and consequently an impact on work abilities and quality of life ⁴ , ⁵ , ⁶.

Figure 2. Treatment by excision of involved skin and fascia.

Figure 3. Follow-up (1 month).

Figure 4. Follow-up (3 months).

Surgery is the mainstay of treatment and is recommended in patients with functional impairment and metacarpophalangeal-joint contractures of at least 30 degrees; however it is invasive, potentially involves a long recovery period and does not offer a definitive cure ⁷ , ⁸ , ⁹ , ¹⁰.

Various nonsurgical treatments (radiotherapy, physical therapy, topical vitamin A and E application, steroid injections, anti-gout medications, interferon-gamma, enzymatic treatments with trypsin, hyaluronidase, lidocaine) have been evaluated for Dupuytren’s Disease treatment; however were generally found to be ineffective or unsuitable for clinical use ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶.

Abnormal synthesis of collagen leading to impaired joint function is the main problem of Dupuytren disease ¹⁷. Collagen as a target of treatment through collagenases is emerging as a nonsurgical treatment for Dupuytren’s contracture. A Clostridium histolyticum collagenase is injected into the affected cord without preliminary local anesthesia; the next day, the treated joint is manipulated to attempt cord rupture. Extensive hand therapy after treatment is not required ¹⁸ , ¹⁹ , ²⁰ , ²¹. The aim of this study is to extend the clinical use of the clostridial collagenase injection as a nonsurgical therapy to fracture Dupuytren’s cords.

PATIENTS AND METHODS

Four patients, in good health, were enrolled in our study; average age was 67 years (patient 1: 72 years old, patient 2: 71 years old, patient 3: 54 years old, patient 4: 72 years old). They presented Dupuytren’s contracture of the metacarpophalangeal joint between 20° and 40°, or of the proximal interphalangeal joint between 20°and 40° in at least one digit.

Everyone of them provided written informed consent.

Exclusion criteria: breast-feeding or pregnancy, bleeding disorder, previous treatment of the primary joint within 90 days before the beginning of the study, the use of an anticoagulant within 7 days before the beginning of the study, the use of a tetracycline derivative within 14 days before the beginning of the study.

Patient 1 presented on the ring finger of the right hand flexion deformity of the metacarpophalangeal and proximal interphalangeal joints of 20° (Figures 5 and 6).

Figure 5. Right ring finger metacarpophalangeal joint contracture of 20°.

Figure 6. Absence of contracture after collagenase injection.

Patient 2 presented on the ring finger of the right and hand flexion deformity of the metacarpophalphalangeal joint of 20°.

Patient 3 presented for 6 months on his right hand thickening and retraction of palmar aponeurosis of 30° with nodules at the head of the ring finger. The disease was responsible of hypoeshesia and mild impairment in grip movements.

Patient 4 presented on his right hand thickening and retraction of palmar aponeurosis of 20° at the head of the ring finger.

Subjects received collagenase injection at a single dose of 10,000 U (Units).

Constitution and application were carried out according to the manufacture’s guidelines: we reconstituted collagenases in sterile diluent. Collagenases were supplied in single use glass vials containing 0.9 mg of sterile, lyophilized powder. Steps for reconstitution were carried out using aseptic technique with sterile alcohol; each vial was reconstituted with 2 mM calcium chloride in 0.9% sodium chloride USP. The reconstitution was done using different amounts of sterile diluents: 0.39 ml for cords contracting the metacarpophalangeal joint and 0.31 ml for cords contracting the proximal interphalangeal joint.

The cords to be treated were confirmed and the areas to inject were marked to prevent misapplications. The diluents were injected into the collagenase-vials and into the placebo-vial; then the vials were agitated.

Injection volumes were different depending on which joint to be treated was contracting: 0.25 ml of the solution was withdrawn using a syringe for cord contracting the metacarpophalangeal joint; 0.20 ml for cord contracting the proximal interphalangeal joint.

Before initiating treatment, the investigators identified a primary joint for treatment in each patient; secondary and tertiary joints were also identified for possible subsequent injections.

At the injection site, skin was prepared witha suitable antiseptic.

The injection was done in a point where cord was not intimately adherent to the skin, to facilitate proper administration and decrease the risk of skin tearing during the finger extension procedure.

After injection procedure, a dressing was placed over the treated hand for one day; patients were instructed to limit the motion and refrain from use of the injected hand; they were advised not to flex or extend the fingers of the injected hand, to reduce extravasation of collagenase out of the cord.

Safety assessments included monitoring vital signs and collecting blood and urine samples for immunologic measurements and routine clinical laboratory tests: patients were observed for a period of 30 minutes for potential adverse reactions or systemic hypersensitivity.

Patients were also instructed to return the following day for the passive finger extension procedure: joints were manipulated with the use of a standardized procedure in an effort to fracture the cord.

A treatment cycle comprised injection, after 24 h manipulation followed by 30-day follow-up.

Angles of extension and flexion were measured during screening, during each treatment cycle and during the follow-up visit. Also grip strength was assessed using a dynamometer during screening visit, before injection, after injection and during the follow-up visit.

RESULTS

All patients entering the trial completed the study and entered the open-label extension.

Clinical success was achieved in all of them, with a single injection of the study drug: the trial showed an initial response to injection results in reduction of joint contracture to within 0°-5° of normal in 90% of patients. Subjects were monitored for adverse response to injection, including lymphadenopathy, allergic reactions and tendon rupture. No arterial, nerve or tendon injuries were reported. There were no reports of loss of sensation, no infections and no skin grafts. Grip strength and flexion were not affected.

Complications of treatment included pain with injection and manipulation, edema and ecchymosis, injection-site swelling, itching, skin laceration. Most treatment-related adverse effects were mild or moderate in intensity and resolved without treatment over several weeks.

No patient had a recurrence of a successfully treated joint during the time of the study.

DISCUSSION

Dupuytren’s contracture can result in hand deformity and impaired function; It results from the interplay between genetic predisposition, environmental factors, local and global protein expression; it’s more common among Caucasians of Northern European and most frequently affects the ring and little fingers, followed in order of frequency by thumb, middle and index finger; occurs more often in men that in women but sex difference in prevalence diminishes with increasing age. Age, sex, ethnicity, family history and environmental factors as alcohol consumption, smoking and manual labor have been implicated in the disease. Epilepsy, diabetes mellitus, HIV infection and cancer are associated with Dupuytren’s disease ²² , ²³ , ²⁴ , ²⁵.

In this disorder genes regulating the natural breakdown of collagen are inhibited and genes promoting structural development of collagen in the epidermis are upregulated ²⁶ , ²⁷.

Recent evidences demonstrate that PDGF and TGF-beta are growth factors associated with myofibrobast proliferation ²⁸, and that metalloproteinases (in particular Gelatinase a), have effect on cell adhesion and proliferation ²⁹ , ³⁰ , ³¹;

The initial stage of the disease is characterized by the appearance of small nodular thickenings composed of myofibroblasts. Nodules over time evolve toward hypocellular bands of collagen-rich cords. The growing nodules and the arrangement of newly formatted fibers entail tissue reorganization coupled with degradation of the surrounding ECM. Patients with Dupuytren disease have also a higher rate of recurrent ectopic disease, for example Lederhose disease (plantarfibromatosis) or Peyronie disease (penile fibromatosis) ³² , ³³.

Surgery is currently the most employed treatment for Dupuytren’s disease ³⁴, but recover can be long as a result of complications, such as tendon rupture, digital nerve injury, digital artery injury and infection, hematomas, skin lesions, wound dehiscence, skin necrosis, edema, cold intolerance, pain, reflex sympathetic dystrophy, and requires postoperative hand therapy. Many patients cannot undergo surgery because of advanced age, a coexisting condition, or both. Recurrence has been reported to occur (from 26 to 80 %): it is seen more commonly in patients with early disease onset, a passive family history, rapid disease progression and distal disease. Because recurrence is high, most multiple corrective surgeries are often required ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰.

Noncollagenase enzymatic fasciotomies with preparations including trypsin, hyaluronidase, and lidocaine were attempted, with limited success ⁴¹. Dupuytren’s disease may also be corrected with less-invasive procedures such as percutaneous needle aponeurotomy. Unfortunately, published data on its efficacy and safety are limited ⁴². A retrospective review was performed for patients with Dupuytren’s disease treated with percutaneous needle fasciotomy or collagenase: in the short term both percutaneous needle fasciotomy and collagenase have similar clinical outcomes and patient satisfaction ⁴³. Various nonsurgical treatments have been evaluated without an effective clinical success, including radiotherapy, physical therapy, topical vitamin A and E application, anti-gout medications and interferon-gamma ⁴⁴ , ⁴⁵ , ⁴⁶.

Steroids have shown promising results but have not been widely used as a nonsurgical treatment modality: steroids injections in Dupuytren’s nodules resulted in modification of disease progression; however, 50% patients experienced disease reactivation in 1 to 3 years ⁴⁷. In a randomized, controlled study, a series of Triamcinolone acetonide injections were combined with percutaneous needle aponeurotomy in patients with Dupuytren’s contracture: it resulted in a significantly higher degree of correction; however this study provides a short-term evidence ⁴⁸.

A recent evidence demonstrates that Dupuytren contracture of the proximal interphalangeal joint can be reversed by an extension torque transmitted from an external device, the Digit Widget, by skeletal pins to the middle phalanx; it gradually seems to restore the length to soft tissues palmar to the proximal interphalangeal joint’s axis of rotation ⁴⁹.

Collagenase emerged as a possible agent for enzymatic fasciotomy in 1996 and offered a potential advantage over nonspecific degradative enzymes by targeting collagen. Collagenase Clostridium histolyticum is composed of two collagenases: AUX-1 and AUX-2; the two collagenases work to cleave the collagen chains and disrupt the collagen cords that cause Dupuytren’s contracture.

In vitro biochemical testing has demonstrated a 93% decrease in the tensile strenght of Dupuytren’s cords injected with collagenases ⁵⁰.

In our study excessive collagen deposition in Dupuytren’s disease has been targeted by a nonoperative method using enzyme injection therapy to lyse and fracture finger cords causing metacarpophalangeal and/or proximal interphalangeal joint contractures. Collagenase-treated joints had a reduction of 50% in contracture from baseline to 30 days after injection and showed improvement in range of motion; treatment with collagenases safely and effectively restored normal finger extension in all patients. No hand therapy was required after treatment with collagenases. Little reductions of contracture were observed in placebo-treated patient: possibly performing finger flexion and extension could have improved the range of motion of placebo-treated cords.

Clearly neither surgical excision of the diseased cords nor enzymatic fasciotomy offers a definitive cure: some patients with metacarpophalangeal and proximal interphalangeal joint contractures will recur with passage of time; however the prospect of reinjection for recurrence is much less troublesome to patients than the prospect of having to undergo additional surgery ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶.

A recent study analysed 2 groups of patients with Dupuytren’s contracture in the same stage of disease. Patients in the first group underwent partial fasciectomy, whereas patients in the second group were treated by injection of collagenase. Side effects like numbness, impaired blood circulation and pain were less after injection of collagenase than after partial fasciectomy. Recovery of grip strength was faster in the collagenase group than after partial fasciectomy and collagenase injection was regarded as less discomforting. Patient satisfaction was higher after collagenase injection due to subjectively perceived less negative impact and a comparable functional outcome ⁵⁷.

Collagenase offers a potential advantage over nonspecific degradative enzymes by targeting collagen, and presents the potential advantages of early return of hand function and avoidance of potential surgical complications, restoring the normal finger extension in the majority of patients ⁵⁸ , ⁵⁹ , ⁶⁰ , ⁶¹ , ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸ , ⁶⁹ , ⁷⁰; however, it is not without risk of complications. Some evidences report a few cases of flexon tendon ruptures and complex regional pain syndrome ⁷¹.

Compared with the well-known postoperative effects of surgery, the adverse effects of collagenase injection are of minor frequency because Clostridium histolyticum collagenase is nerve and vessel sparing, while dissolving contracture and even scar for recurrent cases. Surgery for recurrent Dupuytren contracture carries a high risk of nerve complications, infection, stiffness, and the risk of circulatory compromise and amputation ⁷².

Comparison between surgical approach and collagenases

Limited fasciectomy is used to remove areas of palmar fascia affected by the disease, leaving the other areas. It represents the most frequent type of intervention. The incision must allow an exposition of all the operative field, it mustn’t determinate longitudinal scars, it must allow at the end of the intervention the extension of the fingers. It is possible to do different incisions that differ in relation to the type of intervention that the surgeon wants to do. The incision of Skoog is one of the most used. For the suture are generally used non-resorbable 4/0 or 5/0 monofilament. The incisions on the fingers are generally closed with Z multiple plastics in order to avoid the formation of longitudinal contracting scars, that could reproduce the flexion deformity. A moderately compressive bandage is placed at the center of the palm to exert the pressure at the point where it is most needed. The operated fingers are fixed on a splint in extension while the other fingers are left free. If a drainage has been introduced, the dressing should be carried out after 24 hours, otherwise after 7 days. The compression bandage should be kept in the subsequent dressings until the eighth-ninth day. The stitches are removed after about 10 days; the patient will undergo an intense period of re-education that promotes active and passive absorption of post-operative edema ⁷³. Complications of surgical management include digital nerve injury, infection, ischemia, hematoma, stiffness, skin loss and wound-healing problems. Patients may also suffer from pain and vasomotor disorders. Pain syndroms such as Dupuytren’s “flare” and complex regional pain syndrome can be present in people with aggressive or early disease ⁷⁴ , ⁷⁵ (Table 1).

Use of the open palm technique has minimized the risk of these complications and is advocated by many surgeons as the procedure of choice ⁷⁶.

Collagenases represent a safe and reliable treatment alternative to surgery for Dupuytren’s contracture. The use of collagenases is followed by common adverse events such as bruising, pain, swelling. Major complications rarely occur.

Flexon tendon rupture is a serious adverse event. The overall incidence of tendon rupture reported is around 0.5%. Other rare sequelas after collagenases injection are skin laceration and complex regional pain syndrome. These serious adverse events occurred in less than 1% of patients treated with collagenases ⁷⁷.

This study supports a role for collagenase injection in the treatment of Dupuytren’s disease even for mild cases: collagenase is the first nonsurgical, office-based treatment option for Dupuytren’s disease with proven efficacy and safety. Patient satisfaction and physician ratings of improvement after treatment with collagenase are very high ⁷⁸ , ⁷⁹ , ⁸⁰ , ⁸¹ , ⁸² , ⁸³ , ⁸⁴ , ⁸⁵ , ⁸⁶ , ⁸⁷ , ⁸⁸ , ⁸⁹ , ⁹⁰ showing that collagenase can be considered a cost-effective treatment ⁹¹ , ⁹² , ⁹³ , ⁹⁴.

CONCLUSIONS

Long term efficacy and safety of collagenase Clostridium histolyticum has been evaluated after the third year of a 5-year nontreatment follow-up study: the absence of long-term adverse events, recurrences or disease progression 3 years after the initial treatment indicates that collagease Clostridium histolyticum is an effective and safe treatment for Dupuytren’s contracture ⁹⁵.

However, additional long-term studies are needed to establish the effectiveness and recurrence rate with the collagenase treatment, in comparison with palmar fasciectomy and needle aponeurectomy.

In conclusion, this study shows that a disease treatment and block of progression in patients treated with collagenases is possible. The result is probably due to the weakening of the diseased cord, obtained with collagenase followed by its fracture and by the digit extension procedure.

ACKONOWLEDGEMENTS

We thank Pfizer Italia srl for providing the product we have used. The study had on 13.06.2012 the Ethics Committee approval on protocol 1067.

This study was approved as a compassionate use study.

The following protocol for compassionate use was also sent to AIFA.

CONFLICT OF INTEREST

The Authors declare that there are no conflicts of interest.

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