gms | German Medical Science

Dupuytren’s contracture is a benign disease of the connective tissue, leading to a disruption in fibrocyte proliferation. The resulting fibromatosis of the palmar fascia produces a progressive flexion contracture of the affected finger. This is generally not accompanied by any pain, although, aside from the aesthetics, the functional capability of the hand is naturally also limited.

Although Dupuytren’s contracture has been known since the 12^th century, knowledge of its etiology as well as the therapeutic options available is still limited [1].

Aside from genetic components, environmental factors also appear to have an effect on the formation of a Dupuytren’s contracture. Being male and of Caucasian ancestry are high-risk factors [2]. The prevalence in men is five times higher than in women. In the presence of diabetes mellitus, nicotine abuse or heavy alcohol consumption, the lifetime risk of developing Dupuytren’s contracture also increases [3], [4], [5].

Despite intensive research, the treatment options currently available are often not satisfactory for the affected patients or their treating physicians. Surgical therapy continues to be the gold standard [6]. There are few promising alternatives whereby percutaneous needle fasciotomy is often used as a minimally invasive procedure [7], [8]. The risk of recurrence remains present even with optimal treatment results.

Since the year 2011, there is an additional treatment option in the form of the “Xiapex^®” (Pfizer, Germany) injection, a bacterial collagenase. This collagenase, extracted from clostridium histolyticum, is used to break down the affected connective tissue cords and, at the same time, to inhibit fibrocyte proliferation [9], [10]. The collagenases AUX-I and AUX-II act on the collagen subtypes that predominate in the diseased Dupuytren’s cord (mostly type I and III collagens) [11].

The Xiapex^® injection is given into the affected connective tissue cord at the level of the MCP or the PIP joint. After a reaction time of 24 hours, the cord can be manually broken up. Up to 2 cords or 2 affected joints in the same hand can be treated at a time. The injection must be done by a physician appropriately trained in the correct administration of the product and experienced in the diagnosis and management of Dupuytren’s disease [11].

Aside from local reactions (redness, swelling, pain), the main risks of the Xiapex^® treatment also include the incidence of severe systematic reactions such as anaphylaxis.

The costs for a single Xiapex^® cord treatment are approx. 1,698.27 Euros plus 313.68 Euros for doctor’s fees. For almost all patients, the treatment costs were covered by the health insurance. If not the patients paid for the treatment.

Xiapex^® is approved in Germany both for Dupuytren’s contractures with a palpable cord as well as for Peyronie’s disease of adult men with a palpable plaque and a curvature deformity of at least 30 degrees [12].

The objective of this study is to examine the effectiveness and long-term success of a collagenase treatment on Dupuytren’s contractures.

Our prospective intervention study included a sample group of 19 patients with Dupuytren’s contracture, who received a collagenase treatment between December 2011 and June 2014. Among the patients, a total of 24 injections were applied to 22 different single cords (n=22) (Table 1 [Tab. 1]). Here, the injection (i) of Xiapex^® was given at the level of the MCP joint in 17 cases and at the level of the PIP joint in 7 cases. We injected 0.25 ml solution with 0.58 mg Xiapex^® around the MCP joint and 0.2 ml solution with 0.58 mg Xiapex^® around the PIP joint. This was done according to the manufacturer.

In one female patient, two different cords were treated with Xiapex^® at the levels of the MCP and PIP joints, and two other patients received treatment for two different cords each.

All injections were done by a plastic surgeon, but not by the same one.

In all study patients, break-up of the cord occurred 24 hours after the injection.

In order to evaluate the range of movement, the mobility of the affected finger was measured using the neutral zero method. This measurement was conducted pre-injection, one month post-injection, and also one year post-injection. We examined the active range of motion for each patient. In order to evaluate the general hand function, the Michigan Hand Outcomes Questionnaire (MHQ) was additionally assessed in 16 patients both pre-injection as well as one year post-injection.

The WHO-5 Score was used as a measure of individual patient satisfaction and of quality of life, and the EQ-5D VAS Score was used to assess the general state of health. Both scores were determined before and one year after treatment.

Of the 19 patients in our sample group, 16 patients (≈84.2%) benefitted from the treatment with Xiapex^® in terms of improvement of the overall mobility of the treated cords (see Figure 1 [Fig. 1] and Figure 2 [Fig. 2]).

In one patient (≈5.3%), mobility did not improve at all, and in only two patients (≈10.5%) the extent of movement had worsened by the follow-up exam one year later. Overall, with the collagenase treatment it was possible to increase the average range of movement of the treated finger by 26.1°, whereby the overall improvement in the range of movement was calculated as the sum of the increases in the range of movement in the MCP (≈Ø 21.8°) and in the PIP (≈Ø 4.3°) joint.

A separate examination of the MCP and PIP joints, regardless of the level at which the injection was given yielded the following results:

The range of movement in the MCP joint improved in 77.3% of the treated cords through treatment with Xiapex^®.

The average range of movement in the MCP joint pre-injection was (0-28-78), and post-injection it was (0-9-81). On average, it was possible to improve the range of movement in the MCP joint by 21.8° (range –40–80°; σ=31.9).

In the PIP joint, only minor improvement in the average range of movement could be achieved using Xiapex^®. Here, mobility was (0-27-93) pre-injection and (0-24-95) post-injection according to the neutral zero method. Out of the 2 treated cords, the range of movement in the PIP joint increased in eight cords (≈36.4%). In six cords (≈27.3%), the range of movement in the PIP joint did not change at all, and in eight cords (≈36,4%), a limitation in mobility was experienced during the course of the year. Overall, the range of movement in the PIP joint increased by only Ø 4.3° (range –70–60°; σ=27) after treatment with Xiapex^®.

The average range of motion („ROM“) for the MCP joints at one-month and one-year follow-up was not different whereas the average ROM for the PIP joints was markedly worse at one-year follow up in comparision to the one-month follow-up.

Post-injection, 8 patients (≈42.1%) experienced pain, which lasted for more than one month in four patients and resolved during the follow-up examination period. Aside from this, 7 patients (≈36.8%) experienced ecchymosis, which was so pronounced in one patient that it had to be treated with Cefuroxime (see Figure 3 [Fig. 3]).

Post-injection, each of six patients (≈31.6%) developed a swelling of the subcutaneous tissue, swelling of a lymph node, or a blood blister. A relevant skin defect was observed in 2 cases, and one patient experienced an allergic reaction during repeated treatment. This was accompanied by oedematous swelling and pruritus. Symptoms diminished adequately on treatment with Cetirizine.

Two patients were treated for a relevant and subjectively bothersome relapse involving a selective fasciectomy about 15 months after the injection.

The evaluation of the Michigan Hand Outcomes Questionnaire (MHQ) demonstrated an increase in the average MHQ from Ø 75.9% (range 31.7–97.4%; σ=17) to Ø 80.7% (range 38.8–100%; σ=17.1). This corresponds to an average increase of the MHQ score by 4.9%.

In terms of general hand function, the MHQ value also improved post-injection by 4.9%, from Ø 71.1% (range 45–95%; σ=13.6) to Ø 75% (range 55–100%; σ=13.1). In terms of everyday activities, the average MHQ improved by 6.4%, from Ø 84.7% (range 0–100%; σ=31.6) to Ø 91.1% (range 35–100%; σ=19.4).

In terms of working ability of the affected hand, the average MHQ showed no change whatsoever, but ranged pre-injection as well as post-injection between 84% (range 25–100%; σ=24.1) and 85% (range 44–100%; σ=20.5).

During evaluation of the MHQs, based on the painfulness of the affected hand, the Xiapex^® injection resulted in a clear reduction in pain from Ø 19.4% (range 0–55%; σ=18.8) to Ø 11.2% (range 0–55%; σ=18.3). This corresponds to a relative percentage pain reduction of 42.5%.

In the assessment of outer appearance alone, the MHQ result worsened post-injection. Here, the result before the injection was Ø 71.2% (range 25–93.7%; σ=20.5) and after the injection it was merely Ø 66.3% (range 0–100%; σ=33.8).

The level of satisfaction evaluated through MHQ increased in 72% of patients (pre: Ø 61.5% (σ=25.1); post: Ø 74.5% (σ=16.6)) with a relative increase of approx. Ø 21% (see Figure 4 [Fig. 4] and Figure 5 [Fig. 5]).

Individual patient satisfaction, which was determined using WHO-5, had a WHO-5 value of Ø 19.9 (range 11–25; σ=3.3) before Xiapex^® treatment and improved slightly to Ø 21 (range 15–25; σ=3.1) post-injection.

The evaluation of the EQ-5D VAS was used to determine the general state of health of the patients. It did not show any changes whatsoever as a result of the Xiapex^® treatment (pre: Ø 78.4% (σ=16.7); post: Ø 78.2% (σ=19.1).

In this study, we did not perform further statistical analysis since the sample size was considered to be too small.

Since the introduction of Xiapex^® in the year 2011, diverse studies have shown that the Xiapex^® injection demonstrably leads to an improvement in the range of movement of the treated finger [13], [14], [15], [16], [17]. In particular, early application at the beginning of the disease appears to be advantageous [18].

In our study, break-up of the cord was performed after 24 hours as recommended by the manufacturer. However, Mickelson et al. showed that a cord break-up 7 days post-injection can also lead to comparable results [19].

In addition, it appears that an injection of Xiapex^® at the level of the MCP joint is superior to an injection at the level of the PIP joint [20]. Our study results also led to the same assumption.

Possible complications after a Xiapex^® injection include skin atrophy, skin redness, swelling, and the appearance of lacerations [10], [15], [16].

Severe complications such as the rupture of ligaments, nerve damage, or severe anaphylactic reactions requiring more radical interventions are rare [7], [21]. The reason for this might be

that Xiapex^® interacts mostly with type I and III collagens, wich are predominate in the diseased Dupuytren’s cord [11].

In our study, we also frequently observed swelling and lacerations following the cord break-up. Most frequently, however, there was pain or paraesthesia in the treated finger.

One patient in our study also showed an allergic reaction to the repeated injection of Xiapex^® as mentioned above. However, this case did not result in any systemic involvement and local symptoms diminished adequately with administration of Cetirizine. The complications in our patient group were short-term except 2 patients where we had to do a revision for ongoing disabling Dupuytren’s disease. On 1-year follow-up there were no more side effects detectable. Patients who complained about ongoing pain after the injection were known pain patients even before the Xiapex^® treatment. Therefore, we had no long-term complications in our study group.

Aside from the Xiapex^® injection, other minimally invasive methods are also available. These include among others percutaneous needle fasciotomy, radiation therapy, and also the injection of steroids, vitamin A or interferon γ [22], [23], [24]. Out of these, percutaneous needle fasciotomy is by far the most clinically relevant procedure. The results of treatment with Xiapex^® are similar to those obtained with percutaneous needle fasciotomy although there are significant differences in the treatment costs [7]. An evaluation by the Federeal Joint Committee in 2012 showed no extra benefit using Xiapex^® in comparison to other therapies [25]. This is the reason why it was necessary for us to make an application at the patients’ insurances in order to cover the costs. Every case was approved.

When comparing the minimally invasive procedures (Xiapex^® injection, percutaneous needle fasciotomy) with surgical fasciectomy, overall a clearly lower rate of complications is shown among the minimally invasive procedures, albeit with a simultaneously higher rate of recurrence [26], [27], [28].

Especially in the case of pronounced findings, selective fasciectomy is clearly superior to minimally invasive methods in terms of long-term results [6].

Of course there were some patients who did not benefit from treatment with Xiapex^®, but no one had a long-term complication. Each person recieved detailled patient education about pros and cons of collagenase intervention. After treatment with Xiapex^® they still could decide for surgical fasciectomy.

There are several limitations of the study. First, the patient sample was small. Second, the observation period lasted only for one year. Furthermore, this study does not include a comparison of the benefit of collagenase injections with the benefit of other therapy methods.

In 84.2% of our study participants (n=16), the use of Xiapex^® led to an improvement in the range of movement of the treated finger by an average of 26.1°. Here, in particular, injections of Xiapex^® at the level of the MCP joint led to an increase in the mobility of the affected finger. The injection of Xiapex^® at the level of the PIP joint demonstrated only a slightly positive effect in our study. Ultimately, the injection of Xiapex^® above the MCP joint for the treatment of single cords appears to be a possible treatment alternative to fasciectomy.

The question remains as to whether the use of Xiapex^® offers a significant advantage over other minimally invasive methods such as percutaneous needle fasciotomy, and precisely the significant difference in treatment costs will have to be considered in this regard.

Since selective fasciectomy is still the only treatment option for which the rate of recurrence is relatively low, it is of vital importance to continue searching for treatment alternatives.

In the future, we intend to carry out a prospective, randomised study to compare the results of collagenase injections and percutaneous needle fasciotomy.

The authors declare that they have no competing interests.