Collagenase injection for Dupuytren’s not cure-all or replacement for surgery

Injectable collagenase clostridium histolyticum has revolutionized treatment for Dupuytren’s contracture. In many cases, for the first time clinicians can treat these finger contractures without surgery using a drug that has few complications. But since its introduction in Europe in 2011, some orthopaedists have worried whether the new treatment would completely replace hand surgery as a treatment for Dupuytren’s contracture, according to investigators who treat patients with this disease.

“Collagenase was the first drug in hand surgery that was supposed to replace surgery,” Zsolt Szabó, MD, PhD, of BAZ University Teaching Hospital, in Miskolc, Hungary, told Orthopaedics Today Europe. “We had concern about how an injection can replace a hand surgeon and there was a lack of knowledge at the beginning. We were surprised and our patients were surprised about the good results and the satisfaction of the patient. The patients were so satisfied and the results were so good, we were obliged to use this drug,” he said.

Image: Rapp SM; Orthopaedics Today Europe

History of collagenase injections

When Pfizer introduced Xiapex-brand collagenase clostridium histolyticum (CCH) injection (Collegeville, Pa., USA) in Europe 2 years ago, hand surgeons had uncertainties about how the drug might replace surgery or a hand surgeon’s expertise in these cases. In response, Pfizer organized an advisory board of a group of European hand surgery experts to discuss any concerns with the drug, participate in a clinical study of the injection treatments, and teach other hand surgeons the technique to administer the injections, according to Szabó.

Four sources in this article served on that initial advisory board: Szabó, Lars B. Dahlin, MD, PhD, ofLund University, in Malmö, Sweden, Jarkko Vasenius, MD, PhD, of Omasairaala Hand Surgery and Therapy, in Helsinki, and David Warwick, MD, FRCS (Orth), EDHS, of University Hospital Southampton, in Hampshire, United Kingdom, who chaired the board.

“This was well-prepared in Europe and due to this, no major complications and no big problems were encountered,” Szabó said.

He noted that 2 months ago, Auxilium, in Chesterbrook, Pa., USA, took over marketing and distribution of the CCH product sold in Europe.

Learning curve

The drug in question contains clostridium histolyticum which, when injected into a Dupuytren’s cord, dissolves the affected segment of the cord. Within the next few days after injection, under local anesthetic, the dissolved segments can be manipulated and the fingers straightened, according to Warwick.

“A good proportion of patients with Dupuytren’s will now have the option to avoid surgery and this means we can treat Dupuytren’s without the inherent risk of surgery, but also have a prompt recovery,” Warwick told Orthopaedics Today Europe.

One reason hand surgeons originally hesitated to administer CCH injections for Dupuytren’s contracture, when indicated, was because the drug was new and they did not know what to expect at that early point in time. Clinicians eventually found they needed to be professionally familiar with the drug to best administer it; otherwise, deleterious complications could occur, including tendon rupture, according to Szabó.

“This was something new and interesting,” Szabó said. “In medical decision-making, there are different factors that influence the decision of the doctor and these include patient expectations, evidence-based data and the expertise and experience of the surgeon. Every doctor was thinking at the beginning that to administer an injection does not require any special knowledge or training,” he said.

Among the concerns that surgeons in Europe expressed when CCH was introduced, Szabó said, was whether the drug could dissolve all tissue it came into contact with, including nerves, arteries and tendons.

“Fortunately, this is a special material which will dissolve only the ‘disease’ and not the nerves and arteries. But, unfortunately, it can dissolve the tendons,” Szabó said.

“[Surgeons who use] collagenase need certain knowledge and training to administer the injection,” he said.

According to Szabó, when injectable CCH was launched some cases of tendon rupture were reported after the material was injected directly into the patient’s tendon. As a result, only hand surgeons or physicians with experience with Dupuytren’s treatment can now administer CCH injections in Europe, he said.

Indications, rehabilitation

The main indication for collagenase injection is a discrete cord of Dupuytren’s disease in a finger that the surgeon can palpate and has at least 20° to 30° flexion contracture. The dose of injectable CCH used depends on the size of the Dupuytren’s cord in question, according to Szabó. The Dupuytren’s powder can be diluted based on the articulation affected, he said.

During Pfizer’s multi-cord, off-label studies of CCH, Szabó and others noticed that when they administered twice the amount of collagenase they saw no increase in complications or any increase in the severity of the complications. These studies have yet to be published, he noted.

However, not all cases of Dupuytren’s contracture are amenable to CCH treatment. When multiple Dupuytren’s cords or multiple fingers are affected, the surgeon may have difficulty feeling any one specific cord and Dahlin and Szabó both noted that in such cases, the physician should consider performing surgery.

For the injection approach, “You need to have a patient with a well-defined cord so that you know exactly when you are going through the skin and into the cord,” Dahlin said, and noted that injection procedures and protocol must be carefully followed.

If not, “there is a risk you may put the collagenase into a tendon,” he said.

Sources that spoke with Orthopaedics Today Europe agreed that night splinting for just a few months after collagenase injection treatment might help to stretch out the fingers. They recommended patients see an occupational therapist or physiotherapist if they have a more extreme case of Dupuytren’s contracture, but for less severe contractures night splints may be removed earlier, they said.

After that phase of recovery, the physician can begin the process of gradually mobilizing the hand, but should restrict the amount of weight a patient is allowed to carry.

Contraindications noted

According to Dahlin, injection into a cord that affects the metacarpophalangeal (MCP) joint is preferable to a cord that restricts the extension in the proximal interphalangeal (PIP) joint. It is more difficult to inject the sometimes thinner cords of the PIP joint with collagenase, he said, and there could be an increased risk of hitting a tendon, causing a rupture, particularly in the little finger.

Vasenius described performing a CCH injection as being “more fluid in the MCP joint” and he actually recommended surgery for patients with severe Dupuytren’s contracture in a PIP joint.

“Cords affecting the PIP joints may not be thick and round,” Dahlin said. “There could be one or several thin cords, which could be difficult to hit with the needle accurately.”

Furthermore, injectable CCH may be more difficult to administer in the thumb than in other fingers because the surgeon cannot fully proceed with the “pull on the cord” during the pop-up procedure, he said. For that reason, this may be a possible contraindication to the use of CCH, according to Dahlin, but he noted thumbs are being treated with good results.

Other contraindications to CCH injection for Dupuytren’s contracture include patients who take blood thinners, such as warfarin sodium, those with known allergies to collagenase, and patients who are pregnant, according to Szabó.

To date, European physicians have not encountered any patients with an allergy to the CCH material, he said.

“If someone is taking drugs which are dedicated to blood thinning to prevent thromboembolism, we were afraid that in administering [collagenase], which may rupture the cord, there will be small blood vessels which will rupture and then bleeding will not stop, Szabó said. That could possibly result in a large hematoma. Therefore, we typically propose another treatment be used for patients taking warfarin sodium and other anticoagulants, he said.

Injection complications seen

Besides tendon rupture, patients who undergo CCH injections may experience swelling, hematoma, bruising, painful lymphatic nodules in the axilla or skin ruptures, to a variable extent, in the palm that last a few days or may take up to a few weeks to heal, according to Szabó.

According to Vasenius, these complications are so commonplace that hand surgeons consider them a usual part of the treatment.

“As long as you inform the patient that, for example [with a skin rupture], which is common, the more contracture there is, the higher the rate of extension, and the higher the risk of a skin rupture before you give the injection, there will not be a problem,” Vasenius told Orthopaedics Today Europe.

Warwick said, “If you straighten the finger, there is a space where the cords used to be and that can fill with blood, or if it is skin that has been shortened over the years from Dupuytren’s [disease] and you straighten the finger and there is not enough skin, it splits.”

“I do not regard this as a complication in as much as it is to be expected and [the patient] recovers quickly in a few days or a week,” Warwick said.

Recurrence rates and outcomes

Dupuytren’s contracture recurrence rates reported in the literature vary for the different surgical procedures, but Szabó estimated that needle aponeurotomy has the highest recurrence rate at 50% to 80%. The recurrence rate for open surgery is next highest at 20% to 30%, while about 10% of patients who undergo dermofasciectomy had recurrences, based on published results.

But, to date, little is known about the recurrence rate of collagenase injections because the data are limited to 3-year follow-up, Szabó said. Vasenius and Warwick observed a 35% to 40% recurrence rate at 3-year follow-up in published data on CCH injection.

Szabó said researchers involved in Pfizer’s unpublished, off-label multi-cord study, which included 250 patients treated at 28 centers, found patients were satisfied and had significant improvement in range of motion after CCH injection.

“The patient is happy to avoid an operation,” Szabó said. “The patient is not too concerned about what will happen in 5 years.”

Cost of collagenase injections

The cost of injectable CCH in Europe varies by country and patients in some areas do not have access to this therapy if it is not covered by their national health insurance program.

Image: Seegenschmiedt MH

Injectable CCH costs 900 to 2,000 per injection in Europe, but in Hungary, it is more expensive than surgery and costs about 800 per injection, Szabó said.

“This is a big problem for ex-socialist countries or Eastern European countries where the price, even if it is the cheapest [option], is more expensive than surgery,” he said.

In Sweden, where the government is now weighing the cost-benefit of the drug to other techniques, injectable CCH costs about $1,000 US for one bottle, ie., one cord, according to Dahlin.

“The needle technique costs almost nothing compared to $1,000 and may provide equal results to the collagenase treatment,” he said.

In a study that Vasenius and colleagues conducted, 79% of hand surgeons in Finland surveyed said they use collagenase injection for patients with Dupuytren’s disease. Among physicians who do not use the drug or who would like to use it more often, 50% noted a high price is the main reason that limits its use.

In the United Kingdom, the cost of collagenase with tax is £800, according to Warwick.

“You have to set it against the development cost of the drug, the marketing cost, how much the surgery costs the hospital. In the U.K., the private system does tend to reimburse because they may find their expenditure [for CCH injection] less than traditional surgery,” Warwick said

Other treatments

Patients with Dupuytren’s contracture who have cords that are difficult to palpate, multiple Dupuytren’s cords, cords in the PIP joint, or multiple involved fingers may ultimately require surgery. Another nonsurgical option for early stage Dupuytren’s contracture with no or minimal flexion deformity is radiotherapy, according to radiotherapist M. Heinrich Seegenschmiedt, MD, of Hamburg, Germany.

In multiple controlled clinical studies conducted by Seegenschmiedt, there is only a 10% progression rate of the disease in patients treated with radiotherapy. Although a patient’s skin may be dry following treatment, in long-term follow-up no cancer related to radiotherapy was detected in patients they treated as such, Seegenschmiedt said.

“Radiation therapy effectively interferes with the proliferation of the fibroblasts at the phase when they form nodules and cords during the early phase of Dupuytren’s; thus functional results are excellent,” he told Orthopaedics Today Europe. “The goal is to stabilize a disease that is progressing at that time.”

The “right” surgical technique depends on the condition of the patient and should be the patient’s choice, said Szabó, who said he discusses the various surgical options available and provides his patients with information on the expectations, complications and recovery time for each procedure. When that is done, he said, it becomes the patient’s responsibility.

“In someone who already has had surgery or has scar tissue, I do open surgery because I would like to see the anatomical structures and protect them,” in order to be as safe as possible,” Szabó said. “I teach all my younger surgeons [that] you do not make the decision. You give proper information and then let the patient decide for himself.” – by Renee Blisard Buddle

• Reference:
• Eaton C, Seegenschmiedt M, Bayat A, et al. Dupuytren’s Disease and Related Hyperproliferative Disorders: Principles, Research, and Clinical Perspectives. New York: Springer Verlag Berlin Heidelberg; 2012.
• Lars B. Dahlin, MD, PhD, can be reached at the Department of Sciences – Hand Surgery, Lund University, Skane University Hospital, Jan Waldenstrõms gata 5, SE-205 02 Malmö, Sweden; email: lars.dahlin@med.lu.se.
• M. Heinrich Seegenschmiedt, MD, can be reached at Strahlentherapie & Radiochirurgie, Strahlenzentrum Hamburg, Langenhorner Chaussee 369, 22419 Hamburg, Germany; email: mhs@szhh.info.
• Zsolt Szabó, MD, PhD, can be reached at Traumatology and Hand Surgery Department, Szenpeteri Kapu 72-76, 3501 Miskolc, Hungary; email: zsoltszabo@axelero.hu.
• Jarkko Vasenius, MD, PhD, can be reached at Puutarhurinkuja 2, Helsinki 00300, Finland; email: jarkko.vasenius@omasairaala.fi.
• David Warwick, MD, FRCS (Orth), EDHS, can be reached at Tremona Rd., Southampton, Hampshire, S016 6YD, United Kingdom; email: davidwarwick@handsurgery.co.uk.

Disclosures: Dahlin is on the advisory board of and a principal investigator for clinical studies on Xiapex conducted by Pfizer and Auxilium. Seegenschmiedt has no relevant financial disclosures. Szabó is secretary general of the Federation of European Societies for Surgery of the Hand and member of the Xiapex advisory board and receives fees for lectures on Xiapex from Pfizer. Vasenius is on the advisory board for and receives fees for lectures on Xiapex from Pfizer. Warwick is chair of the Xiapex advisory board and has received remuneration for advisory work and lectures on Xiapex from Pfizer.

What should surgeons do when patients with Dupuytren’s contracture request collagenase injections but are clearly indicated for another procedure?

Let the patient decide

The answer to this question is straightforward: The physician should first take a full history of the patient and perform a physical examination and take note of all relevant medications and allergies, as well as any previous treatments. Then, he or she should counsel the patient about all available treatments and give an explanation of the short- and long-term benefits, as well as the shortcomings of each option, and review in the detail the advantages and disadvantages of each treatment option.

Most importantly, the physician should explain why, in this particular case, it is not a good idea to use a collagenase clostridium histolyticum injection.

Ultimately, the patient makes his or her choice, or may leave it up to the surgeon. The latter situation of course is most convenient for the orthopaedic surgeon because there will be no argument or resistance from the patient. Hopefully the physician will choose what is best for the patient. In the former case, should the disagreement persist, it may be best to refer the patient to another physician for further counseling and treatment.

Paul M.N. Werker, MD, PhD, is chair of the department of plastic surgery at University Medical Centre Groningen, University of Groningen, in Groningen, The Netherlands.
Disclosure: Werker is a consultant for Pfizer Ltd.

Inform patients only

The response to patients in this situation depends on the surgeon’s experience with the surgical and chemical methods of treatment. According to the manufacturer’s prescribing information for collagenase, it should be used only to inject into a clearly palpable cord. If, for example, patients have no palpable cords, then surgery may have a much better chance of addressing a sheet of Dupuytren’s tissue causing contracture than collagenase. In this case the surgeon should (1) carefully explain the reasons why he or she would not consider the patient suitable for collagenase treatment; (2) explain the limitations of the indications for the use of injectable collagenase and (3) offer the patient a second opinion if they remain uncertain about how to proceed.

Another case is when there is a recurrent contracture after a successful previous procedure to correct the deformity and there is a flimsy cord present that is unlikely to explain the contracture. While the surgeon may prefer surgery, he or she must now present the pros and cons of the procedure to the patient so the patient can make an informed choice. If the patient is clearly unsuitable for collagenase treatment, then the surgeon should not offer or accede to the patient’s request for it, as that would be unethical. Furthermore, the surgeon could not be confident that the collagenase, if injected, will not affect the sheath, tendon, nerve or digital vessel. Our responsibility is to give our patients the information they need to make a good decision for their disorder.

Joseph J. Dias, MBBS, FRCS, FRCS (Edinburgh), MD, is acting head of the Department of Health Sciences, Clinical Division of Orthopaedic Surgery at Leicester General Hospital, in Leicester, United Kingdom.
Disclosure: Dias was a member of the European Pfizer advisory group for collagenase clostridium histolyticum.