Collagenase injection is a new option for Dupuytren’s, but surgery still has a role

Injectable collagenase clostridium histolyticum has revolutionized treatment of Dupuytren’s contracture as the first nonsurgical treatment option for this condition. While the drug carries few complications and recent studies show promising outcomes and low recurrence rates with the treatment, surgery still plays a role in the care of some patients with this disease.

“Collagenase injections have changed the treatment options for Dupuytren’s disease, because it is the first time that a drug has been available that helps the problem,” Lawrence D. Hurst, MD, the inventor of collagenase clostridium histolyticum (CCH) injections, told Orthopedics Today. “Until now, the only treatment option was some form of surgery.”

History of collagenase injection

Marie Badalamente, PhD, and Hurst, both of Stony Brook University New York (SUNY), Stony Brook, NY, invented the drug in 1991. In 2010, Auxilium Pharmaceuticals Inc. received FDA approval for its branded version of CCH, which was sold in the United States as Xiaflex, according to F. Thomas D. Kaplan, MD, of the Indiana Hand to Shoulder Center, in Indianapolis.

In 2011, Pfizer introduced injectable CCH as Xiapex in Europe, where surgeons felt uncertain about how the drug might replace surgery or a hand surgeon’s expertise. Pfizer organized an advisory board of European hand surgery leaders there to discuss any concerns about the drug and teach other hand surgeons the technique to administer the injections, according to Zsolt Szabó, MD, PhD, of BAZ University Teaching Hospital, in Miskolc, Hungary. Only July 16, 2013, Auxilium announced a long-term collaboration with Swedish Orphan Biovitrum AB for development, supply and commercialization of Xiapex in Europe and Northern Africa.

Two sources in this article, Szabo and Lars B. Dahlin, MD, PhD, of Malmö, Sweden, served on the initial European advisory board. Auxilium took over marketing and distribution of Xiapex in Europe in April, Szabó noted.

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

Dosage and complications

The collagenase in the drug comes from clostridium histolyticum, according to Kaplan. Xiaflex contains two enzymes in the medicine, fibrillar collagen subtypes 1 and 3, which dissolve the type of collagen that make up the Dupuytren’s cords in a patient’s finger, according to Kaplan and Hurst.

The patient is seen the day following treatment with CCH at which time the surgeon breaks the cord and straightens the finger usually under local anesthesia, according to Kaplan.

CCH dose is 0.58 mg. Hurst recommends a dose of 0.58 mg in 0.2 cc for proximal interphalangeal (PIP) joint contractures and 0.58 mg in 0.25 cc for metacarpophalangeal (MP) joint contractures.

“The reason for the volume to be different was that with proximal interphalangeal joints, the flexor tendons are closer to the pathological tissue,” Hurst said. “We are trying to minimize the volume so there is less chance that the drug will damage other tissues.”

Clinicians in Europe found they needed to be professionally familiar with the drug to administer it; otherwise, deleterious complications could occur, including tendon rupture, according to Szabó.

The tendons and ligaments are made of the same type 1 collagen in Dupuytren’s cords, and one of the more serious complications that can occur are tendon ruptures, according to Kaplan.

“If you inject the entire dose into a tendon, you might break the tendon,” Hurst said.

Tendon rupture has most often occurred while injecting cords contracting in the PIP joint of the little finger, according to Hurst. It happened in three of the 1,082 patients who participated in the phase 3 FDA trial conducted by Hurst and colleagues. Hurst and the other sources who spoke with Orthopedics Today stressed the importance of knowing the anatomy of the hand and the pathoanatomy of Dupuytren’s disease to properly administer the injection without damaging the underlying tissues.

“When this was understood, the injection locations were adjusted,” Hurst said. “The damage to tendons rates dropped precipitously, but if it put it in the wrong place, you can hurt [tendons or ligaments]. It is appropriate to be done by hand surgeons or a surgeon who does hand surgery, whether plastic surgeon, orthopedic surgeon or general surgeon.”

According to Szabó, when injectable CCH was launched in Europe, some cases of tendon ruptures 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 can now administer CCH injections in Europe, he said.

Other complications include bruising, swelling in the hand, or swelling in the arm or armpit from lymph node swelling, skin that tears when the surgeon straightens the finger, and rarely, complex regional pain syndrome, Hurst and Kaplan noted.

Recurrence rates and outcomes

During their 4-year follow-up of 361 patients, Hurst and colleagues found that MP joint recurrence was 35% and PIP joint recurrence was 61% when recurrence was defined as flexion contracture of 20°. Using a flexion contracture of 30° to define recurrence showed rates of 22% and 13 %, respectively.

Kaplan highlighted results from Collagenase Option for Reduction of Dupuytren’s Long-term Evaluation of Safety Study (CORDLESS), in which Peimer and colleagues found a 35% recurrence among 1,080 joints. The recurrence rate was 27% for the MP joint and 56% for the PIP joint, according to Kaplan, who co-authored the study.

“I tell all patients that you cannot cure this disease,” Hurst said. “You are managing it so their hand can function. To that end, collagenase can also be used for recurrence because there is no scar from previous surgery or needling.”

The recurrence rates from surgery range from 20% to 80%, according to Hurst. In a trial conducted by van Rijssen and colleagues in the Netherlands, treatment with needle aponeurotomy showed an 85% recurrence rate and limited fasciectomy had a recurrence rate of 21%, according to Kaplan.

Indications for treatment

CCH is mainly indicated for patients with an isolated cord with MP joint contracture, according to A. Lee Osterman, MD, of The Philadelphia Hand Center, in King of Prussia, Penn. “It obviously has minimum downtime compared to surgery and it does not have the risk of nerve injury that we sometimes see with needle aponeurotomy,” he said.

Osterman, an Orthopedics Today Editorial Board member, also noted that “all Dupuytren’s, no matter which procedure you do, will recur. You cannot cut it all out.”

Kaplan said, “You need to have a contracture secondary to Dupuytren’s with a cord that you can accurately target and inject. Patients who have contractures, but cords that are not well defined, are not good candidates for Xiaflex,” noting he and others involved in the CCH trials typically waited until a patient’s MP or PIP joint contracture reached 20° — the point at which patients start to encounter difficulties using their hands.

According to investigators, the treatment is optimal for MP joint contractures, but can also be successful, to a certain extent, for patients with PIP joint contractures. Some physicians reported the most success when CCH injection was done for contractures of less than 40° to 50°, Kaplan said.

Hurst told Orthopedics Today, “Surgical indications are MP contractures of 30° or greater or a PIP contracture of 20° or greater.”

Consider the contraindications

Not all cases of Dupuytren’s contracture, however, 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. In such cases, Dahlin and Szabó noted that 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 told Orthopedics Today, and noted that injection procedures and protocol must be carefully followed.

A main contraindication to CCH injection is a patient whose Dupuytren’s disease has only progressed as far as the nodular stage, since a well-define palpable cord is needed for CCH injection. However, Hurst noted that nodular patients do not need surgery. “In fact, most nodules do not need treatment,” he said.

According to Osterman, Lynn D. Ketchum, MD, of Leawood, Kan., has conducted research into patients with the painful nodules from which Dupuytren’s cells can form. He said Ketchum’s work showed that pain relief and some quiescence in the ability of the nodule to form a Dupuytren’s cord that might lead to contracture were attained with cortisone injected once or twice into each nodule.

Another contraindication — a cord that is extremely thick and rope-like, and extends from the palm through the skin to a finger. This develops in about one in 100 patients with Dupuytren’s disease and such patients may not respond to CCH injection, according to Hurst.

“You may make a decision that collagenase is not strong enough” to manage the disease in these situations, he said.

Another contraindication to collagenase injection, according to Hurst, is a patient whose skin was severely damaged with prior Dupuytren’s surgery and has a recurrence and skin loss. If it is obvious to the surgeon that when the cord is broken subsequent to injection the insufficient skin will rip, then CCH treatment is probably also contraindicated in such cases.

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

According to Dahlin, injection into a cord that affects the MP joint is preferable to a cord that restricts extension in the 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.

“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.”

While some sources who spoke with Orthopedics Today consider treatment of a Dupuytren’s cord that affects the thumb joint to be a contraindication to the use of CCH, others disagree. Hurst noted that he has used CCH safely and effectively in the thumb.

“If someone is taking drugs that 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.

“I have treated numerous patients on warfarin and other blood thinners by stopping the anticoagulant temporarily, using collagenase and then restarting the anticoagulation,” Hurst said. “This also has to be done if you do surgery. In the United States, several surgeons have used collagenase without stopping anticoagulation drugs. The collagenase worked and excess bleeding was not a problem.”

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.

The “right” surgical technique depends on the condition of the patient and should be the patient’s choice, and all options should be discussed with the patient, said Szabó, who performs open surgery for patients who previously had surgery or have scar tissue present so that he can better visualize the anatomical structures and protect them.

“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,” Szabó said.

Post-treatment rehabilitation

Following fasciectomy for Dupuytren’s contracture, Osterman said rehabilitation can be extensive and usually involves splinting. However, to keep patients from developing a condition known as “Dupuytren’s flare,” which results from stretching out nerves that have been bent for years, the interphalangeal joint of the PIP should be splinted so that it is relatively straight while the MP flexion takes the traction off the nerve in flexion.

“Over 3 weeks to 4 weeks post-surgery or post-injection, you then stretch out [the finger] to get full range of motion of the finger, but you are not putting as much tension on the nerve,” Osterman said.

Patients with lesser contractures usually require minimal post-treatment therapy. It may solely consist of night-time splinting and involve no therapy during the day. These patients are allowed to immediately resume use of their hand for activities of daily living and can return to full unrestricted activities after 4 weeks, as tolerated, he said.

Following needle aponeurotomy, “we protect it for a week. They use night splints with hand use progressing towards unrestricted [use] at 4 weeks to 5 weeks,” according to Osterman.

Hurst discussed the post-CCH injection protocol used in the Xiaflex trials. It is “based on what we did for surgical patients before this was an option. After surgery we splint people at night and [allow] exercise throughout the day and occasionally use dynamic splints for surgery. In clinical practice, I still use the splint. The protocol was 3 months [of splinting], but in reality, no one probably wears it for that long. There was no data saying splints are needed or not needed. But, there is now a new paper in Journal of Hand Surgery from Australia showing splinting does not affect the end result.”

Although some research suggests that PIP joints probably do need splinting after they are treated, this is probably not necessary in MP joints, according to Hurst.

“There need to be more studies. As far as exercising, it is good and we have a protocol we give patients that I wrote and put on our website. That is what we do. Different surgeons who use Xiaflex do it differently,” he said.

Concerning the quality of the results achieved with the various Dupuytren’s contracture treatments, the 5-year findings of the CORDLESS study that are now being compiled should provide helpful insights into more long-term outcomes, Kaplan said.

“We need more head-to-head comparisons between the needle procedure, fasciectomy and collagenase to get a better sense of when we should be using these different [treatments],” Kaplan said. “It is going to be difficult because it is a variable disease in different people, and the trend is toward less invasive procedures and surgery for patients who [have a more severe condition].” – by Renee Blisard Buddle and Susan M. Rapp

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

Explain the indications

I think the surgeon has to explain that they are not a good candidate, here are the reasons and that another procedure or treatment is most likely to give the patient a favorable outcome with fewer complications. Treatment is indicated when patients stop being able to get their hand down flat. That is generally when they ought to consult with someone who can treat this. Prior to that time, most surgeons would advise just leaving things alone if there are just some nodules in the palm and some evidence of the disease, but no contraction in the fingers.

When the patient is sufficiently bothered by the degree of contraction, then that is the indication to do treatment. The patients who should have surgery are those patients who want all evidence of the disease gone. That is not the case with the collagenase because the finger may become straight, but you still may have hard lumps in the finger or palm.

There are others who are not good candidates for collagenase because the joint has been contracted for a long time and, although the cord that initially caused the contraction may respond to collagenase, the joint capsule and ligaments have by now undergone secondary changes. These soft tissues that support the joint have become so shortened and because they are not affected by the collagenase, the joint remains contracted and the patient likely remains dissatisfied.

Vincent R. Hentz, MD, is a professor of surgery at Stanford University School of Medicine, Stanford, Calif.
Disclosure: Hentz has received support for research projects from Auxilium through a contract with Stanford for collagenase injection research and has served on the scientific advisory board for collagenase for Auxilium.

Explain the adverse events

There are a lot of people with Dupuytren’s contracture who have an appropriate indication for an intervention, but collagenase, surgery or needle aponeurotomy are all indicated. My approach is to explain the patient experience with the different treatment options. I explain the risk and benefit profiles, with the most up to date data that we have, and let the vast majority of patients choose their treatment.

The situation that can be harder is if the surgeon believes that collagenase injection is not indicated or is more risky for a given individual than another intervention. The complexity arises because patients and surgeons regard injection as a less invasive and less risky category of procedure. I tell patients there are real side effects that occur with collagenase injection. People have tendon ruptures and skin tears, and the potential exists for a serious allergic reaction. In general, to me this contraindication is based on the pathoanatomy of the Dupuytren’s cords and any scar that is present. When I believe the anatomy is not appropriate, I tell patients that their anatomy puts them at higher risk or is not appropriate and therefore collagenase injection is contraindicated.

Philip Blazar, MD, is an associate professor of orthopedic surgery at Harvard Medical School and fellowship director for the Hand & Upper Extremity Fellowship at Brigham and Women’s Hospital in Boston.
Disclosure: Blazar has previously funded research into collagenase.