A patient’s hand with initial contracture of the PIP joint of 75 degrees, and 4 year follow-up after CCH treatment with no evidence of recurrence and final FFC of 15 degrees.
Courtesy of F. Thomas D. Kaplan, MD

AAOS Now

Published 11/1/2012
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Terry Stanton

Collagenase Treatments for Dupuytren’s Show Good Midterm Results

At 3 years, all joints remained better than at baseline

A 3-year follow-up of patients with Dupuytren’s contracture who were treated with collagenase clostridium histolyticum (CCH) found that nearly two thirds did not have any recurrence, while those who experienced recurrence did so slowly and did not reach baseline levels.

The results were presented at the 2012 annual meeting of the American Society for Surgery of the Hand by F. Thomas D. Kaplan, MD, of the Indiana Hand to Shoulder Center. Patients (n = 643) were enrolled in an ongoing Collagenase Optimal Reduction of Dupuytren’s Long-term Evaluation of Safety Study (CORDLESS). The 5-year industry-sponsored study was designed to determine the long-term safety of CCH and the recurrence rate in patients following CCH treatment. CCH was approved for commercial use in 2010.

Recurrence following treatment is relatively common, Dr. Kaplan said, and varies according to the standard used and the treatment involved. In this group of patients, the overall recurrence was 35 percent at the 3-year follow-up.

“Although the underlying pathophysiology of Dupuytren’s contracture is still not clearly understood, it is evident that regardless of treatment, the underlying processes that lead to recurrence continue,” Dr. Kaplan said. Factors involved in recurrence may include a patient’s biologic load, age, comorbidities, and treatment-related factors, including continued tension on any residual pathologic tissue.

Treatment results and recurrence
A total of 1,080 joints—648 metacarpophalangeal (MCP) and 432 proximal-interphalangeal (PIP)—were treated with CCH. A 0° to 5° contracture following CCH injection was defined as a success. A joint with a reduction of 20° or greater after injection was considered partially improved. A recurrence was defined as a contracture increase of 20° or greater in the presence of a palpable cord or additional medical/surgical intervention for a treated joint. Fixed-flexion contracture (FFC) values were not included for joints that received medical/surgical intervention, Dr. Kaplan said.

Among MCP joints, the contracture did not recur in 77 percent of the joints; successfully treated joints had a mean pretreatment FFC of 38°. At 3-year follow-up, the correction was maintained at 3°. In MCP joints with recurrence, the baseline FFC was 37°, was reduced to 2° following treatment, and was 33° at 3 years.

PIPs joints with no recurrence had undergone a reduction from 35° to 2°, with an 8° FFC at 3 years. PIP joints with recurrence had an initial correction from 40° to 3°, which increased to 37° at 3 years.

Partially improved joints (both MCP and PIP) started with more severe contractures and had more modest reductions.

“We saw two distinct patterns,” Dr. Kaplan said, explaining that in the first pattern, nonrecurrent and durable joints maintained their correction over 3 years. The second pattern comprised joints that had recurrences or were nondurable. These joints “progressed slowly, still had not reached pretreatment mean FFC levels after 3 years, and only reached the 20° threshold for recurrence or the generally agreed 30° threshold for re-treatment after about 2 years,” he noted.

Subgroup analyses for potential factors that might have influenced the patient’s risk of recurrence found that bilateral occurrence (P < 0.001), family history of the disorder (P = 0.01), and age older than 65 years (P = 0.01) weresignificant.

According to Dr. Kaplan, no new or serious adverse events have been identified and attributed to CCH in the ongoing follow-up. Antibodies to CCH developed in most patients, but no evidence of decreased efficacy or safety concerns was found as a result. Titers of antibodies have declined with each year of follow-up and there have been no reports of systemic anaphylaxis.

A patient’s hand with initial contracture of the PIP joint of 75 degrees, and 4 year follow-up after CCH treatment with no evidence of recurrence and final FFC of 15 degrees.
Courtesy of F. Thomas D. Kaplan, MD

More on Dupuytren’s at ASSH
Two other industry-sponsored studies presented at the ASSH meeting also examined the effects of CCH injections on the Dupuytren’s cord. According to Marie A. Badalamente, PhD, Dupuytren’s cords treated with collagenase injection(s) and subsequent fasciectomy for recurrence, primary fasciectomy, or primary fasciectomy and repeat fasciectomy for recurrence are histologically similar and resemble the classic fibromatosis characteristic of the disorder.

Cords in those three categories were obtained at surgery and examined histogically in a blinded manner. Dr. Badalamente said no differences were found in cellular density or collagen alignment among the samples studied.The macroscopic tissue quality of all cord samples was similar. In particular, collagenase-treated cords were of the same hard collagenous consistency as the cords resected during primary or repeat fasciectomy.

In the other presentation, Edward Moon, MD, summarized a study that sought to determine whether CCH weakens the Dupuytren’s cord sufficiently to cause failure during manipulation or if there is actual digestion and reduction in cord volume.

The investigators examined MRI studies of five patients with isolated contractures of the ring or middle metacarpophalangeal joint (MPJ). Patients received a baseline MRI of the hand, and a second MRI 30 days following collagenase injection and manipulation. Range of motion (ROM) data were collected at baseline and at the final MRI follow-up. The Dupuytren’s cord was evaluated with respect to volume, signal intensity, inflammatory changes, and continuity.

All five patients had full correction with zero residual contracture after manipulation, which was maintained at an average of 39 days. MRI demonstrated complete discontinuity of the cord in each case and a significant reduction of cord volume by an average of 72 percent (P = 0.0013).

Dr. Moon said he and his associates reached the following conclusions:

  • Treatment of isolated Dupuytren’s MPJ contractures with collagenase caused cord disruption without injury to surrounding soft-tissue structures by clinical and imaging criteria.
  • A significant increase in signal intensity was found within the cord, demonstrating disorganization of collagen, which is not seen in the tendons.
  • Collagenase causes a statistically significant decrease in cord volume as measured by MRI, indicating a reduction in diseased tissue rather than simple cord division. Local chemical dissolution of the cord may have prognostic implications in terms of correction and recurrence following collagenase injection.

Co-authors with Dr. Kaplan (Auxilium Pharmaceuticals) are Vincent R. Hentz, MD (Auxilium Pharmaceuticals), James Tursi, MD (Auxilium Pharmaceuticals), Greg Kaufman, MD (Auxilium Pharmaceuticals), and Ted Smith, MD (Auxilium Pharmaceuticals). The CORDLESS study was sponsored by Auxilium Pharmaceuticals.

Coauthors of “Histology of Cords from Dupuytren’s Patients: A Comparision After Collagenase Injection/Fasciectomy, Primary Fasciectomy and Repeat Fasciectomy” with Dr. Badalamente (Biospecifics Technologies Corp., Auxilium Pharmaceuticals, Pfizer Pharmaceuticals) were Lawrence C. Hurst, MD (Biospecifics Technologies Corp., Auxilium Pharmaceuticals, Inc., Pfizer, AsahiKASEI Pharma Corporation); Abner Ward, MD (no information available); Travis Parker, MD (no information available); Jingxuan Liu, MD (no information available); Jakub Tatka (no information available).

Coauthors of “Does Collagenase Injection Disrupt or Digest the Dupuytren’s Cord? A Magnetic Resonance Imaging Study” with Dr. Moon (Auxilium Investigator Initiated Trial) were Keith Crivello, MD (no information available); Hollis Potter, MD (Kensey Nash Corporation; BioMimetic; Smith & Nephew; Biomet; General Electric Healthcare; Imaging; Sports Health; Cartilage; Osteoarthritis and Cartilage); and Scott Wolfe, MD (Extremity Medical; Trimed, Inc.; SBI; Small Bone Orthopedics; Elsevier, Inc).

Terry Stanton is senior science writer for AAOS Now. He can be reached at tstanton@aaos.org

Bottom Line

  • Based on the results of three industry-sponsored studies presented at the 2012 ASSH annual meeting, treating patients who have Dupuytren’s contracture with collagenase injections is safe and may reduce recurrence rates.
  • Three years after treatment, joints with Dupuytren’s contracture treated with CCH either retained their corrected contracture level or regressed slowly and remained better than baseline contracture.
  • Significant risk factors for recurrence are bilateral occurrence, age older than 65 years, and family history. Sex is not a significant factor.
  • A study of Dupuytren’s cords found that cords treated with CCH and surgery, primary surgery, or surgery and repeat surgery are histologically similar.
  • Another study of CCH-treated cords found that treatment did not cause injury to surrounding soft tissue and that treatment resulted in a reduction in diseased tissue rather than simple cord division.