Leupeptin accelerates recovery after sciatic transection and repair, but not crush injuries in rats.

We aimed to explore previously reported discrepancies in success with leupeptin by comparing outcomes of two types of injury: transection and crush. Male rats were randomized into vehicle and leupeptin treatment groups (n = 6/transection group; n = 10/crush group). Leupeptin (12 mg/kg) was administered via intramuscular injection into the gastrocnemius muscle twice a week for the duration of the study. Rats were monitored on a weekly basis for electromyographic function and gait for 8 weeks. A total of 83.3% of the rats that were treated with leupeptin began to recover electromyographic activity 1 week after transection, versus 0% that were treated with leupeptin after crush (P < 0.0001). Rats that were treated with leupeptin also had less functional debilitation, as indicated by a greater sciatic functional index at five of the eight time-points after transection versus one of eight after crush (P ≤ 0.05). Leupeptin aids in the rate of recovery after transection and repair but not crush injuries. These findings suggest there may be differences in pathology and recovery associated with these two types of peripheral nerve injury.

Antithrombotic Use with Collagenase Clostridium Histolyticum Injection to Treat Dupuytren Disease.

Background: Collagenase Clostridium histolyticum (collagenase) is an injectable treatment option for Dupuytren disease. The current study was designed to investigate the safety and ensure the effectiveness of collagenase for the treatment of Dupuytren disease, with or without concomitant antithrombotic usage. Methods: One hundred and forty-eight patients with Dupuytren disease were treated with collagenase during this period; 49 taking antithrombotics and 99 not taking antithrombotics. The primary outcomes were clinical success (a reduction in joint contracture to < 5°) and clinical improvement (a reduction in joint contracture by equal to or more than 50%). Results: No statistically significant difference in either clinical success or clinical improvement was found between those taking and those not taking antithrombotics. No significant difference was found in the incidence of any adverse effects or skin splits between the two cohorts. Conclusions: Collagenase can be safely and effectively used to treat patients with Dupuytren disease who take antithrombotics.

Development of Collagenase Treatment for Dupuytren Disease.

Proof-of-principle, basic-science studies, using a rat-tail tendon model and surgically removed Dupuytren cords, began collagenase Clostridium histolyticum (CCH) development. Clinical studies in humans were then conducted, where the primary endpoint was reduction in contracture to within 0° to 5° of extension. Phase 2 studies, which confirmed the optimal dose of collagenase as 0.58 mg, showed injectable CCH reduced contractures in MP and PIP joints to within 0° to 5° in many joints and was well tolerated. Clinical results from phase 3 studies confirmed the efficacy and safety of injectable CCH as a viable nonsurgical intervention.

CORR® ORS Richard A. Brand Award: Clinical Trials of a New Treatment Method for Adhesive Capsulitis.

BACKGROUND: Conservative and even surgical management of adhesive capsulitis often is prolonged and painful. Management of adhesive capsulitis is lacking evidence-based controlled clinical trials. QUESTIONS/PURPOSES: We asked: (1) Does a collagenase clostridium histolyticum (CCH) injection lyse shoulder capsule collagen in adhesive capsulitis and at what dose? (2) Can a shoulder capsule injection be administered extraarticularly? (3) Do CCH injections result in better scores for pain and function than can be achieved with physical therapy among patients with adhesive capsulitis? METHODS: First, 60 patients with adhesive capsulitis were evaluated by clinical examination. To make the diagnosis of adhesive capsulitis, a patient had to have restricted active ROM of at least 60° in total active ROM in the affected shoulder compared with the unaffected contralateral shoulder; with the scapula stabilized, external rotation with the elbow at the side was a very important determinant. Patients were randomized to receive a single injection of 0.5 mL placebo or 0.145, 0.29, or 0.58 mg CCH. All 60 patients were followed up at 30 days. After that, if patients did not attain treatment thresholds they were eligible for up to five open-label 0.58-mg collagenase injections. For the longer-term followup in the open-label phase, 53 patients (83%) were followed to 12 months, 46 (77%) for 24 months, 36 (60%) for 36 months, 37 (62%) for 48 months, and 25 (42%) for 60 months. The extraarticular injection was directed at the anterior shoulder capsule with the patient in the supine position. To prove that these injections could be delivered reliably to the anterior shoulder capsule extraarticularly, the next study involved volunteers without adhesive capsulitis, in which 10 volunteers received a 10-mL injection of normal saline under ultrasound guidance. Finally, to determine the efficacy and dosing of CCH, four cohorts of 10 patients received up to three ultrasound-guided injections separated by 21 days. These injections were administered at one of four dose-volume levels. A fifth cohort of 10 patients was used as a control group and performed standardized home shoulder exercises only. All patients performed standardized home shoulder exercises three times daily. For Study 3, followup was at 22, 43, 64, and 92 days. No patients were lost to followup. RESULTS: In the first study, a single CCH injection did not provide clinically important improvements from baseline in active ROM, passive ROM, and function and pain scores compared with patients who received placebo. Ultrasound guidance confirmed extraarticular injection of the shoulder capsule in Study 2. The CCH injection was more effective than exercise therapy alone at 0.58 mg/1 mL and 0.58 mg/2 mL compared with exercise only in the primary measure of efficacy (active forward flexion) as shown in Study 3. For active forward flexion the mean in degrees in the 0.58 mg/2 mL group was 38° compared with 12° in the exercise-only group (p = 0.03). For active forward flexion the mean in the 0.58 mg/1mL group was 43° compared with 12° in the exercise-only group (p = 0.01). CONCLUSIONS: Extraarticular injections of CCH for treatment of adhesive capsulitis were well tolerated and seem effective compared with exercise therapy. Future FDA-regulated clinical trials must verify CCH injection therapy for adhesive capsulitis. LEVEL OF EVIDENCE: Level II, therapeutic study.

Microsurgical Simulation Exercise for Surgical Training.

OBJECTIVE: Initial training for orthopedic surgical residents (postgraduate years 1-5) in microsurgery using the turkey wing model and evaluation of their proficiency. DESIGN: Residents were given a questionnaire on their comfort level with microsurgery and microsurgical knowledge, followed by a lecture on the subject. They watched a surgical dissection and repair of the turkey wing's neurovasculature. Residents performed the dissection and repairs of the artery, vein, and nerve. A postquestionnaire was administered following the simulation exercise. Their performances on repairs were graded and results compared by academic year. SETTING AND PARTICIPANTS: A total of 21 orthopedic surgery residents were recruited from Stony Brook University Medical Center, Stony Brook, NK. RESULTS: This training activity resulted in significant improvements in both microsurgical knowledge (41%) and comfort (37%). Senior residents scored significantly higher than juniors on 6 microsurgical parameters. The largest effect was in nerve repair showing 4 parameters that differed significantly between groups. CONCLUSION: Microsurgical techniques require extensive training to master. The turkey wing model for repair of the artery, vein, and nerve represents a realistic simulation of a human hand artery, vein, and nerve. It provides an inexpensive method for residents to practice on real tissue for improving microsurgical technique.

Delayed manipulation after collagenase clostridium histolyticum injection for Dupuytren contracture.

BACKGROUND: Collagenase clostridium histolyticum (CCH) injection for Dupuytren contracture was approved in the USA in 2010. Current FDA guidelines stipulate that finger manipulation occurs the day following injection. To investigate the safety and efficacy of delaying manipulation to 2 or 4 days following CCH injection, we conducted a prospective, randomized trial at two sites. METHODS: Patients with Dupuytren contracture involving the metacarpophalangeal (MCP) joint ≥20° caused by a palpable cord participated. All patients received one dose of CCH (0.58 mg/0.25 ml) and were followed for 90 days. The primary end point was the percent of patients maintaining clinical success (reduction of contracture to 0°-5°) at 90 days post-injection. Adverse events and change in Michigan Hand Questionnaire (MHQ) score were recorded as secondary end points. RESULTS: Thirty-seven patients enrolled; 13 were manipulated on day 1, 11 on day 2, and 13 on day 4. At 30 days after injection, the percentage of patients obtaining reduction of contracture to <0°-5° extension was 92, 82, and 85 % in groups 1, 2, and 3, respectively, with no significant difference. At 90 days follow-up, the percentage of patients maintaining 0°-5° extension was 91, 82, and 83 % in groups 1, 2, and 3, respectively, with no significant difference. Adverse events were comparable to rates in prior studies. There were no serious adverse events. There was no statistical difference in MHQ scores between groups at any time point. CONCLUSIONS: Delaying manipulation to day 2 or 4 following CCH injection for MCP joint contractures does not increase adverse events or result in loss of efficacy. LEVEL OF EVIDENCE: Therapeutic, Level II.

Efficacy and safety of collagenase clostridium histolyticum in the treatment of proximal interphalangeal joints in dupuytren contracture: combined analysis of 4 phase 3 clinical trials.

PURPOSE: To examine the results of proximal interphalangeal (PIP) joint contractures from 4 phase 3 clinical trials of collagenase clostridium histolyticum (CCH) injection for Dupuytren contracture. METHODS: Patients enrolled in Collagenase Option for Reduction of Dupuytren I/II and JOINT I/II with one or more PIP joint contractures (20° to 80°) received CCH 0.58 mg/0.20 mL or placebo (Collagenase Option for Reduction of Dupuytren I/II only) injected directly into a palpable cord. The percentage of PIP joints achieving clinical success (0° to 5° of full extension), clinical improvement (50% or more reduction in baseline contracture), and range of motion improvement at 30 days after the first and last CCH injections was assessed. The PIP joint contractures were classified into low (40° or less) and high (more than 40°) baseline severity. Adverse events were recorded. RESULTS: A total of 506 adults (mean age, 63 ± 10 y; 80% male) received 1,165 CCH injections in 644 PIP joint cords (mean, 1.6 injections/cord). Most patients (60%) received 1 injection, with 24%, 16%, and 1% receiving 2, 3, and 4 injections, respectively. Clinical success and clinical improvement occurred in 27% and 49% of PIP joints after one injection and in 34% and 58% after the last injection. Patients with lower baseline severity showed greater improvement and response was comparable between fingers, as were improvements in range of motion. Adverse events occurring in more than 10% of patients were peripheral edema (58%), contusion (38%), injection site hemorrhage (23%), injection site pain (21%), injection site swelling (16%), and tenderness (13%). This incidence was consistent with data reported in phase 3 trials. Two tendon ruptures occurred. No further ruptures occurred after a modified injection technique was adopted. CONCLUSIONS: Collagenase clostridium histolyticum was effective and well tolerated in the short term in patients with Dupuytren PIP joint contractures. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.

Measurement scales in clinical research of the upper extremity, part 1: general principles, measures of general health, pain, and patient satisfaction.

Measurement is a fundamental cornerstone in all aspects of scientific discovery, including clinical research. To be useful, measurement instruments must meet several key criteria, the most important of which are satisfactory reliability, validity, and responsiveness. Part 1 of this article reviews the general concepts of measurement instruments and describes the measurement of general health, pain, and patient satisfaction.

Measurement scales in clinical research of the upper extremity, part 2: outcome measures in studies of the hand/wrist and shoulder/elbow.

Part 1 of this article outlined the basic characteristics of useful clinical measurement instruments and described scales used to measure general health, pain, and patient satisfaction. Part 2 describes the features of some of the scales most commonly used in clinical research in the hand, wrist, elbow, and shoulder.

Injectable collagenase clostridium histolyticum for Dupuytren's contracture.

BACKGROUND: Dupuytren's disease limits hand function, diminishes the quality of life, and may ultimately disable the hand. Surgery followed by hand therapy is standard treatment, but it is associated with serious potential complications. Injection of collagenase clostridium histolyticum, an office-based, nonsurgical option, may reduce joint contractures caused by Dupuytren's disease. METHODS: We enrolled 308 patients with joint contractures of 20 degrees or more in this prospective, randomized, double-blind, placebo-controlled, multicenter trial. The primary metacarpophalangeal or proximal interphalangeal joints of these patients were randomly assigned to receive up to three injections of collagenase clostridium histolyticum (at a dose of 0.58 mg per injection) or placebo in the contracted collagen cord at 30-day intervals. One day after injection, the joints were manipulated. The primary end point was a reduction in contracture to 0 to 5 degrees of full extension 30 days after the last injection. Twenty-six secondary end points were evaluated, and data on adverse events were collected. RESULTS: Collagenase treatment significantly improved outcomes. More cords that were injected with collagenase than cords injected with placebo met the primary end point (64.0% vs. 6.8%, P < 0.001), as well as all secondary end points (P < or = 0.002). Overall, the range of motion in the joints was significantly improved after injection with collagenase as compared with placebo (from 43.9 to 80.7 degrees vs. from 45.3 to 49.5 degrees, P < 0.001). The most commonly reported adverse events were localized swelling, pain, bruising, pruritus, and transient regional lymph-node enlargement and tenderness. Three treatment-related serious adverse events were reported: two tendon ruptures and one case of complex regional pain syndrome. No significant changes in flexion or grip strength, no systemic allergic reactions, and no nerve injuries were observed. CONCLUSIONS: Collagenase clostridium histolyticum significantly reduced contractures and improved the range of motion in joints affected by advanced Dupuytren's disease. (ClinicalTrials.gov number, NCT00528606.)

Efficacy and safety of injectable mixed collagenase subtypes in the treatment of Dupuytren's contracture.

PURPOSE: To further evaluate the efficacy and safety of an injectable mixed subtype collagenase for the treatment of Dupuytren's contracture (DC). METHODS: Patients with flexion deformities of the metacarpophalangeal (MCP) and/or the proximal interphalangeal (PIP) joints of 20 degrees or greater were randomized in a double-blind, placebo-controlled trial. Patients completing this phase could enter an open-label extension phase. The primary efficacy variable was clinical success: contracture correction to within 5 degrees of normal (normal, 0 degrees ). Additional efficacy variables included the time and number of injections required to achieve success in the primary joint. Recurrence of contracture to 20 degrees or greater in successfully treated joints and adverse events (AEs) were recorded. RESULTS: Thirty-three of 35 patients (mean +/- SD, 61 +/- 9 y) entering the double-blind phase completed the study; 19 of them entered the open-label extension. In the double-blind phase, clinical success of the primary joint was achieved in 16 of 23 patients receiving 1 injection and in 21 of 23 patients receiving 3 injections. No placebo-treated patients achieved joint correction. In the open-label extension, 17 of 19 patients achieved clinical success in at least 1 joint. The mean number of injections for clinical success in the double-blind and extension phases was 1.5 and 1.4, respectively; the time to clinical success ranged between 1 and 29 days. Overall, of 62 joints (31 MCP, 31 PIP) treated in 35 patients, 54 joints achieved clinical success. Over the 24-month follow-up period after the last injection, 5 joints had a recurrence. The most frequent treatment-related AEs were local reactions to injections. AEs were mild and resolved over several weeks. There were no serious treatment-related AEs. CONCLUSIONS: The collagenase injections safely and effectively corrected MCP and PIP contractures in patients with 1 or more DC-affected joints. Recurrence rates after treatment appear to be low. Data suggest that this collagenase appears to be a viable nonsurgical treatment option for DC.

Collagen as a clinical target: nonoperative treatment of Dupuytren's disease.

The cellular events leading to abnormal synthesis of collagen are important to our understanding of pathologic processes leading to impaired joint function. The contracture of Dupuytren's disease is a notable example. In a series of controlled phase-2 clinical trials, excessive collagen deposition in Dupuytren's disease has been targeted by a unique nonoperative method using enzyme (Clostridial collagenase) injection therapy to lyse and rupture finger cords causing metacarpophalangeal and/or proximal interphalangeal joint contractures. Forty-nine patients were treated in a random, placebo-controlled trial of one dose of collagenase versus placebo at one center. Subsequently 80 patients were treated in a random, placebo-controlled, dose-response study of collagenase at 2 test centers. The results of these studies indicate that nonoperative collagenase injection therapy for Dupuytren's disease is both a safe and effective method of treating this disorder in the majority of patients as an alternative to surgical fasciectomy. Phase-3 efficacy trials are now being planned to further develop and test this method under Food and Drug Administration regulatory guidelines. The findings of our study may lead to simpler and less invasive nonoperative treatments of joint limitation in which collagen plays a major pathologic role.