Søren Larsen

The Efficacy and Safety of Concurrent Collagenase Clostridium Histolyticum Injections for 2 Dupuytren Contractures in the Same Hand: A Prospective, Multicenter Study

PURPOSE To evaluate efficacy and safety of concurrent administration of 2 collagenase clostridium histolyticum (CCH) injections to treat 2 joints in the same hand with Dupuytren fixed flexion contractures (FFCs). METHODS Patients with 2 or more contractures in the same hand caused by palpable cords participated in a 60-day, multicenter, open-label, phase 3b study. Two 0.58 mg CCH doses were injected into 1 or 2 cords in the same hand (1 injection per affected joint) during the same visit. Finger extension was performed approximately 24, 48, or 72 or more hours later. Changes in FFC and range of motion, incidence of clinical success (FFC ≤ 5°), and adverse events (AEs) were summarized. RESULTS The study enrolled 715 patients (725 treated joint pairs), and 714 patients (724 joint pairs) were analyzed for efficacy. At day 31, mean total FFC (sum of 2 treated joints) decreased 74%, from 98° to 27°. Mean total range of motion increased from 90° to 156°. The incidence of clinical success was 65% in metacarpophalangeal joints and 29% in proximal interphalangeal joints. Most treatment-related AEs were mild to moderate, resolving without intervention; the most common were swelling of treated extremity, contusion, and pain in extremity. The incidence of skin lacerations was 22% (160 of 715). Efficacy and safety were similar regardless of time to finger extension. CONCLUSIONS Collagenase clostridium histolyticum can be used to effectively treat 2 affected joints concurrently without a greater risk of AEs than treatment of a single joint, with the exception of skin laceration. The incidence of clinical success in this study after 1 injection per joint was comparable to phase 3 study results after 3 or more injections per joint. Two concurrent CCH injections may allow more rapid overall treatment of multiple affected joints, and the ability to vary the time between CCH injection and finger extension may allow physicians and patients greater flexibility with scheduling treatment.

Genetic and environmental influences in Dupuytren's disease: A study of 30,330 Danish twin pairs

We aimed to assess the relative contribution of genes and environment in the aetiology of Dupuytren’s disease by studying Danish twins born between 1870 and 2000. Twins with a diagnosis (n = 365) and the subgroup who also had an operation (n = 259) after 1977 were identified through linkage with a nationwide hospital registry among 30,330 monozygotic and same-sexed dizygotic twin pairs. Since monozygotic twins share all their genes and dizygotic twins share on average half of their genetic material, greater phenotypic similarity is expected in monozygotic than in dizygotic twins if a genetic component is involved. The number of concordant male twin pairs with Dupuytren’s disease was 17 and 7 (monozygotic and dizygotic pairs, respectively), compared with 60 and 174 discordant monozygotic and dizygotic pairs, yielding probandwise concordance rates of 0.37 (95% confidence interval (CI): 0.26 to 0.50) and 0.07 (95% CI: 0.04 to 0.14), respectively. The heritability of Dupuytren’s disease was approximately 80%. We conclude that genetic factors play a major role in the development of Dupuytren’s disease. Level of evidence: 3

Bone bank service in Odense, Denmark. Audit of the first ten years with bone banking at the Department of Orthopaedics, Odense University Hospital

There has been an increase in the demand for allograft bone in recentyears. The Odense University Hospital bone bank has been in function since1990,and this paper outlines our results during the 10 year period 1990–1999.Potential donors were screened by contemporary banking techniques which includea social history, donor serum tests for HIV, hepatitis B and C, and graftmicrobiology. The bones were stored at −80 °C. No typeofsecondary sterilisation was made. 423 femoral heads were approved and donatedto300 patients,1–6 heads/operation. The allografts have been used mainly toreconstruct defects at revision hip arthroplasty (34%), and for fracturesurgery(24%). 7 % of all transplanted patients were reoperated because of infection.Inthe hip revision group the infection rate was 4 %. There were no cases ofdisease transmission. During the 10 year period there was a change in theclinical use of the allografts. In the first years the allografts were mainlyused for spinal fusion surgery, but today the majority are used in hip revisionand fracture surgery. The clinical results correspond to those reported inlarger international series.

PXL01 in Sodium Hyaluronate for Improvement of Hand Recovery after Flexor Tendon Repair Surgery: Randomized Controlled Trial

Background Postoperative adhesions constitute a substantial clinical problem in hand surgery. Fexor tendon injury and repair result in adhesion formation around the tendon, which restricts the gliding function of the tendon, leading to decreased digit mobility and impaired hand recovery. This study evaluated the efficacy and safety of the peptide PXL01 in preventing adhesions, and correspondingly improving hand function, in flexor tendon repair surgery. Methods This prospective, randomised, double-blind trial included 138 patients admitted for flexor tendon repair surgery. PXL01 in carrier sodium hyaluronate or placebo was administered around the repaired tendon. Efficacy was assessed by total active motion of the injured finger, tip-to-crease distance, sensory function, tenolysis rate and grip strength, and safety parameters were followed, for 12 months post-surgery. Results The most pronounced difference between the treatment groups was observed at 6 months post-surgery. At this timepoint, the total active motion of the distal finger joint was improved in the PXL01 group (60 vs. 41 degrees for PXL01 vs. placebo group, p = 0.016 in PPAS). The proportion of patients with excellent/good digit mobility was higher in the PXL01 group (61% vs. 38%, p = 0.0499 in PPAS). Consistently, the PXL01 group presented improved tip-to-crease distance (5.0 vs. 15.5 mm for PXL01 vs. placebo group, p = 0.048 in PPAS). Sensory evaluation showed that more patients in the PXL01 group felt the thinnest monofilaments (FAS: 74% vs. 35%, p = 0.021; PPAS: 76% vs. 35%, p = 0.016). At 12 months post-surgery, more patients in the placebo group were considered to benefit from tenolysis (30% vs. 12%, p = 0.086 in PPAS). The treatment was safe, well tolerated, and did not increase the rate of tendon rupture. Conclusions Treatment with PXL01 in sodium hyaluronate improves hand recovery after flexor tendon repair surgery. Further clinical trials are warranted to determine the most efficient dose and health economic benefits. Trial Registration ClinicalTrials.gov NCT01022242; EU Clinical Trials 2009-012703-25.

Difference in Success Treating Proximal Interphalangeal and Metacarpophalangeal Joints with Collagenase: Results of 208 Treatments

Background: Dupuytren disease (DD) is a fibroproliferative disorder of the palmar fasciae causing extension deficit and impaired hand function. Treatment with injection of collagenase clostridium histolyticum (CCH) is a nonsurgical treatment method. The aim of this study was to evaluate the difference in efficiency and recurrence at 12-month follow-up when treating metacarpophalangeal (MP) and proximal interphalangeal (PIP) joints with CCH. None of the patients had received previous treatments of their condition. Methods: This study is a prospective study of a consecutive series of patients with DD presenting with an extension deficit greater than 20° affecting the MP or PIP joint. Results: We found a mean reduction in extension deficit of 47° (91%) for MP joints and 47° (76%) for PIP joints. Full correction (max 5° deficit) was achieved in 76% of MP and 28% of PIP joints. Skin rupture was seen in 34% of treatments. The 1-year relapse rate was 15% for MP and 67% for PIP joints. The reduction in quickDASH score was only statistically significant for MP joints at 1 year. Eighty-one percent of all patients reported being satisfied or very satisfied. No major adverse events were recorded. Conclusion: Excellent results can be achieved in the treatment of MP-joint contractures, whereas the success rate is significantly lower and recurrence rate is greater for PIP joints.

Missed isolated volar dislocation of the scaphoid

A patient presented with volar dislocation of the scaphoid, the diagnosis of which had been missed for two weeks. He was treated with open reduction through a combined volar and dorsal approach with decompression of the median nerve, internal fixation, and a cast for eight weeks. One year postoperatively the functional result was good. A radiograph showed no sign of avascular necrosis.

Five-year results after collagenase treatment of Dupuytren disease

This study assesses the joint-specific sustained effect of collagenase clostridium histolyticum treatment of Dupuytren disease over a 5-year follow-up period. The study includes 107 consecutive treatments in patients with extension deficits greater than 20° affecting the metacarpophalangeal or proximal interphalangeal joints. Success was defined as no follow-up treatment due to relapse or maintained extension deficit less than 20°. The 5-year estimate of no follow-up treatment was 79% (95% CI: 64–88) for metacarpophalangeal and 49% (95% CI: 26–69) for proximal interphalangeal joints, which was a significant difference (log-rank test, p = 0.0044). For those who did not undergo re-treatment, a non-significant relapse was found for metacarpophalangeal joints and a 65% (34°, 95% CI: 24–46) relapse for proximal interphalangeal joints. We conclude that treating metacarpophalangeal joints with collagenase clostridium histolyticum is effective with acceptable recurrence rates. However, when treating proximal interphalangeal joints with collagenase clostridium histolyticum, patients should be informed of the high risk of recurrence and the greater chance of need for further treatment. Level of evidence: II

PXL01 in Sodium Hyaluronate for Improvement of Hand Recovery After Flexor Tendon Repair Surgery: Randomized Controlled Trial : Level 1 Evidence

Background: Postoperative adhesions constitute a substantial clinical problem in hand surgery. Fexor tendon injury and repair result in adhesion formation around the tendon, which restricts the gliding function of the tendon, leading to decreased digit mobility and impaired hand recovery. This study evaluated the efficacy and safety of the peptide PXL01 in preventing adhesions, and correspondingly improving hand function, in flexor tendon repair surgery. Methods: This prospective, randomised, double-blind trial included 138 patients admitted for flexor tendon repair surgery. PXL01 in carrier sodium hyaluronate or placebo was administered around the repaired tendon. Efficacy was assessed by total active motion of the injured finger, tip-to-crease distance, sensory function, tenolysis rate and grip strength, and safety parameters were followed, for 12 months post-surgery. Results: The most pronounced difference between the treatment groups was observed at 6 months post-surgery. At this timepoint, the total active motion of the distal finger joint was improved in the PXL01 group (60 vs. 41 degrees for PXL01 vs. placebo group, p = 0.016 in PPAS). The proportion of patients with excellent/good digit mobility was higher in the PXL01 group (61% vs. 38%, p = 0.0499 in PPAS). Consistently, the PXL01 group presented improved tip-to-crease distance (5.0 vs. 15.5 mm for PXL01 vs. placebo group, p = 0.048 in PPAS). Sensory evaluation showed that more patients in the PXL01 group felt the thinnest monofilaments (FAS: 74% vs. 35%, p = 0.021; PPAS: 76% vs. 35%, p = 0.016). At 12 months post-surgery, more patients in the placebo group were considered to benefit from tenolysis (30% vs. 12%, p = 0.086 in PPAS). The treatment was safe, well tolerated, and did not increase the rate of tendon rupture. Conclusions: Treatment with PXL01 in sodium hyaluronate improves hand recovery after flexor tendon repair surgery. Further clinical trials are warranted to determine the most efficient dose and health economic benefits. Trial Registration: ClinicalTrials.gov NCT01022242; EU Clinical Trials 2009-012703-25. Citation: Wiig ME, Dahlin LB, Fridén J, Hagberg L, Larsen SE, et al. (2014) PXL01 in Sodium Hyaluronate for Improvement of Hand Recovery after Flexor Tendon Repair Surgery: Randomized Controlled Trial. PLoS ONE 9(10): e110735. doi:10.1371/journal.pone.0110735 Editor: Alberto G. Passi, University of Insubria, Italy Received April 13, 2014; Accepted September 15, 2014; Published October 23, 2014 Copyright: 2014 Wiig et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. The data is presented in the body of the paper and in the Supporting Information files, and deposited to public databases (EudraCT: 2009-012703-25, ClinicalTrials.gov: NCT01022242). Funding: The study was financed by Pergamum AB. M. Mahlapuu is CSO of Pergamum, PhD. The funder provided support in the form of salary for author MM, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ’author contributions’ section. Dr. K. Wiklund is employed by Pharma Consulting Group Solutions AB. Pharma Consulting Group Solutions AB provided support in the form of salary for author KW, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ’author contributions’ section. Competing Interests: The authors have read the journal’s policy and the following conflicts have been identified: Dr. M. Mahlapuu was employed by Pergamum AB, Dr. M. Wiig has received honorariums and held advisory board positions for Pergamum AB. The study was financed by Pergamum AB. Dr. K. Wiklund is employed by Pharma Consulting Group Solutions AB. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. * Email: monica.wiig@akademiska.se