Lawrence C. Hurst

Injectable Collagenase Clostridium Histolyticum for Dupuytren's Contracture

BACKGROUND Dupuytrens 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 Dupuytrens 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 Dupuytrens disease. (ClinicalTrials.gov number, NCT00528606.)

Pathobiology of the human A1 pulley in trigger finger

Eighty-nine A1 pulleys from 65 patients with trigger digits and 20 control A1 pulleys from fresh-frozen cadavers were studied comparatively with histology, immunohistochemistry, and transmission electron microscopy. In both normal and pathologic specimens, the A1 pulley was composed of two layers: an outer, vascularized, convex layer and an inner, concave, friction, flexor tendon gliding layer. In the latter, the cells and adjacent matrix had several characteristics of fibrocartilage, including chondrocytes. In trigger digits, the number of chondrocytes and adjacent extracellular matrix was significantly increased when compared with controls. There was no evidence of a synovial cell layer on the surface of the A1 pulleys in either normal or trigger digits. We conclude that the underlying pathobiological mechanism for triggering at the A1 pulley is characterized by a fibrocartilage metaplasia.

The role of transforming growth factor beta in Dupuytren's disease.

This study was undertaken to mark immunologically intracellular and extracellular sites of two common transforming growth factor beta (TGF-beta) isoforms, TGF-beta1 and TGF-beta2, in the proliferative, involutional, and residual stages of Dupuytrens disease. The effect of TGF-beta on myofibroblast proliferation was also studied using explant cultures from Dupuytrens nodules in the proliferative or involutional stage. TGF-beta1, TGF-beta2 and the combination of both isoforms were studied at low and high myofibroblast plating densities to simulate respectively proliferative or involutional disease stage conditions. Our results indicate that TGF-beta1 showed an intense intracellular marking pattern associated with fibroblasts, myofibroblasts, and capillary endothelial cells in all Dupuytrens samples, regardless of disease stage. TGF-beta2 showed an intense intracellular localization within myofibroblasts in the proliferative and involutional stages. Fibroblasts in the residual stage did not contain TGF-beta2. Neither isoform was present in the extracellular matrix. Results of cell culture indicate that compared with control myofibroblasts, the addition of TGF-beta1, TGF-beta2 and TGF-beta1 + beta2 had significant effects on myofibroblast proliferation, especially at higher plating densities. However, TGF-beta2 had the most significant proliferative effect.

Collagenase in the treatment of Dupuytren's disease: An in vitro study***

The effects of clostridial collagenase on the tensile strength of Dupuytrens cords was studied in vitro to assess its potential efficacy as an agent for clinical enzymatic fasciotomy. Collagenase was injected into Dupuytrens cords from patients undergoing fascioctomy. Following a pilot experiment, in which a 3,600-unit dose of collagenase induced a 93% decrease in tensile modulus as compared with control cords, groups of five cords each were injected with 150, 300, and 600 units. These cords and a control group of five cords were tested by loading to failure in tension. The ultimate stress and strain to failure were recorded by a video capture technique. All specimens were stained for histologic examination with hematoxylin and eosin for collagen typing with sirrius red. Comparison of the ultimate stress values obtained with published values of extensor forces obtainable by the individual fingers of 40 normal hands indicated that a 300-unit dose of collagenase was sufficient for cord rupture within the average maximum force limits of the extensors of the index, long, ring, and small fingers (p < .02). All samples were in the residual disease stage histologically and contained type I collagen by sirrius red staining. These results indicate that collagenase may be effective in enzymatic fasciotomy of residual-stage Dupuytrens disease.

The Relationship of the Double Crush to Carpal Tunnel Syndrome (An Analysis of 1,000 Cases of Carpal Tunnel Syndrome)

In this series of 1,000 cases of carpal tunnel syndrome (888 patients) there is a statistically significant incidence of bilaterality in patients with cervical arthritis. There is also a statistically significant increase in the incidence of diabetes mellitus over the general population. These findings lend further support to Uptons Double Crush hypothesis. Further, the double crush syndrome predisposes to bilateral carpal tunnel syndrome and may be an important prognostic factor. It may also be an explanation for some of the failures following carpal tunnel surgery and lead surgeons to look for other associated systemic diseases or mechanical blocks, when attempting to alleviate recalcitrant symptoms.

Platelet-derived growth factor in Dupuytren's disease.

This study investigated whether platelet-derived growth factor, a potent inducer of cell proliferation, was identifiable in association with myofibroblasts in Dupuytrens disease. Myofibroblasts in the hypercellular disease stages showed a strong reaction to platelet-derived growth factor antibody using light and electron microscopic immunochemical labels. Platelet-derived growth factor may play a role as a cellular signal for myofibroblast proliferation in the formation of the pathognomonic nodule in Dupuytrens disease.

The pathogenesis of Dupuytren's contracture: Contractile mechanisms of the myofibroblasts

The role of myofibroblasts in the pathogenesis of Dupuytrens contracture was investigated by light and electron microscopic histochemical methods. Dupuytrens myofibroblasts contain an intracellular contractile mechanism that is driven by the dephosphorylation of adenosine triphosphate. Our study of calcium adenosinetriphosphatase (ATPase) activities verifies that the site of this energy system is on the myofilaments of the myofibroblasts. The degree of ATPase activity, as determined by cell counts, appeared to correlate with the residual contracture as predicted by the Legge and McFarlane Outcome Standard Formula. Further, alcian blue staining on the ultrastructural level indicates that the myofibroblasts are associated with each other and with surrounding collagen by a glycosaminoglycan matrix 300 to 1000 A thick. Collagen fibrils are attached by a similar matrix comprised of 100 A thick fibrils. The dynamic cellular architecture of the multiple adjacent myofibroblasts with their connections to surrounding collagen may be partially responsible for the residual clinical deformities seen in this disease.

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.

Scapholunate dissociation: An experimental kinematic study of two types of indirect soft tissue repairs

Indirect soft tissue repairs of scapholunate dissociation (SLD) address the pathophysiology but have been criticized for significantly limiting wrist flexion and altering wrist kinematics. This study was designed to analyze and compare the kinematics of a normal cadaveric wrist to those of 2 types of soft tissue repairs performed for SLD. Ten uninjured fresh cadaver arms were evaluated by cineradiography and standard x-rays. The average scapholunate (SL) gap was 0.9 mm, with a SL angle of 50 degrees. A model of SLD was produced by sectioning the SL ligaments resulting in an average SL gap of 3.9 mm and SL angle of 66 degrees. The wrists were randomized to a dorsal capsulodesis repair and a distally based split extensor carpi radialis longus (ECRL) repair. The average SL gap after repair was 1.0 mm and the average SL angle was 47 degrees. The split ECRL repair and dorsal capsulodesis reduced scaphoid flexion with only a 10 degree and 18 degree decrease in wrist flexion, respectively. Both repairs reduced the SLD and restored normal wrist kinematics.

The pathobiology of Dupuytren's contracture: Effects of prostaglandins on myofibroblasts

The in vitro response of myofibroblasts to prostaglandins F2alpha (a vasoconstrictor) and E2 (a vasodilator) were evaluated in specimens obtained from the Dupuytrens nodules of 12 patients. Fibroblasts from four control samples of palmar fascia were similarly tested. This study demonstrated the ability of prostaglandin F2alpha to induce significant contraction of myofibroblasts. Prostaglandin E2 was noted to cause significant relaxation of myofibroblasts. The contractile/relaxation responses of control fibroblasts to these prostaglandins were minimal.