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

doi:10.1053/jhsu.2002.35299

The Journal of Hand Surgery

Volume 27, Issue 5, September 2002, Pages 788-798

https://doi.org/10.1053/jhsu.2002.35299 Get rights and content

Abstract

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. (J Hand Surg 2002;27A:788–798. Copyright © 2002 by the American Society for Surgery of the Hand.)

Section snippets

Materials and methods

Two clinical trials were conducted under a Food and Drug Administration (FDA) investigational new drug number and institutional review board approvals. The first trial (clinical trial IIA) was a randomized, double-blind, placebo-controlled study of Clostridial collagenase injection (Advance Biofactures Corp, Lynbrook, NY) at a single dose of 10,000 U versus placebo at a single center (State University of New York [SUNY], Stony Brook, NY). Patients with either MP joint contractures or those with

Clinical trial IIB: Dose-response study

Because the results of clinical trial IIA clearly indicated that 10,000-U collagenase injection had substantial merit in restoring patients to normal hand function, discussions were held with the FDA Center for Biologics Evaluation and Research to determine the design of subsequent clinical testing. It was decided that a random, placebo-controlled, double-blind dose study of collagenase injection for Dupuytren's disease should be performed to test whether 10,000 U of collagenase was indeed the

Clinical trial IIB: Collagenase pharmacokinetics

To determine the acute phase pharmacokinetics of collagenase, 4 male Dupuytren's (MP) patients (mean age 63 y) were enrolled in an open-label substudy to investigate absorption of collagenase into serum and excretion in urine. A 10,000-U dose was delivered to the target finger cord and blood samples were obtained before injection and 1, 10, 30, 60, and 180 minutes after injection. An additional blood sample was obtained at day 1 after injection (19.5 h). Urine samples were obtained before

Clinical trial IIB: Lidocaine local anesthesia

An open-label substudy in 5 male Dupuytren's (MP) patients (mean age 58 y) was conducted by using 5 mL of 1% injectable lidocaine as local hand anesthesia on day 1 after injection before cord manipulation/rupture. This substudy was performed to test the lidocaine anesthesia as an option to offer patients who were unwilling or unable to tolerate the momentary pain of cord rupture. A 10,000-U collagenase dose was injected into the target finger cord. On day 1 after injection, 5 mL of 1% lidocaine

Clinical trial IIA: MP joints

The mean initial contracture in patients with MP joint disease was 44° ± 17.4°, range 20° to 90°. In the 10,000-U collagenase treatment group (n = 18), 9 of the 18 patients showed a reduction in contracture to within 0° to 5° within 7 days after injection, compared with only 2 of the 18 patients in the placebo treatment group. At 1 month after injection, 14 of the 18 patients in the collagenase treatment group showed correction of contracture to within 0° to 5°, compared with 2 of 18 patients

Discussion

These studies have shown that collagenase injection into the cord causing MP and/or PIP joint contractures in Dupuytren's disease is a safe and effective method in the majority of patients in restoring normal finger extension and thus improving range of finger motion. Flexion and grip strength were not adversely affected by collagenase injection.

A random, placebo-controlled, dose-response study in clinical trial IIB showed that 10,000 U of collagenase is the minimum safe and effective dose for

Acknowledgements

The authors thank Gail Trocchio, Yvonne Leippert, RN, Maria Valentino, RN, Karen DeChello, OTR, Carolyn Gordon, OTR-CHT, Frank Albergo, RPh, and Marty Hamilton, RPh, for their assistance.

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Cited by (126)

Dutch Multidisciplinary Guideline on Dupuytren Disease
2023, Journal of Hand Surgery Global Online
To provide a comprehensive, evidence-based overview of the treatment for Dupuytren disease, specifically needle techniques, radiotherapy, primary conservative therapy, surgery, lipofilling, operative arthrolysis, salvage techniques, and the postoperative protocol and to make clinical recommendations for health care practitioners and patients.
Comprehensive multidisciplinary guideline process funded by the Quality Foundation of the Dutch Federation of Medical Specialists. This process included a development, commentary, and authorization phase. Patients participated in every phase. Multiple databases and existing guidelines up to August 2020 were searched. Studies on Dupuytren disease were considered eligible. Specific eligibility criteria were described per module. To appraise the certainty of the evidence, reviewers extracted data, assessed the risk of bias, and used the Grading of Recommendations Assessment, Development and Evaluation method, where applicable. Important considerations were as follows: patient values and preferences, costs, acceptability of other stakeholders, and feasibility of implementation. Recommendations were made based on the evidence from the literature and the considerations. The primary and secondary outcome measures were defined per module based on the input of patients obtained in collaboration with the Netherlands Patient Federation and health care providers from different professions.
The following 8 specific modules were completed for Dupuytren disease: (1) needle techniques, (2) radiotherapy, (3) primary conservative therapy, (4) surgery, (5) lipofilling, (6) operative arthrolysis, (7) salvage techniques, and (8) the postoperative protocol.
Our Dutch multidisciplinary guideline on Dupuytren disease provides 8 modules developed according to the standards of the Dutch Federation of Medical Specialists. Evidence-based recommendations for clinical practice are provided for needle techniques, radiotherapy, primary conservative therapy, surgery, lipofilling, operative arthrolysis, salvage techniques, and the postoperative protocol. This guideline can assist health care providers and patients in clinical practice.
Systematic review/I-II.
Does Use of a Night Extension Orthosis Improve Outcomes in Patients With Dupuytren Contracture Treated With Injectable Collagenase?
2021, Journal of Hand Surgery Global Online
Current prescribing information for the treatment of patients with Dupuytren contracture with injectable collagenase Clostridium histolyticum (CCH) recommends use of a night extension orthosis for 4 months after treatment. The present study examines whether this treatment improves the outcomes.
Adult patients with Dupuytren contracture treated with CCH during the study period were eligible for inclusion. The patients were randomized to orthosis or no orthosis groups and were stratified based on the severity of contracture prior to randomization. The orthosis group was fitted postmanipulation with a hand-based custom orthosis that held the treated finger in maximal comfortable extension, and the patients were instructed to wear the orthosis at night for 3 months. The patients were assessed at 7–10 days, 30 days, and 90 days postmanipulation. Orthosis compliance was measured with a survey. The primary outcome measure was improvement in total active extension (TAE), defined as the sum of active metacarpophalangeal (MCP), proximal interphalangeal, and distal interphalangeal joint extension in the treated finger at 90 days after treatment. Secondary outcomes included total active flexion (TAF), Michigan Hand Questionnaire scores, patient satisfaction, and clinical success.
Twenty-six patients completed the study, 12 in the orthosis group and 14 in the no orthosis group. The majority of contractures (90%) were primarily through the MCP joint. The patients in both the groups demonstrated significant improvements in TAE at 90-day follow-up (orthosis P = .002, no orthosis P = .001) . The difference in improvement in the median TAE between the 2 groups was not significant (P = .40). There were no significant differences between groups for TAE, TAF, Michigan Hand Questionnaire scores, patient satisfaction, or clinical success at any of the time points assessed (P > .05).
In patients with Dupuytren contracture with primarily MCP joint involvement, providing an orthosis after treatment with CCH may not offer a short-term benefit compared with CCH treatment alone in terms of TAE, TAF, or patient-reported outcome measures.
Therapeutic I.
Risk Factors for Skin Tears Following Collagenase Clostridium histolyticum to Treat Dupuytren Contractures
2020, Journal of Hand Surgery
Skin tears are an unpleasant complication that may occur after collagenase Clostridium histolyticum (CCH) administration to treat Dupuytren contractures of the fingers. The purpose of this study was to determine risk factors for the development of this complication.
Over a 6-year period, patients with a measurable metacarpophalangeal or proximal interphalangeal joint Dupuytren contracture and a palpable cord treated with CCH were prospectively observed. Patients were assessed for the development of skin tears immediately on the day of manipulation as well 30 days or more after manipulation.
A total of 117 patients (174 cords) met inclusion criteria. There was a 25.6% incidence of skin tears (30 of 117 patients; 33 skin tears). Multivariable regression analysis revealed that patients with a combined digital flexion contracture (total combined metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joint contracture) of 75° and greater and those treated with 2 simultaneous doses of CCH in the same hand were more likely to sustain a tear. All skin tears healed with nonsurgical management at short-term follow-up.
Although a relatively minor complication, skin tears are not well-tolerated by all patients and may change the postinjection course of orthosis use, wound care, and manual activity. Based on these results, patients with digital contractures 75° or greater and those treated with 2 simultaneous doses of CCH in the same hand may be counseled that they have a higher likelihood of developing a skin tear during manipulation. Pretreatment education may reduce anxiety experienced by patients who otherwise unexpectedly develop a skin tear at the time of manipulation.
Therapeutic II.
Acute Pain Intensity After Collagenase Clostridium histolyticum Injection in Patients With Dupuytren Contracture
2020, Journal of Hand Surgery Global Online
To investigate multidimensional pain intensity and quality after collagenase Clostridium histolyticum (CCH) injection in patients with Dupuytren contracture using a pain visual analog scale (VAS) and the revised version of the Short-Form McGill Pain Questionnaire (SF-MPQ-2).
This prospective observational study was carried out from 2015 to 2017. As a primary end point, patients completed the pain VAS (range, 0 [no pain] to 100) and SF-MPQ-2 before and after CCH injection; 3, 9, and 24 hours after CCH injection; after the extension procedure; and 3 and 7 days after CCH injection. In addition, they reported the dose and duration of supplementary analgesic use during this period.
A total of 41 patients were enrolled in this study (51 joints). Mean pain VAS score (mean ± SD, 34 ± 21) was maximal 9 hours after CCH injection and decreased within the following 7 days. The total score of the SF-MPQ-2 significantly increased after CCH treatment and decreased in the 7 days after the injection. Among the SF-MPQ-2 subscales, the highest and lowest scores after CCH injection were recorded for continuous pain and affected descriptors, respectively. Nonsteroidal anti-inflammatory drugs were most frequently self-administered during 7 days after the extension procedure compared with any other study period.
The pain VAS and SF-MPQ-2 revealed acute pain after CCH injection. However, all examined pain aspects dramatically improved within 7 days after injection. Pain after CCH injection is characterized by low scores in the Affective Descriptors subscale of the SF-MPQ-2.
Prognostic Ⅳ.
Dupuytren's disease, clinical aspects and therapeutic strategy
2019, Actualites Pharmaceutiques
La maladie de Dupuytren est liée à un épaississement de l’aponévrose palmaire s’accompagnant d’une rétraction qui limite l’extension des doigts et peut infiltrer la peau. Le pharmacien d’officine doit connaître aussi bien la clinique que les traitements actuellement disponibles.
Dupuytren's disease, clinical aspects and therapeutic strategy. Dupuytren's disease is linked to a thickening of the palmar fascia, accompanied by a retraction which limits extension of the fingers and can infiltrate the skin. The pharmacist should be familiar with both the clinic and the treatments currently available.
Durability of Collagenase Treatment for Dupuytren Disease of the Thumb and First Web After at Least 2 Years’ Follow-Up
2019, Journal of Hand Surgery
The aim of this study was to analyze the durability of the treatment results of the thumb and first web contractures in Dupuytren disease with collagenase Clostridium histolyticum.
Twelve patients (14 hands) were followed for an average of 35 months (range, 24–42 months). Two patients (3 hands) were excluded, yielding 11 hands available for assessment. Nondurability was defined as a worsening of at least 20° of passive extension deficit at a treated joint or any decrease greater than 5 mm in intermetacarpal head distance, both relative to 30 days after injection or as intervention to correct new/worsening contracture. Durability was compared with that of a historic cohort of treated finger contractures.
Five out of 11 patients with a metacarpophalangeal or interphalangeal joint contracture or first web contracture had a nondurable result at an average of 35 months. Results obtained at metacarpophalangeal joints of thumbs were more durable than those of interphalangeal joints. Most of the recurrences occurred in interphalangeal joints.
Treatment of thumb and first web contractures was not durable in nearly half of the cases at an average follow-up of 35 months, and durability was clearly less than that of treated finger contractures.
Therapeutic IV.

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^*: Supported by grants from the U.S. Food and Drug Administration (FD-R-001437), the National Institutes of Health (General Clinical Research Center Grant [M01RR1071002]), and the Advance Biofactures Corporation, Lynbrook, NY.

^**: The author or one or more of the authors have received or will receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this article.

^*: The investigators have received research support and do not hold stock or stock options nor have a royalty interest in the technology described.

^**: The FDA has not yet cleared the items for the uses described.

^*: Reprint requests: Marie A. Badalamente, PhD, Department of Orthopedics, State University of New York at Stony Brook, Health Science Center T18, Stony Brook, NY 11794.

View full text

Original CommunicationsCollagen as a clinical target: Nonoperative treatment of Dupuytren's disease*,**,*,**,*

Abstract

Section snippets

Materials and methods

Clinical trial IIB: Dose-response study

Clinical trial IIB: Collagenase pharmacokinetics

Clinical trial IIB: Lidocaine local anesthesia

Clinical trial IIA: MP joints

Discussion

Acknowledgements

J Hand Surg

J Hand Surg

J Hand Surg

J Hand Surg

J Hand Surg

J Hand Surg

Int J Radiat Oncol Biol Phys

Hand

J Hand Surg

J Hand Surg

J Hand Surg

Dupuytren's contracture: fibroblast contraction?

An ultrastructural study.

Am J Pathol

Extracellular matrix-cytoskeleton connections at the surface of the specialized contractile fibroblast (myofibroblast) in Dupuytren disease

J Bone Joint Surg

Original Communications
Collagen as a clinical target: Nonoperative treatment of Dupuytren's disease*,**,*,**,*