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Purpose: Injectable collagenase Clostridium histolyticum has been an effective and well-tolerated nonsurgical treatment option for the management of Dupuytren contracture of the hand. The purpose of this study was to determine the efficacy of collagenase injection and adverse event rate in patients who had undergone previous collagenase treatment., Methods: A retrospective chart review was performed on 332 patients treated with collagenase injection for Dupuytren contracture by three fellowship-trained hand surgeons at a single institution from 2009 to 2019. Fifty-nine joints in 45 patients underwent repeat collagenase therapy for recurrent contracture in the same digit. Pretreatment and posttreatment total metacarpophalangeal and proximal interphalangeal joint flexion contractures were recorded, with complete correction defined as <5° residual digital flexion contracture. Postmanipulation skin tears and adverse events were recorded. A comparison was made between average contracture improvement after initial collagenase injection and that after repeat injection., Results: Forty-five patients with an average duration of 30 months (range, 6-73 months) between initial and repeat collagenase therapies were identified. The mean improvement after first collagenase injection was 45° ± 24° (39° for metacarpophalangeal joint and 50° for proximal interphalangeal joint) compared with a mean improvement of 43° ± 23° (41° for metacarpophalangeal joint and 44° for proximal interphalangeal joint) after second injection. Although similar complete correction rates and skin tear rates (32.2 % for initial and 30.5% for repeat) were observed between initial (80%) and repeat injections (73%), the occurrence of adverse events was 3 times higher (3.4% for initial and 10.2% for repeat) in the latter group., Conclusions: Collagenase treatment of Dupuytren contracture yields effective total flexion contracture correction. Repeat collagenase treatment of previously treated digits yields similar deformity correction and complete correction rates but a higher incidence of adverse events., Type of Study/level of Evidence: Therapeutic IV., (Copyright © 2024 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine factors associated with skin tearing at the time of manipulation in patients undergoing collagenase Clostridium histolyticum (CCH) treatment for Dupuytren contractures., Methods: We identified 368 digits in 261 patients who underwent a total of 469 CCH treatments at a tertiary care referral center from April, 2010 to December, 2013. Medical records were reviewed for the primary outcome, skin tearing at manipulation. Patient-related and disease-specific explanatory variables were collected. We used bivariate analysis to screen for risk factors and multivariable logistic regression to determine associated risk factors for skin tearing., Results: The overall rate of skin tearing with CCH treatment was 12%. Multivariable logistic regression analysis showed older age (odds ratio = 1.04; 95% confidence interval, 1.00-1.07) and amount of contracture correction (odds ratio = 1.02; 95% confidence interval, 1.01-1.04) to be associated with skin tearing at manipulation., Conclusions: A 10-year increase in age results in a 1.5 times increase in the odds of skin tearing. A 30° increase in contracture correction results in a 1.8 times increase in the odds of skin tearing. Patients can be counseled before CCH treatment that older age and increased contracture correction are risk factors for this common complication., Type of Study/level of Evidence: Prognostic II., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: The primary objective of this study was to quantify the degree of pain associated with collagenase Clostridium histolyticum (CCH) injection and to determine whether it is related to other factors in the intervention., Methods: A prospective study of 135 patients was performed to evaluate pain at 3 points during treatment: (1) after CCH injection, using a numerical rating scale (NRS), (2) a binary (positive/negative) assessment before manipulation 24 hours after CCH and after removing the bandage, and (3) after joint manipulation performed with wrist block anesthesia., Results: The average NRS for pain during infiltration was 4.7. Pain was present before manipulation in 52.6% of patients. Pain from manipulation showed an average NRS score of 3.6. The amounts of pain at CCH infiltration, pain after 24 hours, and pain from the manipulation were correlated because patients who experienced pain during CCH infiltration were more likely to report experiencing pain during manipulation., Conclusions: Collagenase Clostridium histolyticum injection for treating Dupuytren contracture can be a painful process. There is a clear relationship between a patient's level of pain during injection of CCH and the likelihood that the patient will experience pain during manipulation, even with the use of local anesthesia., Type of Study/level of Evidence: Prognostic IV., (Copyright © 2017 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Purpose: To establish patient satisfaction after collagenase clostridium histolyticum (CCH) injection., Methods: In a cross-sectional study, 213 patients who had been treated for Dupuytren disease with CCH were reviewed between 37 and 1421 days after injection., Results: A total of 73% of the patients were very satisfied or satisfied, and 21% were dissatisfied; 75% would probably or definitely have CCH again, whereas 17% probably or definitely would not. We found that satisfaction and willingness to undergo a second treatment decreased over time and had a negative relationship with recurrence. Dissatisfaction was greater in those with a poor initial outcome but not in those with an initial complication. Of 212 patients, 78 had previously experienced surgery for Dupuytren disease of whom 71% would prefer CCH to surgery and 15% the converse. Satisfaction shows a relationship with function as measured by both QuickDASH and the Southampton Dupuytren Scoring Scheme., Conclusions: Patient satisfaction with CCH is generally high but deteriorates over time as the disease recurs. To manage patient expectation, this issue should be made explicit to patients in the consent process., Clinical Relevance: Overall satisfaction with CCH is high, with initial satisfaction rates especially good. Forewarning of complications and recurrence can help maintain satisfaction levels., (Copyright © 2016 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the short-term effectiveness of collagenase Clostridium histolyticum to treat thumb and first web contractures in Dupuytren disease., Methods: We prospectively included 14 thumbs in 12 patients with a contracture at the metacarpophalangeal or interphalangeal joint of at least 20° with a palpable cord in the thumb (n = 8) or an adduction contracture of the thumb with palpable cords in the first web (n = 6). They received an injection containing 0.58 mg of collagenase Clostridium histolyticum in the fibrous cord divided over 3 spots. The contracture was released by carefully manipulating the thumb under local anesthesia 1 day later. The extension and abduction deficits were measured before and after the intervention (follow-up at 7 and 30 days and 6 months). Wilcoxon signed rank test was used to analyze the data., Results: In the total sample, postintervention extension deficits were statistically significantly lower than preintervention deficits except in one patient who had a recurrence at 6 months compared with the 30-day posttreatment result. Intermetacarpophalangeal head distance (IMD) also improved significantly. In an analysis of subgroups, we compared the separate contributions of treatment of a pretendinous cord and a first web cord on both extension deficit and IMD. Treatment of pretendinous cords significantly affected both extension deficit and IMD. However, treatment of first web contractures did not significantly improve extension or IMD., Conclusions: Collagenase Clostridium histolyticum is a good treatment option for pretendinous cords in thumbs affected with Dupuytren disease because it provides good results, is minimally invasive, and has minor adverse events., Type of Study/level of Evidence: Therapeutic IV., (Copyright © 2016 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2015 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2015 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare the efficacy, tolerance, and safety of manual manipulation at day 7 to day 1 following collagenase Clostridium histolyticum (CCH) injection for Dupuytren contracture., Methods: Eligible patients were randomized to manipulation at day 1 versus day 7 following CCH injection. Preinjection, premanipulation, postmanipulation, and 30-day follow-up metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joint contractures were measured. Pain scores were recorded at each time point. Data were stratified per cohort based on primary joint treated (MCP vs PIP). Means were compared using paired and unpaired t-tests., Results: Forty-three patients with 46 digits were eligible and were randomized to 1-day (22 digits) and 7-day (24 digits) manipulation. For MCP joints, there were no significant differences in flexion contractures between 1- and 7-day cohorts for initial (47° vs 46°), postmanipulation (0° vs 2°), or 30-day follow-up (1° vs 2°) measurements. Premanipulation, the residual contracture was significantly lower in the 7-day group (23° vs 40°). For PIP joints, there were no significant differences between 1- and 7-day cohorts for initial (63° vs 62°), premanipulation (56° vs 52°), postmanipulation (13° vs 15°), or 30-day (14° vs 16°) measurements. There were no significant differences in pain or skin tears between the 2 groups. No flexor tendon ruptures were observed., Conclusions: The effectiveness of CCH in achieving correction of Dupuytren contractures was preserved when manipulation was performed on day 7, with no differences in correction, pain, or skin tears. These data suggest that manipulation can be scheduled at the convenience of the patient and surgeon within the first 7 days after injection., Type of Study/level of Evidence: Therapeutic I., (Copyright © 2014 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

We describe technical tips for injecting collagenase into Dupuytren cords based on experience acquired during the prerelease Food and Drug Administration clinical trials and with subsequent clinical practice. These tips include techniques for extracting the reconstituted enzyme efficiently from the vial, injecting the cord(s) with increased safety to the tendons, and anesthetizing the hand before manipulation. The tips are intended to supplement but by no means replace the manufacturer's prescribing information and training video., (Copyright © 2014 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the safety and efficacy of 2 concurrent injections of collagenase clostridium histolyticum (CCH) in the same hand to treat multiple Dupuytren flexion contractures., Methods: In a multicenter, open-label phase IIIb study, 60 patients received two 0.58-mg CCH doses injected into cords affecting 2 joints in the same hand during 1 visit, followed by finger extension approximately 24 hours later. Efficacy at postinjection day 30 (change in flexion contracture and active range of motion, patient satisfaction, physician-rated improvement, and rates of clinical success [flexion contracture 5° or less]) and adverse events were summarized., Results: The concurrent injections were most commonly administered in cords affecting metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints on the same finger (47%) or 2 MCP joints on different fingers of the same hand (37%). Mean total (sum of the 2 treated joints) flexion contracture decreased 76%, from 87° to 24° (MCP joints: 86%; PIP joints: 66%). Mean total range of motion increased from 100° to 161°. Clinical success was 76% for MCP joints and 33% for PIP joints. Most patients were very satisfied (60%) or quite satisfied (28%) with treatment. Most investigators rated treated joints as very much improved (55%) or much improved (37%). The most common treatment-related adverse events (> 75% of patients) were contusion, pain in extremity, and edema peripheral (local edema). Most adverse events were mild to moderate in severity. Serious complications included 1 pulley rupture related to study medication and 1 flexor tendon rupture (following conclusion of the study). There were no systemic complications., Conclusions: Results suggest that 2 affected joints can be effectively and safely treated with concurrent CCH injections. There was an increased incidence of some adverse events with concurrent treatment (pruritus, lymphadenopathy, blood blister, and skin laceration) compared with treatment of a single joint. High degrees of patient satisfaction and physician-rated improvement were reported., Type of Study/level of Evidence: Therapeutic IV., (Copyright © 2014 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Treatment of Dupuytren disease with collagenase clostridium histolyticum is increasingly used among hand surgeons. Although it is generally safe and efficacious, complications related to enzymatic fasciotomy occur. Postapproval surveillance and communication among hand surgeons continues to refine the indications, contraindications, and complications recognized in the treatment of Dupuytren disease with enzymatic therapy. Major treatment-related adverse events previously reported include flexor tendon rupture and complex regional pain syndrome. We report a patient who experienced total loss of a well-established volar ring finger skin graft following collagenase injection and propose a potential mechanism of vulnerability. This case may illustrate the susceptibility of type I collagen, which is uniformly present in a healed skin graft bed, to degradation with collagenase. We propose a cautious approach when considering treatment of a Dupuytren cord with collagenase in the presence of an overlying skin graft, regardless of the age of the graft., (Copyright © 2013 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate long-term efficacy and safety of collagenase clostridium histolyticum (CCH) after the third year of a 5-year nontreatment follow-up study, Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study., Methods: This study enrolled Dupuytren contracture patients from 5 previous clinical studies. Beginning 2 years after their first CCH injection, we re-evaluated patients annually for joint contracture and safety. Recurrence in a previously successfully treated joint (success = 0° to 5° contracture after CCH administration) was defined as 20° or greater worsening in contracture in the presence of a palpable cord or medical/surgical intervention to correct new or worsening contracture. We assessed partially corrected joints (joints reduced 20° or more from baseline contracture but not to 0° to 5°) for nondurable response, also defined as 20° or greater worsening of contracture or medical/surgical intervention., Results: Of 1,080 CCH-treated joints (648 metacarpophalangeal [MCP]; 432 proximal interphalangeal [PIP]; n = 643 patients), 623 (451 MCP, 172 PIP) had achieved 0° to 5° contracture in the original study. Of these joints, 35% (217 of 623) recurred (MCP 27%; PIP 56%). Of these recurrences, an intervention was performed in 7%. Of the 1,080 CCH-treated joints, 301 were partially corrected in the original study. Of these, 50% (150 of 301; MCP: 38% [57 of 152]; PIP: 62% [93 of 149]) had nondurable response. We identified no new long-term or serious adverse events attributed to CCH during follow-up. Anti-clostridial type I collagenase and/or anti-clostridial type II collagenase antibodies were reported for 96% or more of patients who received 2 or more CCH injections and 82% who received 1 injection., Conclusions: The recurrence rate, which is comparable to other standard treatments, and the absence of long-term adverse events 3 years after initial treatment indicate that CCH is an effective and safe treatment for Dupuytren contracture. Most successfully treated joints had a contracture well below the threshold for surgical intervention 3 years after treatment. Recurrence rates among successfully treated joints were lower than nondurable response rates among partially corrected joints., Type of Study/level of Evidence: Therapeutic IV., (Copyright © 2013 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Purpose: The JOINT I (United States) and JOINT II (Australia and Europe) studies evaluated the efficacy and safety of collagenase clostridium histolyticum (CCH) injection for the treatment of Dupuytren contracture., Methods: Both studies used identical open-label protocols. Patients with fixed-flexion contractures of metacarpophalangeal (MCP) (20° to 100°) or proximal interphalangeal (PIP) joints (20° to 80°) could receive up to three 0.58-mg CCH injections per cord (up to 5 total injections per patient). We performed standardized finger extension procedures to disrupt injected cords the next day, with follow-up 1, 2, 6, and 9 months thereafter. The primary end point (clinical success) was reduction in contracture to within 0° to 5° of full extension 30 days after the last injection. Clinical improvement was defined as 50% or more reduction from baseline contracture., Results: Dupuytren cords affecting 879 joints (531 MCP and 348 PIP) in 587 patients were administered CCH injections at 14 U.S. and 20 Australian/European sites, with similar outcomes in both studies. Clinical success was achieved in 497 (57%) of treated joints using 1.2 ± 0.5 (mean ± SD) CCH injections per cord. More MCP than PIP joints achieved clinical success (70% and 37%, respectively) or clinical improvement (89% and 58%, respectively). Less severely contracted joints responded better than those more severely contracted. Mean change in contracture was 55° for MCP joints and 25° for PIP joints. With average contracture reductions of 73% and improvements in range of motion by 30°, most patients (92%) were "very satisfied" (71%) or "quite satisfied" (21%) with treatment. Physicians rated change from baseline as "very much improved" (47%) or "much improved" (35%). The CCH injections were well tolerated, causing no tendon ruptures or systemic reactions., Conclusions: Collagenase clostridium histolyticum was an effective, minimally invasive option for the treatment of Dupuytren contracture of a broad range of severities. Most treated joints (625 of 879) required a single injection. Treatment earlier in the course of disease provided improved outcomes., Type of Study/level of Evidence: Therapeutic IV., (Copyright © 2013 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Purpose: The Collagenase Option for the Reduction of Dupuytren's (CORD) II study investigated the efficacy and safety of injectable Xiaflex (collagenase clostridium histolyticum), in patients with Dupuytren's contracture., Methods: This was a prospective, randomized, placebo-controlled trial with 90-day double-blind and 9-month open-label phases. We randomized patients with contractures affecting metacarpophalangeal (MCP) or proximal interphalangeal (PIP) joints 2 to 1 to collagenase (0.58 mg) or placebo. Cords received a maximum of 3 injections. Cord disruption was attempted the day after injection using a standardized finger extension procedure. Primary end point was reduction in contracture to 0° to 5° of normal 30 days after the last injection., Results: We enrolled 66 patients; 45 cords (20 MCP to 25 PIP joints) received collagenase and 21 cords (11 MCP to 10 PIP joints) received placebo in the double-blind phase. Statistically significantly more cords injected with collagenase than placebo met the primary end point (44.4% vs 4.8%; p <. 001). The mean percentage decrease in degree of joint contracture from baseline to 30 days after last injection was 70.5% ± 29.2% in the collagenase group and 13.6% ± 26.1% in the placebo group (p < .001). The mean increase in range of motion was significantly greater in the collagenase (35.4° ± 17.8°) than in the placebo (7.6° ± 14.9°; p < .001) group. Efficacy after open-label treatment was similar to that after the double-blind phase: 50.7% of all joints achieved 0° to 5° of normal. More patients were satisfied with collagenase (p < .001). No joint had recurrence of contracture. One patient had a flexion pulley rupture and one patient underwent routine fasciectomy to address cord proliferation and sensory abnormality. No tendon ruptures or systemic allergic reactions were reported. Most adverse events were related to the injection or finger extension procedure., Conclusions: Collagenase clostridium histolyticum is the first Food and Drug Administration-approved, nonsurgical treatment option for adult Dupuytren's contracture patients with a palpable cord that is highly effective and well tolerated., Type of Study/level of Evidence: Therapeutic I., (Copyright © 2010. Published by Elsevier Inc.)

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.