|Year : 2021 | Volume
| Issue : 2 | Page : 49-55
Collagenase clostridium histolyticum injection in the treatment of dupuytren's contracture: A systematic review
Gandavaram Srikanth Reddy1, Raviprasad Kattimani2, Chetan M Dojode3, Dhritiman Bhattacharjee4, Randeep Mohil5
1 Specialty Doctor in Trauma and Orthopaedics, Lancaster Royal Infirmary, Lancaster, UK
2 Specialty Doctor in Trauma and Orthopaedics, Macclesfield District General Hospital, Macclesfield, UK
3 Specialty Doctor in Trauma and Orthopaedics, East Surrey Hospital, Redhill, UK
4 Specialty Doctor in Trauma and Orthopaedics, Glan Clwyd Hospital, UK
5 Consultant in Trauma nd Orthopaedics, Royal Blackburn and Bunrley Genenral Hospitals, UK
|Date of Submission||09-Dec-2021|
|Date of Acceptance||10-Dec-2021|
|Date of Web Publication||27-Jan-2022|
Specialty Doctor in Orthopaedics, Macclesfield District General Hospital Macclesfield
Source of Support: None, Conflict of Interest: None
Background: Dupuytren's Contracture is a condition affecting the fascia in hands and fingers causing finger bends in toward the palm. This debilitating disease can affect the activities of daily living. Surgery has been the main stay of treatment, but it is not devoid of complications. Recently, Collagenase Clostridium histolyticum injection has shown better results. There is concern over the efficacy and safety. There is a need for a systematic review that provides high-quality evidence to help surgeons choose the appropriate treatment. Aims: The aim of the study was to assess the effectiveness of the Collagenase Clostridium histolyticum injection by assessing the outcome; correction of deformity, increase in range of movement (ROM) of the finger, and patient satisfaction and also to identify the adverse reactions and recurrence rate. Methods: A systematic review was undertaken. Literature search was done using strict search criteria from electronic databases (MEDLINE, EMBASE, CINAHL, BNI, and Cochrane Library) and trial registers. Two independent authors conducted the study selection, data extraction, and quality assessment of each study. Narrative approach to data synthesis was adopted. Results: Four randomized controlled trials, four observational studies, and two follow-up studies were included. In all the studies, favorable outcomes in deformity correction and increase in ROM were found. Injection treatment had more mild-to-moderate complications which was statistically significant. Conclusion: The review suggests favorable outcome following collagenase injection, especially in metacarpophalygeal joint contractures. More research is needed to assess its efficacy in proximal interphalygeal joints. There is a need for cost analysis between injection and surgical treatment.
Keywords: Clostridium histolyticum, collagenase, contracture, dupuytrens, injection
|How to cite this article:|
Reddy GS, Kattimani R, Dojode CM, Bhattacharjee D, Mohil R. Collagenase clostridium histolyticum injection in the treatment of dupuytren's contracture: A systematic review. J Orthop Assoc South Indian States 2021;18:49-55
|How to cite this URL:|
Reddy GS, Kattimani R, Dojode CM, Bhattacharjee D, Mohil R. Collagenase clostridium histolyticum injection in the treatment of dupuytren's contracture: A systematic review. J Orthop Assoc South Indian States [serial online] 2021 [cited 2022 May 27];18:49-55. Available from: https://www.joasis.org/text.asp?2021/18/2/49/336660
| Introduction|| |
Dupuytren's disease is an autosomal dominant progressive genetic disorder of hand. Dupuytren's disease affects the palmar fascial complex by fibroblast proliferation and formation of excessive collagen. The disease cords are formed from the normal fascial bands within the palm and the digits. As a result of this, the palmar cords cause contracture at the metacarpophalangeal joint, and the digital cords cause contracture at the proximal interphalangeal joint. The standard treatment for Dupuytren's contracture disease is surgery. The most common surgical procedure being open fasciectomy. Other surgical procedures include open fasciotomy and percutaneous needle fasciotomy. Surgery for Dupuytren's disease is often successful, but it requires extensive hand therapy in postoperative period and is associated with complications. The recurrence rates after surgery is between 26% and 80%.
Over the last few years, Collagenase Clostridium Histolyticum (CCH) injection has been used and is gaining importance in treatment of Dupuytren's disease as this intervention can avoid surgery and the complications associated with it. Collagenase injection is produced by a bacterium Clotridium histiolyticum which lyses the collagen of the diseased cords leading to disruption of contracture. It is a simple procedure which does not require any anesthesia and does not require extensive hand therapy, and therefore it has a theoretical advantage over surgical fasciectomy. This systematic review will provide relevant evidence for the orthopedic surgeons in making decisions to manage Dupuytren's contracture using CCH.
The aim of this study is to ascertain the effectiveness of the clostridium collagenase histolyticum injection (CCH).
To determine the effect of CCH injection on Dupuytren's contracture with respect to deformity correction of finger, range of movements (ROMs), regaining function of fingers and hand, patient satisfaction, and the complications associated with the procedure.
| Methods|| |
Studies with adult population above 19 years were included in this study. Studies on both primary and recurrent Dupuytren's contracture treated with CCH injection were included. Randomised control trial (RCT), Quasi RCTs, cohort studies and case control studies, and case series with good and effective number were included. Studies written in English only were included.
Case reports, expert opinion, and review articles were excluded from the study, and studies done on patients with chronic muscular, neurological, and neuromuscular disorder affecting the hand and allergies to collagenase injection were also excluded.
Electronic databases have been used for the literature search. The search has been undertaken in the National Institute of Clinical Excellence evidence health-care databases 2017, EMBASE, MEDLINE, and CINAHL and Cochrane databases were searched. Manufacturers of CCH injection for Dupuytren's contracture were also contacted for any information about the recent unpublished research and ongoing research in the hospitals. Research centers and specialist libraries have been contacted.
Data collection and analysis
Screening of studies against the inclusion and exclusion criteria and data extraction was undertaken by two independent authors (GS and DB) to reduce selection bias. Disagreements between authors regarding the risk of bias were resolved by consensus. Nonrandomized studies were also independently assessed and scored by the two review authors using the checklist for quantitative studies from health technology assessment.
| Results|| |
The search resulted in the identification of 46 potentially eligible studies from the electronic databases. An additional 17 articles were identified through citation tracking. A total of 22 unique titles and/or abstracts were reviewed, and 16 articles were selected for full-text assessment. After applying the inclusion and exclusion criteria, ten studies were included in this systematic review (see [Figure 1]). In this review, ten articles have been included. There are four RCTs,,,, four prospective studies,,,, and two follow-up studies., All the studies included adult population with Dupuytrens contracture treated with CCH. All the studies have reported the primary outcomes of the study being deformity correction, improvement in the ROM. Patient satisfaction was reported in few studies. Each study characteristics have been summarized in [Table 1]. The total numbers of patients involved in all the studies were 1774. The patients from the two follow-up studies have not been included as the follow-up studies were part of the RCTs which were included, thus avoiding duplication., In this study, there were 882 male and 232 female participants, and the mean age of the participants was 63 years. All studies used CCH injections in their trial except for two studies which are follow-up studies., Among the RCTs included in the study, the dosage of CCH injection in Badalamente et al.'s study was 10,000 units in trial IIa, and in trial IIb patients, 18 patients received 2500 units, 22 patients received 5000 units, and 23 patients received 10,000 units of collagenase to both MCP and PIP joint contractures. In the rest of the three RCTs,, and three prospective studies,,, the dosage of CCH injection is 0.58 mg which is equivalent to 10,000 units. The placebo used in Badalemente et al.'s trial was sterile normal saline containing 2 mmol/L calcium chloride and in other three RCTs,, was 10 mm TRIS per 60 mm sucrose reconstituted in diluent. The procedure mentioned was similar in all the studies. Of the 1774 patients, 178 patients were treated with placebo and the rest of them with CCH injection. ROM, which is another primary outcome, was not mentioned in two studies., Patient satisfaction was mentioned in only two studies., Complications were mentioned in all the studies except for the follow-up studies which reported only the recurrence rate., For the four RCTs, the Cochrane Collaboration's risk of bias tool was used as shown in [Table 2]. All these prospective studies including the follow-up studies were evaluated for bias using a quality assessment for quantitative studies from human technology assessment.
The primary outcome of this study is to assess the correction of deformity of the finger and the improvement in the ROM following CCH injection. The correction of deformity at MCP and PIP joints in the included studies are summarized in [Table 1] and [Table 2] and Increase in Range of movements and grip strength is given in [Table 3]. All Four RCTs have found to have a significant improvement in deformity correction and were clinically and statistically significant in MCP joint,, study and both MCP and PIP joints in.,
The results of deformity correction of MCP and PIP joints are summarized in [Table 1] and [Table 2], respectively. Hayton et al. studied MCP joint contracture injection (Group A) and those with isolated PIP joint contracture injection (Group B). 43% of PIP joint contractures in Group A were corrected and 39% of PIP contractures in Group B were corrected. There was an improvement in correction of deformity in PIP joint but did not find a significant difference in the correction of PIP joint contracture whether treated in isolation or after treatment of MCP joint contracture. Skirven et al. also assessed PIP joint with collagenase injection followed by orthotic intervention protocol and found to have 55% of PIP joints had deformity reduced to 0°–5° of contracture as opposed to 25% in CORD trials. In Coleman et al.'s study, the percent change from baseline for the MCP joints was 76.7% and 65.3% for the PIP joints. It also identified that two cords (affected joints) can be treated concurrently with CCH with similar efficacy which is not part of present protocol. The sample size is too small to determine this effect. In Witthaut et al. study, 70% of MCP joints and 37% of PIP joints are reduced to 0°–5°. There was a clinical improvement (more than 50% improvement of contracture) in 89% of MCP and 58% of PIP joints.
There was a significant increase in ROM following collagenase injection in Badalamente et al., Badalamente et al. studies in MCP and PIP joints. Gilpin et al.'s study found a significant increase in ROM in patients treated with MCP but not for PIP joint. Grip strength was unaffected in these studies. In Coleman et al. study, the mean change in range of motion increased by 29.0 ± 21.0° in the MCP joints, and 32.1 ± 24.3° in the PIP joints for treatment period one and 30.0 ± 10.8° in the MCP joints, and 17.1 ± 2.7° in the PIP joints in treatment period two. In Hayton et al. study, the mean change in the range of motion after injection was 34.3 ± 19.8 in Group A and 29.1 ± 20.0. In Witthaut et al.'s study, there was a mean increase in the ROM by 30°.
Secondary outcome measures were complications, recurrence, and patient satisfaction. Most of the adverse events were mild to moderate. The common side effects in all the studies were peripheral edema, contusion, injection-site hemorrhage, injection-site pain, upper-extremity pain, tenderness, ecchymosis, injection-site swelling, pruritus, skin laceration, lymph-node enlargement and tenderness on palpation, lymphadenopathy, erythema, blister, injection-site pruritus, axillary pain, arthralgia, inflammation, blood blister, joint swelling, headache, swelling, and injection-site vesicles.
In Hurst et al.'s study, 96.6% of patients who received clostridium collagenase injection has at least one treatment-related adverse event as opposed to 21.2% of patients who received placebo. Among the severe side effects, two patients discontinued due to significant pain, one patient discontinued due to mild dizziness, one complex regional pain syndrome, and two patients had flexor tendon ruptures. After a third injection, all patients tested positive for antibodies against Type 1 and Type 2 clostridium histiolyticum in two RCTs., In Gilpin et al.'s study, one patient had flexion pulley rupture. In the other two RCTs,, other than the abovementioned mild-to-moderate side effects, no severe adverse events were reported. In trial IIB: Pharmacokinetics of Badalemente et al., urine samples showed detectable levels of collagenase an estimated 7% to 28% of the collagenase was recovered, mostly in the 30-to 60-min samples. This may indicate the ability of the kidney to concentrate collagenase. However, there were no significant systemic allergic reactions. Two observational studies (Skirven et al. and Hayton et al.) had mild-to-moderate adverse events which settled in 2 weeks without any significant systemic allergic reactions. In Witthaut et al. study, two patients had serious side effects. One patient had deep vein thrombosis in the leg and the other had tendonitis near injection site.
In Gilpin et al. study defined recurrence as an increase in joint contracture to 20° or greater in the presence of a palpable at any time during the study in joints that achieved clinical success. In its 12-month period, there was no recurrence reported. In Badalemente et al., there was recurrence in four patients in MCP joint in 4-year period and 4 in PIP joint in 3.8-year period in phase IIA trial. In phase IIB trial, the recurrence was in one MCP joint in 2 years and one PIP joint in 12.5 months. In other RCTs, Badalemente et al. in 24-month follow–up, recurrence of contracture was found in four MCP joints and one PIP joint. Skirven et al., Coleman et al., nd Hayton et al. are all short-term studies, and the results did not report any recurrence. Watt et al. which is an 8-year follow up study found recurrence in 4 out of 6 contractures in MCP joint (67%), and the recurrence is less severe than the initial contracture, 2 out 2 contractures in PIP joint assessed had recurrence (100%), and the recurrence is more severe than the initial contracture. In Witthaut et al. study, two trials (Joint 1, Joint 2) were assessed, and the recurrence rate was 4%. Peimer et al. study which combined five trials (CORD1, CORD 1 Extension, CORD 2, JOINT 1, and JOINT2), the recurrence rate was 35%. Individually, the recurrence in MCP joint was 27% PIP joint was 56%. The recurrences that were mentioned in all the studies were assessed in patients who were successfully treated patients (reduced to 0°–5° contracture).
Regarding patient satisfaction, the study by Coleman et al. out of 12 patients who had single injection during period one, 9 were very satisfied, and 3 of them were quite satisfied and all the 12 patients were very satisfied in period two where multiple injections were given as per five-level Likert response scale (Appendix-3). In Witthaut et al. study, 92% of the patients were satisfied at the end of the study and out of which 71% of them were very satisfied and 21% were quite satisfied as per five-level response Likert scale. In Watt et al.'s study, patients subjectively rated the overall clinical success at 60 (0-100) and 7 out of 8 patients were keen to pursue for further collagenase injection for the treatment of recurrent or progressive disease.
| Discussion|| |
Although CCH injection is highly effective in treating Dupuytrens contracture, it does not replace surgery in every condition. CCH injections are presently mainly used for primary contractures, whereas surgical fasciectomy is still the surgeon's choice for severe contractures and revision surgeries. It does not replace surgery, but it has a definitive role and can be used as first choice in primary contractures. CCH injection helps in correction of deformity without the risks of surgery and anesthesia. The MCP joint correction was statistically significant following collagenase injection in all the studies, whereas PIP joint correction was not statistically significant except for one study. Although Nash study groups are small that included 21 patients in fasciectomy group and 25 patients in collagenase group, there is a significant difference in deformity correction in PIP joint between fasciectomy group and collagenase group.
In Chen et al. systematic review, there were higher rates of recurrence in needle aponeurectomy and open partial fasciectomy when compared to CCH injection and recommends long term outcomes of these interventions. However, there is no comparison made of the correction of deformity between the interventions selected. The recurrence rate in collagenase injection in this study ranged from 10% to 31%, which is similar to the present study (35%), which included Piemer et al.'s study that combined five trials. The recurrence rate in open fasciectomy in Chen et al.'s study was in the similar ranges (12%–39%). The complications following collagenase injection in Chen et al. study have only showed 9%–25% which are primarily skin tears, but in this systematic review, the complication rates are higher, but almost all the adverse events were mild to moderate. The complication rate after fasciectomy ranged from 14% to 67% which included severe adverse events such as infection, nerve injury, and complex regional pain syndrome. Vollbach et al. in his study assessed the patient satisfaction in partial fasciectomy and collagenase injection and found to have higher patient satisfaction, faster recovery, and better grip strength with patients who received collagenase injection than patients who received fasciectomy in spite of the better correction of deformity which was achieved with open fasciectomy. In this systematic review, patient's satisfaction in the studies which assessed was good, which is comparable to Vollbach et al. study.
All the studies included have clearly mentioned the funding details.,,,,,, All of them were funded from the company that manufactures clostridium collagenase injection. Two studies by Badalemente et al. and Badalamente et al. received grants from the U. S. Food and Drug Administration and were not funded by the manufacturing company. Conflict of interest is mentioned in two studies., None of the included studies have done power analysis. Ethical clearance is only mentioned in five studies.,,,,,,
This study did not investigate the cost analysis. The costs of the procedure, pharmaceuticals, and rehabilitation vary widely between open surgery and injection. In Mehta et al. study surgical fasciectomy for Dupuytren's contracture of a single digit in patients was over £5000 more than treatment for the same condition using collagenase injection. The costs of theatre time, equipment, physiotherapy, and follow-up were calculated. However, the period of follow-up was only 1 year, and the recurrence rates after that period and its cost implications were not done. In a retrospective study by Atroshi et al., collagenase injection treatment was found to be 33% less expensive than the surgical fasciectomy with equivalent effective correction of deformity. Roush et al. reported the only major series dedicated to revision fasciectomy. It is yet to be found out whether needle aponeurotomy or collagenase injection can be used in the revision of Dupuytren's management. Open partial fasciectomy after collagenase injection could potentially be equally or more difficult than revision fasciectomy. On the other hand, judicious collagenase injection may be worthwhile to treat recurrence after open partial fasciectomy.
| Conclusion|| |
In this review, all the studies with medium quality of evidence reported favorable results on the efficacy and safety of injectable CCH in patients with advanced Dupuytren's disease. The review identified the collagenase injection is not devoid of complications. There is recurrence in Dupuytren's contracture following collagenase injection and the percentage of patients with recurrence is more common in PIP joint as compared to MCP joint, and the severity of the recurrence is less when compared to the original contracture before the injection. It is evident that there is no definitive cure for Dupuytren's contracture with either surgical excision of the diseased cords or with Collagenase injection, but CCH injection offers a potential nonsurgical treatment for Dupuytren's disease and gives the advantages of early return of hand function and avoidance of potential surgical complications. We need more studies comparing collagenase injections with surgical interventions including cost analysis which will be helpful in the effective management of Dupuytren's contracture.
This is a systematic review of articles so no patients were reviewed or had any intervention for this study, so ethical clearance was not taken from the hospital clinical governance department.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]