Dupuytren’s disease and collagenase: evidence for a paradigm shift in management

Introduction: Dupuytren’s disease is a common condition that leads to significant functional impairment of the hand. The recent introduction of collagenase clostridium histolyticum (CCH) as a therapeutic option has changed the approach to disease management. Currently no nonsurgical management paradigm exists for treating Dupuytren’s disease within Australia. Methods: Databases were searched for Dupuytren’s disease patients receiving CCH. PRISMA guidelines were used to screen predefined classifications of the effectiveness, safety and recurrence of disease following treatment with CCH. Results: In this review, 18 studies were included and analysed to evaluate the effectiveness, safety and recurrence after treatment of CCH. Conclusion: CCH has the potential as a non-surgical therapeutic option to expand the paradigm of management for Dupuytren’s disease. This may minimise treatment time and cost and improve the public healthcare sector’s treatment of Dupuytren’s disease.


Introduction
Dupuytren's disease is a common, benign fibrotic disease resulting in finger flexion contractures. 1 This can lead to significant functional hand impairment through decreased range of motion, 2 with patients thus seeking treatment. 3 As no cure currently exists for Dupuytren's disease, treatment primarily focuses on four characteristics identified by Tubiana in 1975 'to correct deformity, avoid Surgical correction of Dupuytren's disease via fasciotomy, fasciectomy and dermofasciectomy has been the mainstay of therapy over recent decades. 5,6 Percutaneous needle fasciotomy is advantageous due to rapid recovery times and the ability for outpatient management, thus reducing costs. 7 However, as the cord is not excised during fasciotomy, recurrence rates are higher compared with fasciectomy or dermofasciectomy. 8 These two more radical treatment options are associated with a lengthier recovery time but a lower recurrence rate. Furthermore, adverse effects such as pain, infection and nerve injury have a higher likelihood. 6 In 2013, collagenase clostridium histolyticum (CCH) was licensed by the Therapeutic Goods Administration in Australia for the treatment of Dupuytren's disease. CCH is delivered as an injection into the palpable cord, containing a fixed-ratio solvent of two enzymes, clostridial type I and II collagenase. These enzymes combine to hydrolyse the pathological type I and III collagen. 9 More than 24 hours post injection, the finger is manually manipulated by a hand surgeon. This straightens the affected digit by disrupting the cord responsible for causing contracture. 10 Other non-surgical options explored for treatment of Dupuytren's disease include pharmacological therapy (steroid injections, vitamin A or E application, 5-fluorouracil treatment), physical therapy and radiotherapy. 11 Radiotherapy is hypothesised to inhibit the early proliferative phase of Dupuytren's disease, but the evidence and its use are currently limited. 12  Data were collated and synthesised using the Cochrane Collaboration data collection tool. 14 A qualitative analysis of the data was undertaken.

Results
Eighteen studies were eligible for full review after deletion of duplicates and application of exclusion criteria (Figure 1). 15     Only three studies recorded PROMs, but none used the same measures and two did not include post-treatment scores. Of these, Verstreken used URAM, Zhou used MHQ and Skov used DASH. 18,20,22 The lower the URAM score, the lower the degree of impairment or concern noted by the patient. 31 The single study using both pre and post PROM showed patient perceived improvement post CCH injection. 18

Patient satisfaction
Three studies assessed patient satisfaction at 30 days following CCH injection. Of these, patient satisfaction was recorded as 92 percent, 92.3 percent and 93 percent respectively. 18,24,26 Clinical success was documented in two of these studies as 64.9 percent (92 percent patient satisfaction) and 57 percent (93 percent patient satisfaction). 18,26 This suggests that patient opinions of treatment effectiveness vary from the objective outcomes measured.

Safety
Adverse events can have serious consequences on morbidity. 18,35 The safety of collagenase is commonly reported within the literature by using the outcomes: treatment-related adverse effects and serious adverse effects. 36 This is important, as many patients with Dupuytren's disease are elderly with comorbidities and existing limitations upon their daily activities.

Treatment-related adverse effects
Of the nine studies analysing safety, three reported Common treatment-related adverse effects were recorded but they were variable across the studies.  [18][19][20][21][22][23][24][25][26]30 Furthermore, only one study reported using the same clinician for baseline and post-treatment measurements. 19 Consequently, the remaining studies may have been exposed to inter-and intra-reporter variability, leading to discrepancies within their results. 43  The current evidence suggests that splints offer no therapeutic benefit following surgery, yet extended use in the literature emphasises the need for further assessment. 46,47 PROMs were not well recorded across the literature. This can be attributed to two factors: the lack of validity and consistency of using PROMs and the length of time these questionnaires take to complete. 48 The URAM score was validated in 2011 and is quicker to complete than both the MHQ and the DASH but its relevance to Englishspeaking populations has been questioned due to translation concerns. 49 The MHQ is reliable yet lengthier to complete (average 10 minutes) and far more complicated to calculate, which limits its use. 34 The DASH and the QuickDASH have been found to have inadequate validity for Dupuytren's disease and have a lengthy completion time.
Finally, the Southampton has been declared more reliable, consistent and specific compared with the QuickDASH but due to its recent introduction there are limited data available. 33 There has been inconsistent use and reporting of PROMs. Furthermore, when patient satisfaction has been measured against clinical success, results were higher for patient satisfaction. 18,26 Overall, variability in how effectiveness is measured and reported across the literature highlights that minimal consensus currently exists,

Recurrence
Recurrence was poorly reported in the literature.
The lengthy follow-up required to observe recurrence appeared to hinder investigation.
Our review of recurrence only discussed joints successfully treated, due to the limited literature describing joints that either failed CCH treatment or were partially responsive. Only Peimer et al acknowledged this. 28 Long-term follow-up of partially and non-successfully treated joints needs further research to accurately assess recurrence.

Follow-up
The