Dupuytren's Contracture Treatments

Number: 0800

Policy

Aetna considers collagenase clostridium histolyticum (Xiaflex) injections medically necessary for the treatment of adults with Dupuytren's contracture with a palpable cord.

Aetna considers collagenase clostridium histolyticum injections experimental and investigational for all other indications (e.g., uterine fibroids; except for Peyronie's disease -- see CPB 0007 - Erectile Dysfunction) because its effectiveness other than the one listed above has not been established.

Aetna considers percutaneous needle aponeurotomy (also known as percutaneous needle fasciotomy) medically necessary for the treatment of adults with Dupuytren's contracture with a palpable cord.

Aetna considers ortho-voltage radiation medically necessary for the treatment of early-stage Dupuytren's contracture (stage N, N/I). (Note: stage N: nodules/cords, no extension deficit = flexion deformity; stage N/I: less than or equal to 10 degrees deficit).

Aetna considers intralesional glucocorticoid injection medically necessary in early-stage Dupuytren's for treatment of local tenderness (tenosynovitis) or for rapidly growing palmar nodules.

Aetna considers the following experimental and investigational:

  • Autologous fat grafting
  • Collagenase nanocapsules
  • Cryopreserved placental membrane
  • Extracorporeal shock wave therapy for prevention of the progression as well as for the treatment of Dupuytren's contracture
  • Night-time splinting / orthosis for all individuals after fasciectomy or dermofasciectomy for Dupuytren's contracture
  • Percutaneous needle aponeurotomy in combination with lipografting for the treatment of adults with Dupuytren's contracture.

Notes: Injections of Xiaflex may be administered up to 3 times per cord at approximately 4-week intervals.  Up to 2 cords may be injected at a time.  If members have other cords with contractures of metacarpophalangeal (MCP) or proximal interphalangeal (PIP) joints, these cords should be injected in sequential order.

Background

Dupuytren's disease, a progressive fibro-proliferative disorder, is characterized by nodule formation and contracture of the palmar fascia, and may result in flexion deformity of the fingers and loss of hand function.  The disease is common in men older than 40 years; in persons of Northern European descent; and in persons who smoke, use alcohol, or have diabetes mellitus.  The symptoms of Dupuytren's contracture are often mild and painless and do not require treatment. Patients present with a small, pitted nodule (or multiple nodules) on the palm, and may stay the same for months or years. In some patients, however, it may progress to the next stage, in which cords of fibrous tissue form in the palm and run into the fingers or thumb, eventually, pulling them into a permanently flexed position, making it difficult to perform activities of daily living. 

The disease initially can be managed with observation and non-surgical therapy.  It will regress without treatment in about 10 % of patients.  Injection of steroids into the nodule has been shown to reduce the need for surgery.  Surgical referral should be made when metacarpophalangeal (MCP) joint contracture reaches 30 degrees or when proximal interphalangeal (PIP) joint contracture occurs at any degree.  In-office percutaneous needle aponeurotomy is an alternative to surgery (Trojian and Chu, 2007).

Swartz and Lalonde (2008) stated that treatment of Dupuytren's disease is offered to symptomatic patients with painful nodular or disabling contracture.  Limited fasciectomy of the involved abnormal structures followed by hand therapy is standard treatment, but it is associated with serious potential complications.  Moreover, recurrence is common.  New treatments include the injection of clostridial collagenase, which works by breaking down the excessive build-up of collagen in the hand.

In a phase II open-label clinical trial, Badalamente and Hurst (2000) examined the clinical safety and effectiveness of clostridial collagenase injection as a non-surgical treatment of Dupuytren's disease.  A total of 35 patients entered the study (3 women and 32 men).  The mean age was 65 years.  The first 6 patients were treated following a dose escalation protocol and received 300, 600, 1,200, 2,400, 4,800, and 9,600 units (U) collagenase injected into the cord that was causing contracture of the MCP joint.  There were no beneficial clinical effects of these injections.  The remaining 29 patients had collagenase injections at a dose level of 10,000 U into cords that are causing contractures of 34 MCP joints, 9 PIP joints, and 1 thumb.  Twenty-eight of the 34 MCP joint contractures corrected to normal extension (0 degrees) and 2 of the 34 MCP joint contractures corrected to 5 degrees of normal extension, with full range of motion, within 1 to 14 days of injection.  In patients with PIP joint contractures, 4 of the 9 joints corrected to normal (0 degrees).  One PIP joint corrected to within 10 degrees of normal and 2 corrected to within 15 degrees of normal.  There were 2 failures; these patients required surgery.  The mean follow-up period was 20.0 +/- 5.6 months for the MCP joints and 14.1 +/- 6.6 months for the PIP joints.  Clostridial collagenase injection of Dupuytren's cords causing MCP and PIP joint contractures appears to have merit as non-surgical treatment of this disorder.  The authors stated that pending further placebo, double-blind studies, collagenase injection to treat Dupuytren's disease may be a safe and effective alternative to surgical fasciectomy.

Badalamente et al (2002) reported that in a series of controlled phase II clinical trials, excessive collagen deposition in Dupuytren's disease has been targeted by a unique non-operative method using clostridial collagenase injection therapy to lyse and rupture finger cords causing MCP and/or PIP joint contractures.  A total of 49 patients were treated in a random, placebo-controlled trial of one dose of collagenase versus placebo at 1 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 indicated that non-operative 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.

In a prospective, randomized, double-blind, placebo-controlled, multi-center study, Hurst et al (2009) examined the effects of injectable collagenase clostridium histolyticum for the treatment of Dupuytren's contracture.  These investigators enrolled 308 patients with joint contractures of 20 degrees or more .  The primary MCP or PIP joints of these patients were randomly assigned to receive up to 3 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.  Collagenase treatment significantly improved outcomes.  More cords that were injected with collagenase than cords injected with placebo met the primary end point (64.0 % versus 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 versus 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: 2 tendon ruptures and 1 case of complex regional pain syndrome.  No significant changes in flexion or grip strength, no systemic allergic reactions, and no nerve injuries were observed.  The authors concluded that collagenase clostridium histolyticum injection significantly reduced contractures and improved the range of motion in joints affected by advanced Dupuytren's disease.

On February 2, 2010, the Food and Drug Administration approved collagenase clostridium histolyticum (Xiaflex) as the first drug to treat Dupuytren's contracture.  Xiaflex is injected directly into the collagen cord of the hand and should be administered only by a health care professional experienced with injections of the hand, because tendon ruptures may occur.  The product insert of Xiaflex states that injections may be administered up to 3 times per cord at approximately 4-week intervals.  Up to two cords may be injected at a time.  If patients have other cords with contractures of MCP or PIP joints, these cords should be injected in sequential order.

The most common adverse reactions in patients treated with Xiaflex were peripheral edema (mostly swelling of the injected hand), contusion, injection site reaction, injection site hemorrhage, and pain in the treated extremity.  Serious adverse reactions included tendon ruptures and other serious injuries to the injected extremity.

Clostridial collagenase has also been used in the treatment of Peyronie's disease.  Jordan (2008) evaluated the safety and effectiveness of intra-lesional clostridial collagenase injection therapy in a series of patients with Peyronie's disease.  A total of 25 patients (aged 21 to 75 years) who were referred to a single institution with a well-defined Peyronie's disease plaque were treated with 3 intra-lesional injections of clostridial collagenase 10,000 U in a small volume (0.25 cm(3) per injection) administered over 7 to 10 days, with a repeat treatment (i.e., 3 injections of collagenase 10,000 U/25 cm(3) injection over 7 to 10 days) at 3 months.  Primary efficacy measures were changes from baseline in the deviation angle and plaque size.  Secondary efficacy end points were patient responses to a Peyronie's disease questionnaire and improvement according to the investigators' global evaluation of change.  Significant decreases from baseline were achieved in the mean deviation angle at 3 months (p = 0.0001) and 6 months (p = 0.0012), plaque width at 3 months (p = 0.0052), 6 months (p = 0.0239), and 9 months (p = 0.0484), and plaque length at 3 months (p = 0.0018) and 6 months (p = 0.0483).  More than 50 % of patients in this series considered themselves "very much improved" or "much improved" at all time points in the study, and the drug was generally well-tolerated.  The authors concluded that the benefits of intra-lesional clostridial collagenase injections in this trial lend support to prior studies supporting its use in the management of Peyronie's disease.  They noted that a double-blind, placebo-controlled study is currently under development.

Another treatment of Dupuytren's contracture (DC) is injection of steroids into the nodule; and has been shown to reduce the need for surgery.  Surgical referral should be made when MCP joint contracture reaches 30 degrees or when PIP joint contracture occurs at any degree.  In-office percutaneous needle aponeurotomy is an alternative to surgery (Trojian and Chu, 2007).

Manet and associates (2011) stated that DC is a retractile fibrosis of the superficial palmar aponeurosis of the hand, resulting in a progressive and fixed flexion of the fingers that may result in severe limitation of hand function.  It affects several millions of people in Europe and North America.  Risk factors are genetic and sometimes related to mellitus diabetes.  There is no spontaneous remission.  Until recently, surgery was the only treatment, but now needle aponeurotomy emerges as a therapeutic alternative.  It should be performed as first-line treatment by a trained practitioner.  Short-term and long-term results of needle aponeurotomy appear identical to those of surgery, with milder complications.  It is indicated in palmar, palmo-digital, as well as in strictly digital forms of the disorder.

In a review on percutaneous needle aponeurotomy, Foucher and colleagues (2003) reviewed the charts of 211 patients treated consecutively on 261 hands and 311 fingers to assess the rate of post-operative complications.  The first 100 patients were evaluated with a mean follow-up of 3.2 years to assess the rate of recurrences and extension of the disease.  In the whole group the mean age was 65 years and delay between onset and treatment was 6 years.  Division of the cords were performed only in the palm in 165 cases, in the palm and finger in 111 and purely in the finger in 35.  Complications were scarce without infection or tendon injury but 1 digital nerve was found injured during a second procedure.  Post-operative gain was prominent at MCP joint level (79 % versus 65 % at interphalangeal level).  The re-operation rate was 24 %.  In the group assessed at 3.2 years follow-up, the recurrence rate was 58 % and disease "activity" 69 %.  Fifty-nine hands need further surgery.  The ideal indication for this simple and reliable technique is an elderly patient with a bowing cord and predominant MP contracture.

Cheng et al (2008) reviewed the safety and effectiveness of needle aponeurotomy for DC in Chinese patients.  A total of 7 men and 1 woman aged 50 to 80 (mean of 67) years underwent needle aponeurotomy for DC.  Five were manual workers and the other 3 were retired.  Their chief complaints were difficulty moving the fingers, clumsiness of the hand, and occasional pain in the palm.  No patient had any family history of DC.  A total of 41 points were released in 13 fingers (3 middle, 3 ring, and 7 little).  Immediately after release, the mean flexion contracture correction of the MCP and PIP joints were 50 (from 50 to 0) and 35 (from 46 to 11) degrees, respectively.  At 22-month follow-up, the mean residual flexion contracture of both joints were 12 and 27 degrees; the corresponding long-term improvements were 70 and 41 %, respectively.  No patient had a wound complication or neurovascular injury.  All had a normal score for Disabilities of the Arm, Shoulder, and Hand.  The authors concluded that for Chinese patients with DC, needle aponeurotomy is safe and effective.  Long-term correction is better maintained in MCP than PIP joints (70 % versus 41 %).

Lellouche (2008) stated that DC or Dupuytren's disease of the hand is the retraction of the palmar aponeurosis.  Its course is progressive and leads to an irreducible flexion deformity of one or more fingers.  Early diagnosis is necessary for the table test, which determines the need for treatment.  Needle aponeurotomy should be the first option treatment.  This minimally invasive out-patient procedure minimizes sick leave and does not require immobilization or physical therapy.  Several studies confirmed the short-term and intermediate-term effectiveness of this treatment and the minimal side effects when performed by experienced operators.  Multiple procedures for extensive disease (several knots) can be performed in the hospital.  Close medical and surgical collaboration is necessary for treatment of severe forms, treatment failures, and multiple recurrences.

Guidance from the National Institue for Clinical Excellence (NICE, 2004) concluded: "Current evidence on the safety and efficacy of needle fasciotomy for Dupuytren’s contracture appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance."  The guidance explained that the main benefit offered by this procedure is a short-term reduction in the degree of contracture.  The guidance stated that the evidence shows that the recurrence rate is approximately 50 % at 3 to 5 years and seems to depend on the severity of the disease.  The guidance stated that some data suggest that individuals with less severe disease or with metacarpophalangeal joint contracture benefited most from this procedure.

Knobloch et al (2011) noted that Dupuytren's disease is a progressive disease due to unknown causal agents or genetics.  An epidemiological analysis of 566 cases in North Germany estimated that around 1.9 million Germans are suffering from Dupuytren's disease.  Beside Dupuytren's disease, there are a number of further less common forms of progressive fibromatosis, such as knuckle pads, plantar fibromatosis or Peyronie's disease.  Surgery in plantar fasciectomy yields to a 60 % recurrence rate depending on the extent of the plantar fasciectomy.  Peyronie's disease of the penis affects middle-aged men between 40 and 60 years with penile pain, curvature during erection and potential erectile dysfunction.  In a randomized controlled trial (RCT) in Peyronie's disease 2,000 focused extracorporeal shock waves reduced pain significantly and improved erectile function and quality of life.  These researchers hypothesize that focused extracorporeal shock wave therapy (ESWT) is able to reduce Dupuytren's contracture.  Given the fact that recurrence rate in Dupuytren's disease is high und unpredictable, ESWT as a non-invasive tool might be applicable both, in primary and secondary prevention of the progression as well as for treatment.  As such, these investigators have planned a RCT studying the effect of high-energy focused ESWT on patients suffering Dupuytren's disease with patient-related outcome measures such as the Disabilities of the Arm, Shoulder and Hand (DASH) score and the Michigan Hand Outcome Questionnaire as primary outcome parameters.

Sanjuan Cervero et al (2013) compared the use of direct health resources and costs generated in the treatment of DC using 2 different techniques:

  1. subtotal fasciectomy and
  2. infiltration with collagenase clostridium histolyticum (CCH) in regular clinical practice. 

Observational, retrospective study based on data from the computerized clinical histories of 2 groups of patients:

  1. those treated surgically using a 1- or 2-digit subtotal fasciectomy technique (FSC) and
  2. those treated with CCH infiltration, monitored in regular clinical practice from February 2009 to May 2012.

Demographic (age, sex), clinical (number of digits affected and which ones) and use of resources (hospitalizations, medical visits, tests and drugs) data were collected.  Resource use and associated costs, according to the hospital's accounting department, were compared based on the type of treatment from Spain's National Health Service.  A total of 91 patients (48 (52.8 %) in the FSC group) were identified.  The average age and number of digits affected was 65.9 (9.2) years and 1.33 (0.48) digits affected in the FSC group, and 65.1 (9.7) years and 1.16 (0.4) digits in the CCH group.  Overall, the costs of treating DC with subtotal FSC amount to €1,814 for major ambulatory surgery and €1,961 with hospital stay including admission, surgical intervention (€904), examinations, dressings and physiotherapy.  As to collagenase infiltration, costs amount to €952 (including minor surgery admission, vial with product, office examination and dressings).  Finally, comparing total costs for treatments, a savings of €388 is estimated in favor of CCH treatment in the best-case scenario (patient under MAS system with no need for physiotherapy) and €1,008 in the worst-case scenario (patient admitted to hospital needing subsequent physiotherapy), implying a savings of 29 % and 51 %, respectively.  The authors concluded that this study demonstrated that treating patients with DC by injection with CCH generated a total savings of 29 % and 51 % (€388 and €1008) compared with fasciectomy at the time of treatment.  Moreover, they stated that long-term evolution of CCH treatment is uncertain and the recurrence rate unknown.

In a retrospective cohort study, Atroshi et al (2014) compared CCH injections and FSC for DC regarding actual total direct treatment costs and short-term outcomes.  Patients aged 65 years or older with previously untreated DC of 30° or greater in the MCP and/or PIP joints of the small, ring or middle finger were included in this study.  The CCH group comprised 16 consecutive patients treated during the first 6 months following the introduction of CCH as treatment for DC at the study center.  The controls were 16 patients randomly selected among those operated on with FSC at the same center during the preceding 3 years.  Treatment with CCH was given during 2 standard outpatient clinic visits (injection of 0.9 mg, distributed at multiple sites in a palpable cord, and next-day finger extension under local anesthesia) followed by night-time splinting.  Fasciectomy was carried out in the operating room (day surgery) under general or regional anesthesia using standard technique, followed by therapy and splinting.  Outcome measures included actual total direct costs (salaries of all medical personnel involved in care, medications, materials and other relevant costs), and total MCP and PIP extension deficit (degrees) measured by hand therapists at 6 to 12 weeks after the treatment.  Collagenase injection required fewer hospital outpatient visits to a therapist and nurse than FSC.  Total treatment cost for CCH injection was US$1,418.04 and for FSC US$2,102.56.  The post-treatment median (IQR) total extension deficit was 10 (0 to 30) for the CCH group and 10 (0 to 34) for the FSC group.  The authors concluded that treatment of DC with 1 CCH injection cost 33 % less than FSC with equivalent effectiveness at 6 weeks regarding reduction in contracture.

Peimer et al (2013) evaluated long-term safety and effectiveness of CCH after the 3rd year of a 5-year non-treatment follow-up study (Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study [CORDLESS study]).  This study enrolled DC patients from 5 previous clinical studies.  Beginning 2 years after the 1st CCH injection, these investigators 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.  Of 1,080 CCH-treated joints (648 MCP; 432 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 non-durable response.  These researchers 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.  The authors concluded that recurrence rate, which is comparable to other standard treatments, and the absence of long-term adverse events 3 years after initial treatment indicated that CCH is safe and effective treatment for DC.  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 non-durable response rates among partially corrected joints.

Uterine Fibroids

Jayes and colleagues (2016) tested the hypothesis that a highly purified collagenase clostridium histolyticum will digest interstitial collagen in uterine fibroids and reduce their stiffness and evaluated the feasibility that clostridium histolyticum collagenase can be developed into an alternative treatment for fibroids. A secondary objective was to describe the collagen content of the fibroid tissue.  Fibroid tissue cubes (1-cm3; n = 154) were cut from 17 uterine fibroids that were obtained from 7 consented subjects undergoing scheduled hysterectomies.  Tissue cubes were injected with diluent, placebo, or highly purified collagenase clostridium histolyticum (0.05, 0.1, or 0.2 mg per cube) and incubated at 37°C for 24, 48, 72, or 96 hours.  At each time-point, 6 non-injected control cubes were also evaluated.  Tissue cubes were photographed before and after incubation.  Myometrial samples (n = 21) were also evaluated.  Stiffness was quantified through rheometry by measuring complex shear moduli of the tissues.  Percent fibrosis was determined by computerized analysis of Masson-Trichrome stained slides.  Digestion of collagen fibrils was confirmed by transmission electron microscopy.  Fibrosis in untreated fibroids ranged from 37 % to 77 % reflecting the collagen-rich nature of these tumors.  After treatment with collagenase for 96 hours, fibrosis ranged from 5.3 % to 2.4 %.  Transmission electron microscopy confirmed complete digestion of collagen fibrils.  Tissue stiffness was reduced with all 3 doses of collagenase treatment and at all 4 time-points.  Longer incubation times with collagenase caused greater reduction in stiffness and treated cubes lost their cuboidal shape and had gelatinous/liquefied centers.  At 96 hours stiffness in tissues treated with the lowest dose was reduced to 966 ± 106 Pascal compared to diluent-treated control at the same time (5,323 ± 903 Pascal; p < 0.0001; by analysis of variance with Tukey-Kramer).  The authors concluded that uterine fibroids have a high content of collagen that can be effectively digested by highly purified collagenase clostridium histolyticum resulting in reduced tissue stiffness.  Loss of stiffness may decrease bulk symptoms in-vivo and possibly lead to shrinkage of fibroids through changed mechano-transduction leading ultimately to reduced fibroid symptoms of pain and bleeding.  The authors stated that clinical trials are needed to evaluate safety and effectiveness of clostridium histolyticum collagenase including the rate of regrowth of fibroids.  They noted that the data of this study provided a strong rationale for using this purified collagenase in clinical trials as a local treatment for women with fibroids.

Percutaneous Needle Aponeurotomy in Combination with Lipografting

Hovius and colleagues (2011) described a novel minimally invasive alternative for Dupuytren disease and its outcome.  The procedure consists of an extensive percutaneous aponeurotomy that completely disintegrates the cord and separates it from the dermis.  Subsequently, the resultant loosened structure is grafted with autologous lipo-aspirate.  After 1 week of post-operative extension splinting, patients are allowed normal hand use and are advised to use night splints for 3 to 6 months.  These investigators treated and reported on their experience with 91 patients (99 hands) operated on in Miami and Rotterdam; from 50 patients, the authors reported on goniometry (average follow-up of 44 weeks).  The contracture from the PIP joint improved significantly from 61 degrees to 27 degrees, and contracture from the MCP joint improved from 37 degrees to -5 degrees; 94 % of patients returned to normal use of the hand within 2 to 4 weeks and 95 % were very satisfied with the result.  No new scars were added, and a supple palmar fat pad was mostly restored.  Complications were digital nerve injury in 1 patient, post-operative wound infection in 1 patient, and complex regional pain syndrome in 4 patients.  The authors concluded that this new minimally invasive technique shortens recovery time, adds to the deficient subcutaneous fat, and leads to scarless supple skin.  By its ability to treat multiple rays, it addresses the abnormality in the entire hand.  The procedure is safe and effective, especially for primary cases.  Moreover, they stated that comparative prospective randomized studies are currently in process to fully determine the role of percutaneous aponeurotomy plus lipografting in the treatment of Dupuytren contracture.

Tuncel and colleagues (2017) described their experience with treating Dupuytren's disease using needle aponeurotomy and non-centrifuged autologous fat grafting.  The study included 17 patients (18 hands).  Patients were treated with needle aponeurotomy and non-centrifuged autologous fat graft under general anesthesia.  The fat grafts were injected into the surgical area so as to stay in contact with the operated site.  An extension splint was used for 1 week post-operatively and the patients received hand therapy for 3 weeks.  Before the treatment, the contracture in the PIP and MCP joints was a mean of 45.06 ± 13.44 degrees and 36.56 ± 13.09 degrees, respectively.  It was 1.61 ± 1.65 and -0.56 ± 3.78 degrees at 3 months, respectively.  The difference between these measurements was statistically significant.  The mean follow-up period was 12 months.  The results were satisfactory and no complications were observed during the follow-up period.  The authors concluded that based on the results of the study, percutaneous aponeurotomy with non-centrifuged autologous fat grafting was found to have significantly beneficial effects in the treatment of Dupuytren's disease.  These preliminary findings from a small (n = 17 subjects) study need to be validated by well-designed studies.

Intralesional Steroid Injection

Ball and colleagues (2016) Dupuytren's disease is a common fibrotic disorder of the palm characterized by the development of progressive flexion deformities in the digits, leading to significant functional impairment.  Surgical excision remains the most common treatment.  However, this is only indicated in patients with established contractures rather than those with early disease.  Early disease is generally characterized by the presence of palmar nodules with limited or no contracture of the fingers.  The ideal treatment would be directed at patients with early progressive disease to prevent future deterioration.  Various non-surgical treatment modalities have been described but there is currently no systematic assessment of the role and effectiveness of these treatments in patients with early disease.  Using a PICOS analysis, these investigators reviewed publications of studies of patients with early disease who had received physical therapies, pharmacological treatment, or radiotherapy.  Following PRISMA guidelines titles and abstract were screened using pre-defined criteria to identify those reporting outcomes specifically relating to the treatment of early disease.  In the absence of a definition of early disease studies were included if early Dupuytren's disease (DD) was described clinically, with digital contractures not exceeding 30°, Tubiana grades N to 1, and which reported identifiable data.  Studies were excluded if data for early Dupuytren's disease patients could not be extracted for analysis.  In this systematic review, a total of 26 studies were identified and analyzed to evaluate the effect of pharmacological therapy (n = 11), physical therapy (n = 5) and radiotherapy (n = 10) on early Dupuytren's disease.  The studies comprised 20 case series, 1 cohort study with the remainder reporting case studies.  All publications were graded level of evidence IV or V assessed using the Oxford Centre for Evidence Based Medicine grading.  Narrative descriptions of the data were presented.  The authors concluded that physical therapies were the most robustly assessed, using objective measures but the studies were under-powered, providing insufficient evidence of efficacy.  Intralesional steroid injection and radiotherapy appeared to lead to softening of nodules and to retard disease progression, but lacked rigorous evaluation and studies were poorly designed.  These researchers stated that there is an urgent need for adequately powered, double-blinded, randomized trials for this common disorder which affects 4 % of the population.

An UpToDate review on “Dupuytren's contracture” (Aggarwal and Blazar, 2017) states that "[i]ntralesional glucocorticoid injection with triamcinolone acetonide and lidocaine hydrochloride may be helpful if local tenderness is bothersome (eg, the patient develops tenosynovitis) or if the palmar nodule is growing rapidly. ....Glucocorticoid injection is helpful in patients with more recent disease onset; cords with or without significant contracture do not respond to glucocorticoid injection." Regarding use of glucocorticoids as a treatment for flexion contractures, the review stated that “[o]ther interventions, including continuous slow skeletal traction, dimethyl sulfoxide, vitamin E, allopurinol, physical therapy, ultrasound therapy, glucocorticoid injections, interferon, and splinting, have generally not been successful.”

Radiotherapy

Prophylactic external beam radiation therapy (RT) has been reported to prevent disease progression in early-stage DC.

Keilholz et al (1996) evaluated initial response, long-term outcome, as well as treatment toxicity of RT for the prevention of disease progression in early-stage DC.  A total of 96 patients (142 hands) received ortho-voltage RT, which consisted of 2 courses with daily fractionation of 5 x 3 Gy (total dose of 30 Gy) separated by a 6-week interval.  The extent of disease was staged according to the Tubiana's classification.  Initial evaluation was performed 3 months after completion of RT; long-term outcome was analyzed at last follow-up.  The mean follow-up was 6 +/- 2 (range of 1 to 12) years.  Fifty-seven patients with a minimum follow-up of 5 (median 7.5; mean of 9.5 to 12) years were separately evaluated for long-term outcome (i.e., prevention of disease progression).  Acute and late treatment toxicity was assessed using the Radiation Therapy Oncology Group/EORTC criteria.  According to stage, 130 cases (92 %) remained stable at 3 months follow-up, 10 improved (7 %), and 2 progressed (1 %).  An objective reduction of symptomatic cords and nodules was achieved in 107 cases (75 %) at 3 months follow-up.  Moreover, 87 % of the patients reported a subjective relief of symptoms.  In long-term follow-up, only 16 of 142 cases (11 %) had progressed according to stage.  In the group with minimum follow-up 5 years (n = 57), 44 patients (77 %) experienced no disease progression, whereas 13 progressed (23 %) inside [8 cases (14 %)] or outside [5 cases (9 %)] of the RT field.  Most failures could have been avoided with appropriate choice of larger safety margins included in the treated portals; however, the failures outside were still amenable for another RT course.  The authors concluded that RT is effective to prevent disease progression for early-stage DC, which helps to avoid an otherwise necessary surgical procedure that is performed in advanced stages of DC.

Seegenschmiedt et al (2001) presented the 1-year results of a prospective randomized trial that compared two different RT dose concepts for early-stage DC.  A total of 129 patients (62 females; 67 males) were entered in this study: 69 had bilateral and 60 unilateral involvement of DC accounting for 198 irradiated hands.  According to Tubiana's classification, 73 hands had Stage N (nodules/cords, no extension deficit = flexion deformity), 61 had Stage N/I (less than or equal to 10 degrees deficit), 59 had Stage I (11 to 45 degrees deficit), and 5 had Stage II (46 to 90 degrees deficit) DC.  Prophylactic RT was randomly delivered; in Group A, 63 patients (95 hands) received 10 x 3 Gy (total dose of 30 Gy) in 2 series (5 x 3 Gy) separated by 8 weeks; in Group B, 66 patients (103 hands) received 7 x 3 Gy (total dose of 21 Gy) in 1 series within 2 weeks.  Ortho-voltage RT (120 kV) was applied using standard cones and individual shielding of un-involved areas of the palm.  Relevant patient and disease parameters were equally distributed in both groups.  Evaluation (toxicity, efficacy) was performed at 3 and 12 months after RT.  Subjective (patient's opinion) and objective parameters (measurements, palpation, and comparative photographs) were applied to assess treatment response.  Minimum follow-up was 1 year.  Acute toxicity was minimal, but slightly more pronounced in Group B.  Seventy-six (38 %) hands developed skin reactions common toxicity criteria [CTC] 1 degrees (A, 30; B, 46); and 12 (6 %) had skin reactions CTC 2 degrees (A, 4; B, 8).  Chronic side effects were limited to dryness, desquamation, skin atrophy, and change of sensation (LENT 1 degrees ) in 9 (5 %) sites without differences between the two groups.  At 3 and 12 months after RT, subjective and objective reduction of symptoms, nodules, and cords occurred in both groups (p < 0.01) with no differences between the groups: in Group A, 55 (56 %) sites regressed, 35 (37 %) remained stable, and 7 (7 %) progressed, whereas in Group B, 55 (53 %) regressed, 39 (38 %) remained stable, and 9 (9 %) progressed at 12-month follow-yp (non-significant).  Overall and mean number of nodules, cords, and skin changes decreased at 3 and 12 months.  The "treatment failure" rate at 1 year was 16 of 198 (8 %), but only 4 (2 %) sites required hand surgery for disease progression.  Seven of 60 patients with unilateral DC received prophylactic RT for the initially un-involved, contralateral hand due to progression of DC.  The authors concluded that both prophylactic RT concepts have been well-accepted and well-tolerated by patients.  Within the first year, they were equally effective to prevent further disease progression of DC and obtain considerable symptomatic improvement.  Although 1-year results suggested similar response rates for both treatment groups, long-term follow-up of greater than 5 years has to be awaited for final assessment and recommendation of an optimized RT treatment schedule.

In a retrospective analysis, Betz et al (2010) reported the long-term outcome and late toxicity of RT to prevent disease progression in patients with early-stage DC.  A total of 135 patients (208 hands) were irradiated with ortho-voltage (120 kV; 20 mA; 4-mm Al filter) in 2 courses with 5 daily fractions of 3.0 Gy to a total dose of 30 Gy; separated by a 6- to 8-week interval.  The extent of disease was described according to a modified Tubiana's classification.  Long-term outcome was analyzed at last follow-up with a median follow-up of 13 years (range of 2 to 25 years).  Late treatment toxicity and objective reduction of symptoms as change in stage and numbers of nodules and cords were evaluated and used as evidence to assess treatment response.  According to the individual stages, 123 cases (59 %) remained stable, 20 (10 %) improved, and 65 (31 %) progressed.  In stage N 87 % and in stage N/I 70 % remained stable or even regressed.  In more advanced stages, the rate of disease progression increased to 62 % (stage I) or 86 % (stage II).  A total of 66 % of the patients showed a long-term relief of symptoms (i.e., burning sensations, itching and scratching, pressure and tension).  Radiotherapy did not increase the complication rate after surgery in case of disease progression and only minor late toxicity (dry desquamation, skin atrophy) could be observed in 32 % of the patients.  There was no evidence for a second malignancy induced by RT.  The authors concluded that after a mean follow-up of 13 years, RT is effective in prevention of disease progression and improves patients' symptoms in early-stage DC (stage N, N/I).  In case of disease progression after RT, a "salvage" operation is still feasible.

In a systematic review, Kadhum and colleagues (2017) examined the evidence on the use of radiotherapy in Dupuytren's disease.  Only 6 articles met a minimum set standard, 5 of which were retrospective cohort studies and 1 a RCT.  A total of 770 Dupuytren's hands, nearly all with Tubiana stage 0 to 1 disease, were irradiated with an average 30 Gy.  Disease regression ranged from 0 % to 56 %, stability from 14 % to 98 % and progression from 2 % to 86 %.  Salvage surgery was successful in all cases of disease progression post-radiotherapy.  There were no reports of adverse wound healing problems associated with such surgery or radiotherapy-associated malignancy.  The authors concluded that radiotherapy should be considered an unproven treatment for early Dupuytren's disease due to a scarce evidence base and unknown long-term adverse effects.  They stated that well-designed RCTs are needed to confirm the benefits of radiotherapy treatment.

An UpToDate review on “Dupuytren's contracture” (Aggarwal and Blazar, 2017) states that “Prophylactic external beam radiation therapy can prevent progression and can provide symptomatic benefit in patients with mild to moderate flexion deformities; however, no controlled studies have been published”.

Guidance from the National Institute for Health and Care Excellence (NICE, 2016) concluded that "[t]he evidence on radiation therapy for early Dupuytren's disease raises no major safety concerns. Current evidence on its efficacy is inadequate in quantity and quality, and is difficult to interpret because of uncertainty about the natural history of Dupuytren's disease."

Tension and Compression Orthoses

In a randomized study, Brauns and colleagues (2017) determined how much improvement 2 types of orthotic device (tension and compression) as only treatment intervention can provide on a Dupuytren's contracture.  Is a compression orthosis better than a tension orthosis?  A total of 30 patients with measurable flexion contractures of the fingers were identified.  Both primary and recurrence cases were included.  Patients were randomized in 2 groups of 15 patients: one group had a standard tension orthosis (Levame), and the other group a newly designed silicon compression orthotic device.  Patients were instructed to wear the orthotic devices 20 hours a day during 3-month study period.  Data were collected at 1st visit and after 3 months of orthotic treatment.  Primary outcomes were active extension deficit of each joint and total active extension (TAE) of the digit; secondary outcome was patient satisfaction.  Visual analog scale (VAS) score of function and esthetics (0 to 10 points) were recorded at the start and after 3 months.  Flexion contracture was reduced at least 5 degrees in all patients.  After 3 months, TAE was significantly reduced in both groups (both p < 0.001).  The mean change in TAE was 32.36° in the tension group and 46.47° in the compression group.  Although reduction of TAE deficit was bigger in the compression group, this difference was not statistically significant (p = 0.39); VAS scale of esthetics and functionality was significantly increased in both treatment groups.  The functional VAS scale after 3 months was 11 % higher in the compression group than in the tension group (p = 0.03).  A major complication of a tension orthotic is skin ulcers.  The authors concluded that tension and compression orthotic devices can be used as a non-operative treatment of Dupuytren's disease in both early proliferative untreated hands and aggressive post-surgery recurrence.  Moreover, they stated that although there is no statistically significant difference, compression orthoses appeared to be more effective and are better-tolerated; nevertheless, adjustment of orthotic design and research on long-term results are needed.

Night Orthosis

In a multi-center, open, randomized controlled trial, Jerosch-Herold et al (2011) evaluated the effect of night splinting on self-reported function, finger extension and satisfaction in patients undergoing fasciectomy or dermofasciectomy for Dupuytren's contracture.  A total of 154 patients from 5 regional hospitals were randomized after surgery to receive hand therapy only (n = 77) or hand therapy with night-splinting (n = 77).  Primary outcome was self-reported function using the DASH questionnaire.  Secondary outcomes were finger range of motion and patient satisfaction.  Primary analysis was by intention-to-treat.  A total of 148 (96 %) patients completed follow-up at 12 months.  No statistically significant differences were observed on the DASH questionnaire (0 to 100 scale: adjusted mean diff. 0.66, 95 % CI: - 2.79 to 4.11, p = 0.703), total extension deficit of operated digits (degrees: adjusted mean diff 5.11, 95 % CI: -2.33 to 12.55, p = 0.172) or patient satisfaction (0 to 10 numerical rating scale: adjusted mean diff -0.35, 95 % CI: -1.04 to 0.34, p = 0.315) at 1 year post surgery.  Similarly, in a secondary per protocol analysis no statistically significant differences were observed between the groups in any of the outcomes.  The authors concluded that no differences were observed in self-reported upper limb disability or active range of motion between a group of patients who were all routinely splinted after surgery and a group of patients receiving hand therapy and only splinted if and when contractures occurred.  Given the added expense of therapists' time, thermoplastic materials and the potential inconvenience to patients having to wear a device, the routine addition of night-time splinting for all patients after fasciectomy or dermofasciectomy is not recommended except where extension deficits re-occur.

In a pilot study, Kemler and colleagues (2012) evaluated the effectiveness of post-operative splinting after limited fasciectomy for Dupuytren's disease.  A total of 54 patients with a PIP joint flexion contractures of at least 30° were randomized to receive either a 3-month splinting protocol together with hand therapy under the direct supervision of hand therapists, or the same hand therapy alone.  Extension deficit of the PIP joint (primary outcome measure), global perceived effect, pain intensity, comfort and complications were assessed at baseline and 1 year after surgery.  In an intention-to-treat analysis, the group assigned to splint-plus-hand therapy had a mean reduction of 21° in flexion contracture after 1 year, compared with 29° in the group receiving hand therapy alone (p = 0.1).  There was no difference between the groups regarding other parameters.  After operative release of a Dupuytren's contracture, a post-operative protocol using a splint and hand therapy was no better than hand therapy alone in minimizing post-operative flexion contractures.

In a single-center RCT, Collis et al (2013) examined the effectiveness of night extension orthoses on finger range of motion and hand function for 3 months following surgical release of Dupuytren contracture.  These researchers also determined how well finger extension was maintained in the total sample.  They randomized 56 patients to receive a night extension orthosis plus hand therapy (n = 26) or hand therapy alone (n = 30).  The primary outcome was total active extension of the operated fingers (degrees).  Secondary outcomes were total active flexion of the operated fingers (degrees), active distal palmar crease (cm), grip strength (kg), and self-reported hand function using the Disabilities of the Arm, Shoulder, and Hand questionnaire (0 to 100 scale).  There were no statistically significant differences between the no-orthosis and orthosis groups for total active extension or for any of the secondary outcomes.  Between the first post-operative measure and 3 months after surgery, 62 % of little fingers had maintained or improved total active extension.  The authors concluded that the use of a night extension orthosis in combination with standard hand therapy has no greater effect on maintaining finger extension than hand therapy alone in the 3 months following surgical release of Dupuytren contracture.  These findings indicated that the practice of providing every patient with a night extension orthosis following surgical release of Dupuytren contracture may not be justified except for cases in which extension loss occurs after surgery.  They stated that their results also challenged clinicians to research ways of maintaining finger extension in a greater number of patients.

Samargandi and colleagues (2017) examined the role of night orthosis use after surgical correction of Dupuytren's contracture.  These investigators searched Medline, Embase, CINAHL, AMED, OTSeeker, and CENTRAL for articles published from inception of the databases to August 2015.  Assessment was undertaken by 2 independent reviewers.  Methodological quality of RCTs was assessed using the Cochrane risk of bias tool and the Newcastle-Ottawa instrument.  A total of 7 studies met the standard for inclusion in this review; 659 patients across these 7 studies were included in the analysis, with follow-up ranging from 3 to 72 months.  None of the included studies assessed recurrence.  The analysis revealed no significant improvement in range of motion (ROM) of hand joints for patients who received a static night orthosis after Dupuytren surgery compared with patients without an orthosis.  Similarly, no differences were found in patient-reported functional status across the 2 groups.  The authors concluded that the current literature does not appear to support the use of static night orthosis in addition to hand therapy after surgical correction of Dupuytren contracture.

Autologous Fat Grafting

Tuncel and co-workers (2017) described their experience with treating DD (17 patients; 18 hands) using needle aponeurotomy and non-centrifuged autologous fat grafting.  Patients were treated with needle aponeurotomy and non-centrifuged autologous fat graft under general anesthesia.  The fat grafts were injected into the surgical area so as to stay in contact with the operated site.  An extension splint was used for 1 week post-operatively and the patients received hand therapy for 3 weeks.  Before the treatment, the contracture in the proximal interphalangeal and metacarpophalangeal joints was a mean of 45.06 ± 13.44 degrees and 36.56 ± 13.09 degrees, respectively.  It was 1.61 ± 1.65 and -0.56 ± 3.78 degrees at 3 months, respectively.  The difference between these measurements was statistically significant.  The mean follow-up period was 12 months.  The results were satisfactory and no complications were observed during the follow-up period.  The authors concluded that percutaneous aponeurotomy with non-centrifuged autologous fat grafting was found to have significantly beneficial effects in the treatment of DD.  This was a small study (n = 17 patients); these preliminary findings need to be further validated.

Collagenase Nanocapsules

Villegas and associates (2018) noted that fibrosis is a common lesion in different pathologic diseases and defined by the excessive accumulation of collagen.  Different approaches have been used to treat different conditions characterized by fibrosis.  The FDA and EMA approved the use of collagenase to treat palmar fibromatosis (Dupuytren's contracture).  The EMA approved additionally its use in severe Peyronie's disease, but it has been used off-label in other conditions.  The approved treatment includes up to 3 (in palmar fibromatosis) or up to 8 (in penile fibromatosis) injections followed by finger extension or penile modeling procedures, typically causing severe pain.  Frequent single injections are adequate to treat palmar fibromatosis.  The need to repeatedly inject doses of this enzyme can be due to the labile nature of collagenase, which exhibits a complete activity loss after a short period of time. 

Villegas, et al. (2018) presented a novel strategy to manage this enzyme based on the synthesis of polymeric nanocapsules that contain collagenase encapsulated within their matrix.  These nanocapsules have been engineered for achieving a gradual release of the encapsulated enzyme for a longer time, which can be up to 10 days.  The efficacy of these nanocapsules has been tested in a murine model of local dermal fibrosis, and the results demonstrated a reduction in fibrosis greater than that with the injection of free enzyme; this type of treatment showed a significant improvement compared to conventional therapy of free collagenase.  The authors concluded that these findings indicated a high potential for this novel system to improve the current treatment for fibrotic diseases.

Cryopreserved Placental Membrane

Dress and Tassis (2018) noted that DD is a rare connective tissue disorder resulting in progressive fibrosis and thickening of the palmar fascia, and contracture of the fingers due to excessive collagen deposition.  Staged surgical interventions are reserved for severe cases, yet worsening of fibrosis and contracture of fingers post-surgery, has been reported to have a recurrence rate as high as 85 %.

Dress and Tassis (2018) reported on the use of viable cryopreserved placental membrane (vCPM) allograft as an adjunct to open fasciectomy. In a patient with debilitating bilateral DD contractures of more than 20 years duration, this novel approach resulted in a 34.8 % ROM improvement and ability to fully extend all digits of the right hand.  No adverse events (AEs) were recorded.  At 1 year post-surgery, the patient had no decrease in ROM.  The authors concluded that these findings indicated that vCPM incorporation in open fasciectomy may provide benefit in reducing contracture recurrence in DD patients.  Moreover, they stated that long-term follow-up data are needed to provide additional insight on the utilization and clinical outcomes of vCPM in surgical fasciectomies.

Appendix

The Xiaflex prescribing information recommends the following dosing for Dupuytren’s contracture:

  • Xiaflex should be administered by a healthcare provider experienced in injection procedures of the hand and in the treatment of Dupuytren’s contracture.
  • Reconstitute Xiaflex lyophilized powder with only the supplied diluent prior to use.
  • Inject 0.58 mg of Xiaflex into each palpable Dupuytren’s cord with a contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint according to the injection procedure.
  • Up to 2 joints in the same hand may be treated during a treatment visit.
  • Approximately 24 to 72 hours following an injection, perform a finger extension procedure if a contracture persists.
  • Injections and finger extension procedures may be administered up to 3 times per cord at approximately 4-week intervals.
  • Inject up to 2 cords in the same hand at a treatment visit. If a patient has other cords with contractures, inject those cords at another treatment visit.

Source: Auxilium (2015).

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

20527 Injection, enzyme (eg, collagenase), palmar fascial cord (ie, Dupuytren's contracture)
26040 Fasciotomy, palmar (eg, Dupuytren's contracture_
26341 Manipulation, palmar fascial cord (ie, Dupuytren's cord), post enzyme injection (eg, collagenase), single cord
77401 Radiation treatment delivery, superficial and/or ortho voltage, per day

CPT codes not covered for indications listed in the CPB (not all-inclusive):

0019T Extracorporeal shock wave involving musculoskeletal system, not otherwise specified, low energy
0101T Extracorporeal shock wave involving musculoskeletal system, not otherwise specified, high energy
15770 Graft; derma-fat-fascia
20926 Tissue grafts, other (eg, paratenon, fat, dermis)
28890 Extracorporeal shock wave, high energy, performed by a physician or other qualified health care professional, requiring anesthesia other than local, including ultrasound guidance, involving the plantar fascia

Other CPT codes related to the CPB:

20550 Injection(s); single tendon sheath, or ligament, aponeurosis (eg, plantar "fascia")

HCPCS codes covered if selection criteria are met:

J0775 Injection, collagenase clostridium histolyticum, 0.01 mg

HCPCS codes not covered for indications listed in the CPB (not all-inclusive):

Cryopreserved placental membrane - no specific code:

ICD-10 codes covered if selection criteria are met:

M72.0 Palmar fascial fibromatosis [adults with Dupuytren's contracture with a palpable cord]

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

D25.0 - D25.9 Leiomyoma of uterus

The above policy is based on the following references:

  1. Badalamente MA, Hurst LC. Enzyme injection as nonsurgical treatment of Dupuytren's disease. J Hand Surg Am. 2000;25(4):629-636.
  2. Badalamente MA, Hurst LC, Hentz VR. Collagen as a clinical target: Nonoperative treatment of Dupuytren's disease. J Hand Surg Am. 2002;27(5):788-798.
  3. National Institute for Clinical Excellence (NICE). Needle fasciotomy for Dupuytren’s contracture. Interventional Procedure Guidance 43. London, UK: NICE; February 2004.
  4. Trojian TH, Chu SM. Dupuytren's disease: diagnosis and treatment. Am Fam Physician. 2007;76(1):86-89.
  5. Swartz WM, Lalonde DH. MOC-PS(SM) CME article: Dupuytren's disease. Plast Reconstr Surg. 2008;121(4 Suppl):1-10.
  6. Jordan GH. The use of intralesional clostridial collagenase injection therapy for Peyronie's disease: A prospective, single-center, non-placebo-controlled study. J Sex Med. 2008;5(1):180-187.
  7. Hurst LC, Badalamente MA, Hentz VR, et al. Injectable collagenase clostridium histolyticum for Dupuytren's contracture. N Engl J Med. 2009;361(10):968-979.
  8. U.S. Food and Drug Administration. FDA approves Xiaflex for debilitating hand condition. FDA News. Silver Spring, MD; FDA; February 2, 2010.
  9. Auxilium Pharmaceuticals, Inc. Xiaflex (collagenase clostridium histolyticum). Prescribing Information. Malvern, PA; Auxilium; February, 2010. 
  10. Keilholz L, Seegenschmiedt MH, Sauer R. Radiotherapy for prevention of disease progression in early-stage Dupuytren's contracture: Initial and long-term results. Int J Radiat Oncol Biol Phys. 1996;36(4):891-897.
  11. Seegenschmiedt MH, Olschewski T, Guntrum F. Radiotherapy optimization in early-stage Dupuytren's contracture: First results of a randomized clinical study. Int J Radiat Oncol Biol Phys. 2001;49(3):785-798.
  12. Foucher G, Medina J, Navarro R. Percutaneous needle aponeurotomy: Complications and results. J Hand Surg Br. 2003;28(5):427-431.
  13. Trojian TH, Chu SM. Dupuytren's disease: Diagnosis and treatment. Am Fam Physician. 2007;76(1):86-89.
  14. Cheng HS, Hung LK, Tse WL, Ho PC. Needle aponeurotomy for Dupuytren's contracture. J Orthop Surg (Hong Kong). 2008;16(1):88-90.
  15. Lellouche H. Dupuytren's contracture: Surgery is no longer necessary. Presse Med. 2008;37(12):1779-1781.
  16. Oxfordshire NHS Trust. Surgery for Dupuytren’s contracture. Interim Treatment Threshold Statement. Priorities Forum Policy Statement. Oxford, UK: NHS; October 15, 2009.
  17. Betz N, Ott OJ, Adamietz B, et al. Radiotherapy in early-stage Dupuytren's contracture. Long-term results after 13 years. Strahlenther Onkol. 2010;186(2):82-90.
  18. Manet MP, Roulot E, Teyssedou JP, et al. Dupuytren's contracture: Needle aponeurotomy is an alternative to surgery. Rev Med Interne. 2011;32(4):241-248.
  19. National Institute for Health and Clinical Excellence (NICE). Radiation therapy for early Dupuytren’s disease. Interventional Procedure Guidance 368. London, UK: NICE; November 2010.
  20. Knobloch K, Kuehn M, Vogt PM. Focused extracorporeal shockwave therapy in Dupuytren's disease -- a hypothesis. Med Hypotheses. 2011;76(5):635-637.
  21. Jerosch-Herold C, Shepstone L, Chojnowski AJ, et al. Night-time splinting after fasciectomy or dermo-fasciectomy for Dupuytren's contracture: A pragmatic, multi-centre, randomised controlled trial. BMC Musculoskelet Disord. 2011;12:136.
  22. Chen NC, Shauver MJ, Chung KC. Cost-effectiveness of open partial fasciectomy, needle aponeurotomy, and collagenase injection for dupuytren contracture. J Hand Surg Am. 2011;36(11):1826-1834.
  23. Hovius SE, Kan HJ, Smit X, et al. Extensive percutaneous aponeurotomy and lipografting: A new treatment for Dupuytren disease. Plast Reconstr Surg. 2011;128(1):221-228.
  24. Azzopardi E, Boyce DE. Clostridium histolyticum collagenase in the treatment of Dupuytren's contracture. Br J Hosp Med (Lond). 2012;73(8):432-436.
  25. Kemler MA, Houpt P, van der Horst CM. A pilot study assessing the effectiveness of postoperative splinting after limited fasciectomy for Dupuytren's disease. J Hand Surg Eur Vol. 2012;37(8):733-737.
  26. Karabeg R, Jakirlic M, Arslanagic S, et al. Results of surgery treatment of Dupuytren's contracture in 115 patients. Med Arh. 2012;66(5):329-331.
  27. Collis J, Collocott S, Hing W, Kelly E. The effect of night extension orthoses following surgical release of Dupuytren contracture: A single-center, randomized, controlled trial. J Hand Surg Am. 2013;38(7):1285-1294.
  28. Corradino B, Di Lorenzo S, Moschella F. Treatment of stages III-IV of the Dupuytrens Disease using a personal approach: Percutaneous needle fasciotomy (PNF) and minimal invasive selective aponeurectomy. Acta Chir Plast. 2013;55(1):19-22.
  29. Sanjuan Cervero R, Franco Ferrando N, Poquet Jornet J. Use of resources and costs associated with the treatment of Dupuytren's contracture at an orthopedics and traumatology surgery department in Denia (Spain): Collagenase clostridium hystolyticum versus subtotal fasciectomy. BMC Musculoskelet Disord. 2013;14:293.
  30. Atroshi I, Strandberg E, Lauritzson A, et al. Costs for collagenase injections compared with fasciectomy in the treatment of Dupuytren's contracture: A retrospective cohort study. BMJ Open. 2014;4(1):e004166.
  31. Peimer CA, Blazar P, Coleman S, et al.  Dupuytren contracture recurrence following treatment with collagenase clostridium histolyticum (CORDLESS study): 3-year data. J Hand Surg Am. 2013;38(1):12-22.
  32. Auxilium Pharmaceuticals, Inc. Xiaflex (collagenase clostridium histolyticum) for injection, for intralesional use. Prescribing Information. PL-0108-001.g. Malvern, PA; Auxilium; revised July 2015. 
  33. Nehra A, Alterowitz R, Culkin DJ, et al. Peyronie's disease: AUA guideline. Linthicum (MD): American Urological Association Education and Research, Inc.; April 2015.
  34. Brazzelli M, Cruickshank M, Tassie E, et al. Collagenase clostridium histolyticum for the treatment of Dupuytren's contracture: Systematic review and economic evaluation. Health Technol Assess. 2015;19(90):1-202.
  35. Smeraglia F, Del Buono A, Maffulli N. Collagenase clostridium histolyticum in Dupuytren's contracture: A systematic review. Br Med Bull. 2016;118(1):149-158.
  36. Jayes FL, Liu B, Moutos FT, et al. Loss of stiffness in collagen-rich uterine fibroids after digestion with purified collagenase clostridium histolyticum. Am J Obstet Gynecol. 2016;215(5):596.e1-596.e8.
  37. Ball C, Izadi D, Verjee LS, et al. Systematic review of non-surgical treatments for early dupuytren's disease. BMC Musculoskelet Disord. 2016;17(1):345.
  38. Brauns A, Van Nuffel M, De Smet L, Degreef I. A clinical trial of tension and compression orthoses for Dupuytren contractures. J Hand Ther. 2017;30(3):253-261.
  39. Kadhum M, Smock E, Khan A, Fleming A. Radiotherapy in Dupuytren's disease: A systematic review of the evidence. J Hand Surg Eur Vol. 2017;42(7):689-692.
  40. Tuncel U, Kurt A, Gumus M, et al. Preliminary results with non-centrifuged autologous fat graft and percutaneous aponeurotomy for treating Dupuytren's disease. Hand Surg Rehabil. 2017;36(5):350-354.
  41. National Institute for Health and Care Excellence (NICE). Radiation therapy for early Dupuytren's disease. Interventional Procedure Guidance (IPG) 573. London, UK: NICE; December 21, 2016. 
  42. Samargandi OA, Alyouha S, Larouche P, et al. Night orthosis after surgical correction of Dupuytren contractures: A systematic review. J Hand Surg Am. 2017;42(10):839.e1-839.e10.
  43. Tuncel U, Kurt A, Gumus M, et al. Preliminary results with non-centrifuged autologous fat graft and percutaneous aponeurotomy for treating Dupuytren's disease. Hand Surg Rehabil. 2017;36(5):350-354.
  44. Aggarwal R, Blazar PE. Dupuytren's contracture. UpToDate Inc., Waltham, MA. Last reviewed Julyy 2018.
  45. Villegas MR, Baeza A, Usategui A, et al. Collagenase nanocapsules: An approach to fibrosis treatment. Acta Biomater. 2018;74:430-438.
  46. Dress CM, Tassis EK. A case of Dupuytren's disease managed with viable cryopreserved placental membrane adjunct to open palmar fasciectomy. J Surg Case Rep. 2018;2018(3):rjy055.
  47. Scherman P, Jenmalm P, Dahlin LB. Three-year recurrence of Dupuytren's contracture after needle fasciotomy and collagenase injection: A two-centre randomized controlled trial. J Hand Surg Eur Vol. 2018 Jan 1: [Epub ahead of print].