Treatment of Dupuytren's disease [PDF]

Diplomarbeit

Treatment of Dupuytren’s disease Comparison of functional outcome between non surgical collagenase treatment and fasciectomy

eingereicht von

Tanja Guggenbichler

zur Erlangung des akademischen Grades

Doktorin der gesamten Heilkunde (Dr. med. univ.) an der

Medizinischen Universität Graz ausgeführt an der klinischen Abteilung für Plastische, Ästhetische und Rekonstruktive Chirurgie unter der Anleitung von Dr. Daryousch Parvizi Priv.Doz.Dr. Martin Hubmer

Graz, 03.11.2015

Eidesstattliche Erklärung Ich erkläre ehrenwörtlich, dass ich die vorliegende Arbeit selbstständig und ohne fremde Hilfe verfasst habe, andere als die angegebenen Quellen nicht verwendet habe und die den benutzten Quellen wörtlich oder inhaltlich entnommenen Stellen als solche kenntlich gemacht habe.

Graz, am 03.11.2015……

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Guggenbichler Tanja eh.

Danksagung

Zuallererst möchte ich mich bei meinen zwei Diplomarbeitsbetreuern Dr. Daryousch Parvizi und Priv. Doz. Dr. Martin Hubmer bedanken, die mich bei der Arbeit sehr unterstützt haben und die ich immer um Hilfe bitten konnte. Mein Dank ergeht auch an die Physiotherapeutinnen der plastischen Chirurgie, die die objektiven Messungen an den Patient/innen durchgeführt haben und mir ihre Daten zur Verfügung gestellt haben. Weiters möchte ich mich recht herzlich bei Prof. Herwig Friedl vom Statistikinstitut der TU Graz bedanken, der mich bei der Auswertung meiner Ergebnisse tatkräftig unterstützt hat. Mein allergrößter Dank gebührt meiner Mutter Anna und meinen zwei Schwestern Katrin und Vanessa. Von Beginn an haben sie mich in allen Lebenslagen unterstützt und sind immer hinter mir gestanden. Auch in den schwierigsten Zeiten haben wir es doch zusammen geschafft uns immer weiter durchzukämpfen und zusammenzuhalten. Ein Leben ohne sie wäre unvorstellbar und nicht auszudenken. Auch meinen Großeltern Rupert und Elisabeth, die immer wieder erwähnt haben, wie stolz sie auf mich sind, bei denen ich einen Großteil meiner Kindheit verbringen durfte und die mich auch in vielen Lebenslagen unterstützt haben bin ich aufs tiefste dankbar. Einen sehr großen Teil in meinem Leben nimmt seit den letzten drei Jahren mein Partner Rainer ein. Auch ihm möchte ich vom Herzen für alles danken. Sowohl für die ständige Motivation, als auch für seine unglaubliche Fähigkeit mich einfach jeden Tag glücklich zu machen.

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Auch allen meinen Freunden, die ich in den letzen sechs Jahren kennen gelernt habe gebührt mein größter Dank für alles. Sowohl für das sich gegenseitige durch das Studium boxen, als auch für alle Partys, die Reisen und für das einfach füreinander da sein, wenn man dringend wen zum Reden braucht. Ich möchte diese Personen in meinem Leben nicht mehr missen und hoffe, dass der Kontakt auch durch die Entfernung weiterhin bestehen bleiben wird. Nicht zuletzt möchte ich auch noch meinem Vater Manfred danken, der mich gerade durch unsere Auseinandersetzungen und Streitigkeiten so stark gemacht hat.

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Contents Danksagung ........................................................................................................... II Contents ................................................................................................................ IV Abbreviation .......................................................................................................... VI Figures ................................................................................................................. VII Tables ................................................................................................................. VIII Zusammenfassung ............................................................................................... XII Abstract ............................................................................................................... XIV 1. Introduction......................................................................................................... 1 2. Dupuytren’s Disease .......................................................................................... 2 2.1. Anatomy....................................................................................................... 2 2.2. Epidemiology ............................................................................................... 5 2.3. Aetiology ...................................................................................................... 5 2.4. Pathogenesis ............................................................................................... 6 2.5. Symptoms .................................................................................................... 6 2.6. Diagnosis ..................................................................................................... 7 2.7. Treatment of Dupuytren’s Disease .............................................................. 9 2.7.1. Surgical Treatment ................................................................................ 9 2.7.2. Nonsurgical Treatment ........................................................................ 13 3. Patients and Methods ....................................................................................... 17 3.1 Patient data/Inclusion criteria ...................................................................... 17 3.2 Methods ...................................................................................................... 17 3.2.1 Data evaluation .................................................................................... 17 3.2.1.1 MHQ .............................................................................................. 18 3.2.1.2 DASH ............................................................................................. 18 3.2.1.3. Sensibility based on Semmes Weinstein Monofilaments .............. 19

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3.2.1.4 Progress of Dupuytren's contracture PIP and MCP and total range of motion .................................................................................................... 19 3.2.1.5. Strength level of the injured hand ................................................. 20 3.2.1.6. Measurement of Pain Sensitivity................................................... 20 3.2.1.7. Preoperative values ...................................................................... 21 3.2.2 Statistical Methods ............................................................................... 24 4. Results ............................................................................................................. 25 4.1. Wilcoxon Tests .......................................................................................... 25 4.2. Boxplots ..................................................................................................... 27 4.3. Regression models .................................................................................... 57 5. Discussion ........................................................................................................ 63 6. Conclusion........................................................................................................ 65 7. References ....................................................................................................... 66

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Abbreviation CCH

Collagenase Clostridium Histolyticum

DASH

Disabilities of the Arm, Shoulder and Hand

DIP

Distal interphalangeal joint

MCP

Metacarpophalangial joint

MHOS

Michigan Hand Outcome Score

MHQ

Michigan Hand Outcomes Questionnaire

PIP

Proximal interphalangeal joint

ROM

Range of motion

TROM

Total range of motion

VAS

Visual analogue scale

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Figures Figure 1 Anatomy of the Hand (7) .......................................................................... 4 Figure 2 Dupuytren’s Disease Stadiums (8) ........................................................... 4 Figure 3 Hueston Tabletop test (12) ....................................................................... 8 Figure 4 Tubiana Stages (14) ................................................................................. 8 Figure 5 midline longitudinal incisions closed with Z-plasties (16)....................... 10 Figure 6 Bruner - type zigzag incision (17) ........................................................... 10 Figure 7 Planing for Bruner incision (18) .............................................................. 11 Figure 8 Identification of the cord (black arrows) and neurovascular bundles (red arrows) (19) .......................................................................................................... 11 Figure 9 Excision of affected tissue (20) .............................................................. 12 Figure 10 Needle aponeurotomy (23) ................................................................... 13 Figure 11 Three Step Injection of Xiapex into the Cord (25) ................................ 15 Figure 12 Three Step Injection of Xiapex (25) ...................................................... 16 Figure 13 Goniometer (31) ................................................................................... 19 Figure 14 Hydraulic Hand Dynamometer (32) ...................................................... 20 Figure 15 VAS Scale (33) ..................................................................................... 20 Figure 16 Differences MHQ General Score .......................................................... 28 Figure 17 Differences MHQ Work Score .............................................................. 30 Figure 18 Differences MHQ Pain Score ............................................................... 32 Figure 19 Differences MHQ Appearance Score ................................................... 34 Figure 20 Differences MHOS ............................................................................... 38 Figure 21 Differences DASH Score ...................................................................... 40 Figure 22 Differences TROM................................................................................ 42 Figure 23 Differences Strength Level ................................................................... 44 Figure 24 Differences Semmes Weinstein Monofilaments ................................... 46 Figure 25 Differences Progress of Contracture MCP ........................................... 48 Figure 26 Differences Progress of Contracture PIP ............................................. 50 Figure 27 Differences Progress of Contracture MCP + PIP ................................. 52 Figure 28 Differences Pain Sensitivity in Rest ...................................................... 54 Figure 29 Differences Pain Sensitivity in Motion .................................................. 56

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Tables Table 1 Grading System of Dupuytren’s Disease after Tubiana et al. (1968) ........ 8 Table 2 Grading System of Semmes Weinstein Monofilaments ........................... 19 Table 3 Range of Motion Norm ............................................................................ 19 Table 4 p-values of the Wilcoxon Tests: Comparison of the median of fasciectomy and Xiapex Score-differences preoperative – 2 and 6 weeks postoperative ........................................................................................................ 25 Table 5 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences MHQ General Score ............................................................................................. 27 Table 6 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, MHQ General Score ......................................................................... 27 Table 7Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, MHQ Work Score ................................................................................................. 29 Table 8 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, MHQ Work Score .............................................................................. 29 Table 9 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, MHQ Pain Score .................................................................................................. 31 Table 10 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, MHQ Pain Score ............................................................................... 31 Table 11Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, MHQ Appearance Score ...................................................................................... 33

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Table 12 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, Appearance Score ............................................................................ 33 Table 13 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, MHQ Final Score .................................................................................................. 35 Table 14 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, MHQ Final Score .............................................................................. 35 Table 15 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, MHOS .................................................................................................................. 37 Table 16 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, MHOS ............................................................................................... 37 Table 17 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, DASH Score ......................................................................................................... 39 Table 18 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, DASH Score ..................................................................................... 39 Table 19 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, TROM ................................................................................................................... 41 Table 20 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, TROM ............................................................................................... 41 Table 21 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, Strength Level ...................................................................................................... 43 Table 22 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, Strength Level ................................................................................... 43

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Table 23 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, Semmes Weinstein Monofilaments ...................................................................... 45 Table 24 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, Semmes Weinstein Monofilaments ................................................... 45 Table 25 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, Progress of Contracture MCP joints ..................................................................... 47 Table 26 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, Progress of Contracture MCP joints.................................................. 47 Table 27 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, Progress of Contracture PIP joints ....................................................................... 49 Table 28 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, Progress of Contracture PIP joints .................................................... 49 Table 29 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, Progress of contracture MCP + PIP joints ............................................................ 51 Table 30 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, Progress of contracture MCP + PIP joints......................................... 51 Table 31 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, Pain Sensitivity in Rest ......................................................................................... 53 Table 32 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, Pain Sensitivity in Rest ..................................................................... 53 Table 33 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, Pain Sensitivity in Motion...................................................................................... 55

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Table 34 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, Pain Sensitivity in Motion .................................................................. 55 Table 35 Results: Regression Model MHQ General Score .................................. 57 Table 36 Results: Regression Model MHQ Work Score ....................................... 57 Table 37 Results: Regression Model MHOS ........................................................ 58 Table 38 Results: Regression Model DASH ......................................................... 58 Table 39 Results: Regression Model TROM ........................................................ 59 Table 40 Results: Regression Model Strength Level ............................................ 59 Table 41 Results: Regression Model Monofilament Testing ................................ 60 Table 42 Results: Regression Model Progress of Contracture MCP .................... 60 Table 43 Results: Regression Model Progress of Contracture PIP ...................... 61 Table 44 Results: Regression Model Progress of Contracture MCP + PIP .......... 61

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Zusammenfassung Die subtotale Fasziektomie ist nach wie vor der Goldstandard in der Behandlung des Mb. Dupuytren (1). Seit 2011 gibt es am europäischen Markt eine neue, nicht operative, Behandlungsmethode mit dem Namen Xiapex. Dabei handelt es sich um die injizierbare Kollagenase clostridium histolyticum, bestehend aus den zwei unterschiedlichen Kollagenasen AUX I und AUX II (2). Das Ziel der vorliegenden Arbeit ist es, aufzuzeigen, ob es einen besseren Outcome bei Patient/innen gibt, die mit der neuen Methode behandelt wurden. Methoden: Für diese Arbeit wurden Daten aus dem MEDOCS System des Landeskrankenhauses Graz verwendet, von Patient/innen die in den letzen zwei Jahren entweder mittels partieller Fasziektomie oder mittels Xiapex behandelt wurden. Die Patient/innen wurden vor dem Eingriff, zwei Wochen und sechs Wochen nach dem Eingriff untersucht. Der Outcome wurde sowohl durch objektive als auch subjektive Methoden untersucht. In der Xiapex Gruppe befanden sich elf Patient/innen und in der Fasziektomie Kontrollgruppe zwölf. Für die subjektiven Untersuchungsergebnisse wurde einerseits der Michigan Hand Outcome Questionnaire und andererseits der DASH Score herangezogen. Die objektiven Methoden beinhalteten: Messung der Sensibilität nach Semmes Weinsteins Monofilamenten, Ausmaß des Streckdefizits im PIP und MCP, Messung der totalen aktiven Bewegung, Kraftmessung der betroffenen Hand und Messung des Schmerzes in Bewegung und Ruhe anhand der VAS Schmerzskala. Ergebnisse: Anhand von statistischen Boxplots der Mediane der Differenzen konnte in 6 von 15 Tests ein signifikant besseres Ergebnis bei der Xiapex Gruppe nachgewiesen werden. Um auch das Alter und den Faktor Zeit einfließen zu lassen wurden Regressionsmodelle erstellt. Dabei konnte in 9 von 15 getesteten Scores ein signifikant besseres Ergebnis bei Patient/innen, die mit Xiapex behandelt wurden, nachgewiesen werden. Weiters scheint auch die Zeit eine große Rolle zu spielen. In 6 von den 15 Scores, die mittels Regressionsmodellen überprüft wurden ergaben sich signifikant bessere Ergebnisse sechs Wochen nach der Behandlung als nach zwei Wochen.

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Schlussfolgerung: Obwohl ich bei meiner Studie eine sehr geringe Patient/innen – Anzahl zur Verfügung hatte, gab es signifikant bessere Ergebnisse bei der Gruppe, die mit Xiapex behandelt wurde. In der Zukunft wäre es medizinisch sinnvoll in Langzeitstudien herauszufinden, ob dies auch über einen längeren Zeitraum konstant bleibt.

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Abstract Palmar fasciectomy is still the accepted gold standard in the treatment of Dupuytren’s disease (1). Since 2011 a new treatment option has been made available in Europe, called Xiapex, which enables the nonsurgical treatment of Dupuytren’s disease. It consists of the injectable collagenase clostridium histolyticum consisting of two distinct collagenases AUX I and AUX II (2). The aim of the present thesis is to research the outcome in patients treated with fasciectomy compared to those treated using Xiapex. Methods: For this thesis I retrospectively analysed patients in the MEDOCs System, who underwent either fasciectomy or Xiapex injection within the last two years at the department of plastic surgery at the State Hospital in Graz. Patients were examined preoperative, and then two weeks and six weeks after treatment. There were 11 patients in the Xiapex group and 12 patients treated with fasciectomy. The outcome after these two different interventions was measured using subjective and objective methods. For subjective measurement the Michigan Hand outcome Questionnaire and the DASH score were used. Objective methods included: Sensibility based on Semmes Weinstein Monofilaments, progress of Dupuytren’s contracture in PIP and MCP, total range of motion, strength level of the injured hand, and measurement of pain sensitivity on the basis of the VAS scale in rest and in motion. Results: On the basis of boxplots of the median of the differences significantly better results could be proved in subjects treated with Xiapex in 6 out of 15 tested scores. Further regression models were created to prove the influence of the age and factor time. Significantly better results for Xiapex could be proved in 9 out of 15 tested scores. In 6 out of this 15 scores patients had significantly better results six weeks after intervention than two weeks after it Conclusion: Although the number of patients analysed is relatively low, there were significantly better results in people treated with Xiapex compared to those who

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underwent total fasciectomy. It would be interesting and worthwhile to conduct studies on the long term success or recurrence rate of patients treated with Xiapex.

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1. Introduction Dupuytren’s disease is a benign nodular fibromatosis, which affects the palmar fascia of the hands. The pathogenic cord causes the fingers to flex progressively, resulting in impaired hand function and deformity (3). The disease was first described nearly 400 years ago by Plater (4). Nowadays it is named after Baron Guillaume Dupuytren who was the first to treat it with an operation. The understanding of the pathopysiology, anatomy, and treatment of the disease is still evolving. Dupuytren’s disease is very common in northern Europeans, while it is very rare in dark skinned populations. It is very uncommon to occur in the teens and twenties but numbers start to rise in the decades thereafter. Myofibroblast proliferation and altered collagen matrix composition lead to thickened and contracted palmar fascia (4).

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2. Dupuytren’s Disease 2.1. Anatomy The palmar and digital fascias form a three dimensional array of ligaments, consisting of transverse, longitudinal and vertical components (5). The Palmar fascial complex of the hand consists of the following five components: 

The radial aponeurosis o Thenar fascia o Thumb pretendinous band o Distal commissural ligament o Proximal commissural ligament



The ulnar aponeurosis o Hypothenar muscle fascia o Pretendinous band to the small finger o Abductor digiti minimi coalescence



The central aponeurosis: it is the core of Dupuytren’s disease activity. It is a triangular fascial layer with proximal apex and distal base. The fibers are orientated into three dimensions: o Longitudinal fibres: They fan out as three pretendinous bands root the central digits. Each of them bifurcates distally. The superficial layer inserts into the dermis, the middle one continues to the digit as the spiral band and the deep layer passes almost vertically in the vicinity of the extensor tendon. o Transverse fibres: They encompass the natatory ligament, located in the palmodigital region and the transverse ligament of the palmar aponeurosis. The transverse ligament of the palmar aponeurosis is located proximal and parallel to the natatory ligament and reaches deep to the pretendinous bands. It continues radially as the proximal commissural ligament. The transverse ligament gives origin to the septa of Legueu and Juvara and protects neurovascular structures. o Vertical fibres: they encompass the vertical bands of Grapow and the septa.



The palmodigital fascia: The palmodigital fascia constists of a lot of structures. The most notable ones are the spiral band and the natatory ligament. The spiral band

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is the connection between palmar and digital fascial structures. Each spiral band begins proximally as the middle layer of a bifurcated pretendinous band, tangential to the palm and then spirals on its axis. There it becomes perpendicular to the palm distally, lateral to the MCP joint capsule. They emerge distal to the natatory ligament, to continue as the lateral digital sheet. The fibers of the natatory ligament run in a transverse layer. Distal most fibers form a U and run longitudinally along the side of adjacent digits toward the lateral digital sheet. 

The digital fascia The neurovascular bundle in the digits is surrounded by four fascial structures: o Palmar: Grayson’s ligament o Dorsally: Cleland’s ligament o Laterally: Gusset lateral digital sheet o According to Thomine 1985 a retrovascular fascia medially and dorsally, which has not been confirmed by other studies. (6)

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Figure 1 Anatomy of the Hand (7)

In the normal hand the palmar fascial structures are called bands or ligaments, and cords when affected by Dupuytren’s disease (5).

Figure 2 Dupuytren’s Disease Stadiums (8)

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2.2. Epidemiology The highest prevalence of Dupuytren’s disease occurs in people with northern European origin (9). In Norway the disease shows a high prevalence as 30% of men over 60 years are affected. In England there is prevalence of 15% of men over 60 years. In the Mediterranean basin the prevalence is much lower. In Africa and Asia it is very rare (5). The disease is very uncommon in the teens and twenties and starts to rise in the decades thereafter (4). Early age of onset has a higher rate of disease progression and recurrence than late onset. The incidence of Dupuytren’s disease is 5-15 times higher in men than in women and also becomes symptomatic nearly 10 years earlier in lives of men. In the 8th and 9th decade the sex ratio is nearly 1:1 (9,10).

2.3. Aetiology There are a lot of different factors associated with Dupuytren´s disease. 

Genetic predisposition: A genetic influence of Dupuytren’s disease is supported on one site by the geographic variation in prevalence and on the other hand by clustering of cases in families. Examination of genetic influence is complicated because of the high prevalence, late onset, incomplete penetrance and the possibility that some cases have non-genetic causes.



Diabetes: Dupuytren’s disease has an increased prevalence in Type I as well as in Type II diabetes (5). Patients with diabetes mellitus have more nodules and less contraction (10).



Trauma: In few cases, there seems to be a clear link between a single episode of trauma and the appearance of Dupuytren’s disease at the same hand. Causal relationships with repeated trauma or types of manual work have not been established and there is no association with exposure to vibration (5).



Habits: There is a connection with alcoholism and cigarette smoking (9).



Other fibromatoses: Dupuytren’s disease can be associated with Ledderhose disease, Peryonie´s disease or fibromatosis of the dorsum of the PIP joint (10).

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2.4. Pathogenesis The pathopysiology of Dupuytren’s disease is multifactorial and still a topic of research and debate. It includes genetic predisposition, trauma, inflammatory response, ischemia, environment and variable expression of proteins and growth factors within local tissue (4). Processes are similar to wound healing with fibroblast proliferation, collagen deposition and myofibroblast contraction (10). During the early stages fibroblasts predominate, which are replaced by myofibroblasts as the contracture develops (11). The normal palmar and digital fascia is replaced by cords of collagen that are thicker and shorter than the original bands. The ratio of type III to type I collagen is higher than in normal fascia. Myofibroblasts are one of the characteristic features of Dupuytren’s disease. They share the morphological characteristics of fibroblasts and smooth muscle cells. Myofibroblasts contain arrays of cytoplasmic actin filaments that attach to specialized adhesion sites at the cell membrane. Through this connection force can be transmitted to the extracellular matrix. The mechanical environment may influence myofibroblast differentiation. The role of the transforming growth factor BETA 1 and other growth factors remains unclear at present (5). The disease mainly affects the longitudinal fibres of the palmar fascia in the subcutaneous tissue of the palm (10).

2.5. Symptoms 

Skin changes: Earliest manifestations of Dupuytren’s disease appear especially in the palm of the hand. They can occur in the dorsal and palmar skin. Dorsal skin changes are either in the form of dorsal Dupuytren’s nodules or dorsal cutaneus pads, named after Garrod. Palmar skin changes begin with the formation of microcords from Grapow fibers which begin to connect the dermis to the palmar fascia. This formation of the microcords leads to pseudocallus or thickening of the skin and the underlying subcutaneous tissue. As a result the skin becomes attached to the underlying fascial structures and loses its mobility.



Formation of a nodule: The nodule is a firm soft tissue mass that is fixed to the skin and the deeper fascia. It develops from superficial components of the palmar or digital fascia. Usually it is well defined, localized, and raised from the surface.

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Nodules can be located in the palm or the digits. Palmar nodules are located near the distal palmar crease and often in line with the ring and small fingers. Digital nodules are usually located near the PIP joint and proximally at the digits base. Usually nodules are painless, but can enlarge. They cause pain when there is association with stenosing tenosynovitis which can develop if the nodule forms direct pressure on the flexor tendons. 

Nodule regression



Cord formation: The nodule may regress gradually till the cord appears. With time the cord becomes prominent and changes the appearance and consistency to that of a tendon. The locations of cords are in the palm, palmodigital area, or digits.



Maturation and contracture

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Progressive digital flexion deformity (6) Dupuytren’s disease commonly begins in the palm and spreads into the distal parts of the digits (4).

2.6. Diagnosis Clinical examination should include: 1.

Sites of nodules and contracted cords, skin pitting and dimpling in palm and digits

2.

Degree of skin involvement

3.

Measuring the MCP and PIP joint angle

4.

Knuckle pads

5.

Plantar nodules

6.

Sensation in palm and fingers A very useful test is the Hueston Tabletop Test. Here the patient has to put the hand and fingers flat on the table. The test is positive when the hand will not go flat because of the contracture of the fingers (10).

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Figure 3 Hueston Tabletop test (12)

A grading system to assess the involvement of Dupuytren’s disease was described by Tubiana et al. in 1968 (13). N

palmar nodule without presence of contracture

0

no lesion

1

Total flexion deformity between 0° and 45°

2

Total flexion deformity between 45° and 90°

3

Total flexion deformity between 90° and 135°

4

Total flexion deformity greater than 135°

Table 1 Grading System of Dupuytren’s Disease after Tubiana et al. (1968)

Figure 4 Tubiana Stages (14)

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2.7. Treatment of Dupuytren’s Disease 2.7.1. Surgical Treatment Surgical treatment continues to be the gold standard for Dupuytren’s disease. Intervention is recommended in patients with MCP joint contractures of 30° or more and any PIP joint contractures with functional impairment. (15) Also thumb deformity is an indication for surgical treatment (11). Metacarpophalangeal joint: MCP joint contracture is correctable almost without any recurrence. Secondary joint contracture is rare. The indication for surgery is a contracture that is interfering with hand function or joint contractures of 30° and more. A good testing option is the Hueston’s Tabletop test. Proximal interphalangeal joint: In the PIP joint excision of contracted fascia often fails to restore full extension because of secondary shortening of other structures that cross the palmar aspect of the joint. Especially the check - rein ligaments of the palmar plate and the accessory collateral ligaments play a role as well as in some cases also a shortness of skin, involvement of the flexor tendon sheath, and shortening of the flexor muscles limit extension. The greater the severity and duration of contracture, the greater the risk of secondary joint contracture. Progressive contracture is a good indication for surgery. For this, serial measurements with a goniometer at intervals of a few months can be helpful. Distal interphalangeal joint: Involvement of the DIP joint is very uncommon but can be associated with contracture of the PIP joint of the little finger through a band that spans both joints (5). Palmar (regional/subtotal) fasciectomy Nowadays this method is the accept gold standard procedure for primary contracture release. It involves careful dissection and excision of the diseased, thickened fascia. There are multiple options for skin incisions, including Bruner -

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type zigzag incisions, multiple Y-V advancement flaps, midline longitudinal incisions closed with Z-plasties and transverse incisions. After surgery the hand is splinted, with MCP and PIP joint in extended position. The splint is removed after a few days and from then on an active range of motion is initiated. This method is associated with a lower rate of recurrence than fasciotomy (1).

Figure 5 midline longitudinal incisions closed with Z-plasties (16)

Figure 6 Bruner - type zigzag incision (17)

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Figure 7 Planing for Bruner incision (18)

Figure 8 Identification of the cord (black arrows) and neurovascular bundles (red arrows) (19)

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Figure 9 Excision of affected tissue (20)

Open fasciotomy This has been the original treatment for Dupuytren’s contracture for over 200 years. The original descriptions of Baron Guillaume Dupuytren’s technique require a transverse incision through the skin and the removal of the pathological cord at the level of the MCP joint. Needle aponeurotomy Percutaneous needle fasciotomy was one of the first treatment options of Dupuytren’s contracture. Due to its high recurrence rate it fell out of favour. In the late 70s French rheumatologists began to use with this treatment again and it has since been used increasingly (21). It is the least invasive surgical intervention, ideal for elderly individuals with multiple comorbidities (15). The method requires a percutaneous fasciotomy by using a small gauge needle as a scalpel blade. Compared to fasciectomy, there is a lower incidence of nerve injury. During the procedure, distal sensibility and motion of the fingers are monitored (22). It is a safe option for high- risk patients with multiple comorbidities because it can be performed under local anaesthetics and has a minimal recovery time (15). Usually it can be repeated safely and effectively for a recurrence of the disease (22).

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Figure 10 Needle aponeurotomy (23) The yellow arrow shows the direction of the oscillatory movements of the needle for sectioning the cord at several levels.

2.7.2. Nonsurgical Treatment Injectable collagenase clostridium histolyticum is a new non-surgical treatment for adults with Dupuytren’s disease with one palpable cord. The collagenase consists of 2 distinct collagenases AUX I and AUX II. They split strands at different sites. AUX I cleaves the terminal ends of collagen, while AUX II cleaves the internal sections of collagen. In vitro studies suggest that after the injection into the cord, AUX I and AUX II work synergistically to provide hydrolysing activity toward collagen. This weakens the contracted cord and improves elasticity and mobility (24). Since February 28th, 2011 collagenase clostridium histolyticum has been available in Europe, called Xiapex (2).

Xiapex Each vial of powder contains 0.9 mg of collagenase clostridium histolyticum, which is a formulation of two collagenase enzymes.

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Indications: 

Treatment of Dupuytren´s contracture in adult patients with a palpable cord



Peyronie’s disease with a palpable plaque and deformity of at least 30 degrees at the start of therapy. The recommended dose of Xiapex is 0.58 mg per injection. 24 hours after injection, a finger extension procedure may be performed if necessary. The injection and finger extension procedures may be repeated at least four weeks after the first injection. The procedure should not be repeated more than three times. Clinical experience with Xiapex is limited to three injections per cord and a maximum of eight injections in total. Local anaesthetics are not recommended before injection, because it may interfere with proper injection placement. The patient should return to see a physician the next day for finger extension procedure to disrupt the cord. The fingers of the injected hand must not be extended or flexed until the finger extension procedure is completed, to reduce extravasation of Xiapex out of the cord. The patients are not allowed to disrupt the injected cord by self manipulation. They should elevate the injected hand as much as possible until the day after finger extension procedure. During the finger extension procedure local anaesthesia may be used. With the patient’s wrist in flexed position a moderate stretching pressure should be applied to the injected cord. Then the fingers should be extended for approximately 10 to 20 seconds. If the first finger extension procedure does not disrupt the cord a second and third attempt can be performed at 5 to 10 minute intervals. If the cord has not been disrupted after the third attempt of extension, the procedure can be repeated after 4 weeks. Volume of injection: MCP joints 0.25 ml PIP joints 0.20 ml

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Special warnings: Xiapex must only be injected into the Dupuytren’s cords, because injection into collagen containing structures may result in their damage and possible permanent injury such as tendon rupture or ligament damage. Undesirable effects: The most frequently reported adverse reactions during the Xiapex clinical studies were local injection site reactions such as oedema, contusion, injection site haemorrhage and pain. If the insertion of the needle into a tendon is suspected or the patient recognizes any paresthesia, the needle has to be replaced. If the needle is correctly placed in the cord one third of the dose has to be injected. After this, the needle has to be moved 2-3 mm distal to inject another third of the dose. The last step is to move the needle 2-3 mm proximal to the first site and inject the final portion of the dose into the cord. The needle has to be kept under the skin during the entire time of its repositioning (25).

Figure 11 Three Step Injection of Xiapex into the Cord (25)

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Figure 12 Three Step Injection of Xiapex (25)

Advantages of this new technique include no need for hospitalization, surgery or any kind of anaesthesia. Low risk of infection or wound healing complications and little if any need for traditional hand therapy are further advantages (1). According to Watt et al. the complications in phase II trial included pain during injection and manipulation, oedema, ecchymosis, lymphadenopathy and skin tearing (26).

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3. Patients and Methods 3.1 Patient data/Inclusion criteria For this thesis I retrospectively reviewed patients in the MEDOCS system, which underwent either subtotal fasciectomy or Xiapex injection in the last two years at the Department of Plastic Surgery at the State Hospital in Graz. The inclusion criteria were 

Singular affected strand of the palmar aponeurosis



Age over 18 years All patients had to give written consent after medical information. The patients were examined preoperatively, two weeks, six weeks, and twelve weeks after the intervention. Results in my thesis only include preoperative, two and six week postoperative data, because there was insufficient patient data for an analysis after twelve weeks. In the Xiapex group there were eleven patients with an average age of 60 years, 10 of them male and 1 female. In the control group, that underwent subtotal fasciectomy there were 12 patients with an average age of 61.25 years consisting of 10 males and two females.

3.2 Methods 3.2.1 Data evaluation Subjective and objective methods were used to measure the outcome after the interventions. MHQ and DASH, two questionnaires, were completed by the patients on their own. The website http://www.orthopaedicscore.com was used to analyse the results. Limitations of the hand function were measured by the physiotherapists, including: 

Sensibility based on Semmes Weinstein Monofilaments



Progress of Dupuytren's contracture by neutral zero method of the PIP and MCP joints



Total range of motion



Strength level of the injured hand with the dynamometer

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

Measurement of pain sensitivity on basis of the VAS 0-10 (at rest and in motion)

3.2.1.1 MHQ

The MHQ is a hand-specific questionnaire that can be used pre- and postoperatively to appraise changes in hand function. It consists of the six following categories: 1.

overall hand function

2.

activities of daily living

3.

pain

4.

work performance

5.

aesthetics

6.

patient satisfaction with hand function

There are 37 core questions which take the patient approximately 15 minutes to answer. Higher scores in the pain category represent greater pain, while in the other categories higher scores stand for better hand function. If 50% or more of items in one category are remain unanswered, this category cannot be analysed (27). 3.2.1.2 DASH

The DASH questionnaire was designed to measure physical functions in patients with disorders of the upper limb and includes 30 items (28). 21 questions are about the degree of difficulty in performing different physical activities, 5 items about the severity of each of the symptoms of pain, activityrelated pain, tingling and weakness and 4 items about the problem’s impact on social activities, work, sleep, and self-image. Each item has five response options from “no difficulty” to “unable” to do so. The scores of all items are then used to calculate a scale score ranging from 0 to 100. 0 stands for no disability and 100 for the most severe disability (29). If there are more than 3 items are unanswered, the score cannot be calculated (30).

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The test also includes the optional high performance sport, music, or work section. This optional score provided insufficient data in my research and was therefore not analyzed in the present thesis. 3.2.1.3. Sensibility based on Semmes Weinstein Monofilaments

This test is based on measuring sensibility with nylon filaments. There are 5 different types of nylon filaments with the following markings: Green

Normal

2,83

Blue

Diminished light touch

3,61

Purple

Diminished protective

4,31

sensation Red

Loss of protective sensation

6,65

Red-lined

Untestabel

greater than 6,65

Table 2 Grading System of Semmes Weinstein Monofilaments

3.2.1.4 Progress of Dupuytren's contracture PIP and MCP and total range of motion

The progress of Dupuytren’s contracture was measured using a goniometer.

Figure 13 Goniometer (31)

Physiotherapists annotated the results by the neutral-zero-method. It is a standardised index for the total range of joint movement. Flexion

Extension

MP joint

85°

0°

PIP joint

110°

0°

DIP joint

65°

0°

Total range of motion

260°

Table 3 Range of Motion Norm

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3.2.1.5. Strength level of the injured hand

Strength level was measured three times with the Hydraulic Hand Dynamometer.

Figure 14 Hydraulic Hand Dynamometer (32)

The dynamometer evaluates the grip strength in kilogram with a maximum of 90 kilograms. For the best results the patient has to sit with arms outstretched in a 90° angle. First the non-injured hand was measured followed by the injured one. There were three measurements per side and the average was taken as the result. In the tables below the average strength is split into age groups. R stands for the dominant hand, L for the non-dominant.

3.2.1.6. Measurement of Pain Sensitivity

Figure 15 VAS Scale (33)

Pain sensitivity was measured on basis of the VAS 0-10. Patients had to describe it once resting and once in motion.

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3.2.1.7. Preoperative values

In the Xiapex group in 6 out of the 11 patients the dominant hand was the affected one, while in the fasciectomy group the dominant hand was affected in 5 out of 12 patients. MHQ General Score Mean value of the MHQ general score was 78.21 Xiapex and 82.23

15.13 in patients treated with

18.63 in patients treated with fasciectomy. The minimum was

47.06 in the Xiapex group and 35.29 in the fasciectomy group. Maximums were 97.06 by patients treated with injection and 101.47 in patients treated with operation. MHQ Work Score The mean work score in patients treated with Xiapex was 75.91 in patients treated with fasciectomy 76.25

18.44. The one

25.99.

The lowest score was 45 in the injection group and 20 in the operative one. Both groups had a highest score of 100 (2 patients of the Xiapex group and 4 of the fasciectomy group). MHQ Pain Score Mean value of pain score before intervention amounted to 41.82 Xiapex group and 27.92

34.53 in the

27.72 in the fasciectomy group. The minimum values

were 0 in both groups (3 times in patients treated with injection and 5 times in patients treated with operation). Maximum values amounted to 90 in patients treated with Xiapex according to 80 in patients of the operative group. MHQ Appearance Score In the Xiapex group the mean value of the MHQ appearance score was 46.59 26.96 before injection. The mean value of preoperative MHQ appearance score amounted to 58.33

22. The lowest score in the Xiapex group was 12.5 and it

was 25 in the fasciectomy group. In both groups one patient had the highest score of 100.

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MHQ Final Score The mean value of the final MHQ Score was 55.30 and 58.68

26.77 in the Xiapex group

28.28 in the fasciectomy group. In each of the groups one patient had

the minimum score of 12.50. The maximums were 95.83 in patients treated with injection and 100 in patients treated with operation. MHOS Mean value of MHOS amounted to 66

14.6 in the Xiapex group and 67.75

16.47 in the fasciectomy group. The minimum in the Xiapex group was 39, and the maximum 89. In the operative group it was a minimum of 32 and a maximum of 91. DASH Score Pre – injection DASH score had a mean value of 20.29 group. Mean preoperative value was 17.92

14.34 in the Xiapex

19.35. The lowest DASH values

amounted 0 in both groups. The highest ones were 39.2 in the Xiapex group and 64.2 in the fasciectomy group. TROM Patients treated with Xiapex had a pre-injection TROM of 147.82

49.47

compared to patients in the fasciectomy group with a preoperative average TROM of 192.92

42.74. The minimum in the Xiapex group was 70 and the maximum

value 235, while it was a minimum value of 130 in the fasciectomy group and a maximum of 260. Strength Level Patients treated with Xiapex injection showed a pre – injection strength level with a mean value of 35.70

10.64 kg, compared to patients treated with fasciectomy,

who had a preoperative mean strength level of 34.50

9.92 kg. The lowest

strength value in the Xiapex group amounted 20 kg and the highest 49.67 kg. In the fasciectomy group the lowest value was 16 kg and the highest one 51.33 kg.

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Sensibility based on Semmes Weinstein Monofilaments In the Xiapex group as well as in the fasciectomy group the mean sensibility value was 2

1. In both groups the minimum value was 1 and the maximum 3.

Contracture of the MCP and PIP joints In the group of patients treated with Xiapex 9 patients had contracture in the MCP and PIP joints, one only in the PIP joint and one in the MCP joint. For patients treated with Xiapex injection the average pre – injection contracture was 39.5° 20.67° for the MCP joints, and 41.30°

20.72° for the PIP joints. The lowest

contracture in the MCP joint amounted to 10° and in the PIP joint 15°. The highest one was measured with 80° in the MCP joint and 90° in the PIP joint. 5 patients in the fasciectomy group had the contracture preoperatively in both joints, 3 of them only in the MCP, and 4 in the PIP. The average of the MCP contracture was 33.75°

13.40° with a minimum of 10°, and a maximum of 55°. In

the PIP joints mean preoperative contracture was 31.67°

17.64°, with a

minimum contracture of 10° and a maximum of 60°. Pain Sensitivity in Rest Preoperative Pain Sensitivity had an average of 1.27 and 0.75

2.73 in the Xiapex group

1.36 in the fasciectomy group. Highest values have been 8 in subjects

treated with Xiapex and 4 in those, treated with fasciectomy. Lowest score was 0 in both groups. Pain Sensitivity in Motion Pain Sensitivity in Motion was 1.27

2.26 in the Xiapex group and 1.50

1.98 in

the fasciectomy group before intervention. Highest value was 8 in the injection group and 6 in the operative one. 0 was the lowest value in both groups.

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3.2.2 Statistical Methods In all Progress of Contracture Scores hyperextension was classified as 0° to prevent underestimation of extension deficit. At the beginning boxplots of the two specific treatments were constructed including the differences between the pre- and postoperative scores after 2 and 6 weeks. The thick horizontal line represents the median of each group. Additional 2 Wilcoxon-tests were calculated for p-values including preoperative – postoperative after 2 weeks and preoperative values of the median – postoperative values after 6 weeks. The two p-values refer to the general difference between the medians of both groups. To simplify the results in the boxplots and in the Wilcoxon tests differences in age were ignored. To include the difference in age and in the preoperative scores of both groups, further regression models were used with the preoperative score as offset. The response variable is the particular score at two end-points after 2 and 6 weeks. The program R was used for reading the Excel data. First of all a statistic model was estimated including all predictors (age, time, treatment). Through an ANOVA (analysis of variance) the model was simplified until only the relevant predictors were left. The intercept was estimated by the program and represented by the ß 0 value. In all of the following formulas the suffix 0 marks the preoperative value from the different scores. Except from Semmes Weinstein Monofilaments all scores and values were calculated with a classical linear regression model for normally distributed responses. Due to the fact that Semmes Weinstein Monofilaments only include numbers from 1 to 5, it was not possible to use the formula for the Gaussian distribution and the Poisson distribution was used instead. The last column of the tables represents the p- values. For easier interpretation they were divided by two, because of indirectional differences (unilateral hypothesis).

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4. Results 4.1. Wilcoxon Tests Score

MHQ General Score MHQ Work Score MHQ Pain Score MHQ Appearance Score MHQ Final Score Michigan Hand Outcome Score DASH TROM Strength Level Monofilaments Progress of Contracture MCP Progress of Contracture PIP Progress of Contracture MCP + PIP Pain Sensitivity in Rest Pain Sensitivity in Motion

p-value Wilcoxon Median Test preoperative - 2 weeks 0.0015 0.8770 0.9004 0.4183

p-value Wilcoxon Median Test preoperative 6 Weeks 0.0846 0.5924 0.1040 0.3069

0.1755 0.1394

0.1391 0.4408

0.00098 < 0.0001 0.0074 0.1237 0.3038

Significance 2 weeks

Significance 6 weeks

**

°

0.0106 0.0150 0.0106 0.4465 0.4559

*** *** **

* * *

0.0876

0.0180

°

*

0.0263

0.0162

*

*

0.5969

0.6379

0.8959

1

Table 4 p-values of the Wilcoxon Tests: Comparison of the median of fasciectomy and Xiapex Score-differences preoperative – 2 and 6 weeks postoperative P-values in the above table show, that at most of the medians there is no significant difference between the two treatment options. The MHQ General Score shows a significant difference after two weeks with a p-value of 0.0015. This difference between the two groups disappears six weeks after intervention. Progress of contracture in the PIP joints shows significant difference between Xiapex and fasciectomy six weeks after intervention with a p-value of 0.0180. Further significant differences of the medians appeared at the TROM (p-value after two weeks = < 0.0001, p-value after six weeks = 0.0150), Strength Level (p-

25

value after two weeks = 0.0074 , p-value after six weeks = 0.0106), DASH Score (p-value after two weeks = 0.00098 , p-value after six weeks = 0.0106), and Progress of Contracture in MCP + PIP joints (p-value after two weeks = 0.0263, pvalue after six weeks = 0.0162). In the following boxplots, scores with a significant difference of the medians are marked with an (S).

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4.2. Boxplots MHQ General Score (S) Xiapex values: preinjection 89.71 47.06 97.06 95.59 64.71 91.18 73.53 69.12 73.53 67.65 91.18

Xiapex values: 2 weeks postinjection

Xiapex values: 6 weeks postinjection

Pre- injection – 2 weeks postinjection

Preoperative – 6 weeks post-injection

91,18 47.06 97.06 100.00 83.82 100.00 69.12 63.24 98.53 82.35 97.06

95.59 86.76 98,53 100.00 58.82 100.00 85.29 76.47 98.53 100.00 98.53 Median

-1.47 0.00 0.00 -4.41 -19.12 -8.82 4.41 5.88 -25.00 -14.71 -5.88 -4.41

-5.88 -39.71 -1.47 -4.41 5.88 -8.82 -11.76 -7.35 -25.00 -32.35 -7.35 -7.35

Table 5 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences MHQ General Score

Fasciectomy values: preoperative 79.41 76.47 35.29 69.12 95.59 89.71 61.76 85.29 97.06 95.59 101.47

Fasciectomy values: 2 weeks postoperative 66.18 52.94 39.71 73.53 91.18 80.88 45.59 70.59 67.65 92.65 77.94

Fasciectomy values: 6 weeks postoperative 86.76 64.71 77.94 80.88 95.59 97.06 61.76 86.76 95.59 91.18 98.53

100.00

80.88

92.65

19.12

7.35

Median

13.97

0.00

Preoperative – 2 weeks postoperative 13.24 23.53 -4.41 -4.41 4.41 8.82 16.18 14.71 29.41 2.94 23.53

Preoperative – 6 weeks postoperative -7.35 11.76 -42.65 -11.76 0.00 -7.35 0.00 -1.47 1.47 4.41 2.94

Table 6 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, MHQ General Score

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Figure 16 Differences MHQ General Score Two weeks after intervention, subjects treated with Xiapex get a better MHQ General Score with a median of -4.41, using the values preoperative – two weeks postoperative, according to subjects treated with fasciectomy who had a median of 13.97. Six weeks after treatment with a value of -7.35 the median of the difference: preoperative - six weeks postoperative is better in people treated with Xiapex than in people treated with fasciectomy who had a value of 0 which means there is no difference between preoperative scores in people treated with fasciectomy and scores evaluated six weeks postoperative.

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Work Score Xiapex Xiapex values: 2 Xiapex values: 6 values: preweeks postweeks postinjection injection injection 80 45 100 75 65 100 95 75 60 50 90

75 35 100 50 80 100 70 35 70 15 85

85 60 100 100 55 100 80 55 100 100 90 Median

Pre- injection – 2 weeks postinjection

Preoperative – 6 weeks postinjection

5 10 0 25 -15 0 25 40 -10 35 5 5

-5 -15 0 -25 10 0 15 20 -40 -50 0 0

Table 7Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, MHQ Work Score Fasciectomy values: preoperative 75 80 35 20 100 80 50 85 100 100 100 90

Fasciectomy Fasciectomy Preoperative – Preoperative – values: 2 weeks values: 6 weeks 2 weeks 6 weeks postoperative postoperative postoperative postoperative 15 60 60 15 45 60 35 20 50 65 -15 -30 45 55 -25 -35 85 100 15 0 90 85 -10 -5 50 50 0 0 75 100 10 -15 95 100 5 0 95 80 5 20 100 100 0 0 25 90 65 0 Median 5 0

Table 8 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, MHQ Work Score

29

Figure 17 Differences MHQ Work Score

The MHQ Work Score shows no difference between subjects treated with Xiapex or fasciectomy. In both groups the difference: preoperative score – two weeks postoperative score shows a median of 5, and preoperative score – six weeks postoperative score shows a median of 0.

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Pain Score Xiapex Xiapex values: 2 Xiapex values: 6 values: preweeks postweeks postinjection injection injection 40 40 0 0 25 0 85 80 80 20 90

65 50 0 60 65 0 90 40 80 65 90

65 55 0 0 25 0 75 80 85 0 95 Median

Pre- injection – 2 weeks postinjection

Preoperative – 6 weeks postinjection

-25 -10 0 -60 -40 0 -5 40 0 -45 0 -5

-25 -15 0 0 0 0 10 0 -5 20 -5 0

Table 9 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, MHQ Pain Score Fasciectomy values: preoperative 80 20 35 55 0 0 30 55 0 0 0 60

Fasciectomy Fasciectomy Preoperative – Preoperative – values: 2 weeks values: 6 weeks 2 weeks 6 weeks postoperative postoperative postoperative postoperative 70 0 10 80 45 45 -25 -25 40 0 -5 35 60 75 -5 -20 0 80 0 -80 80 0 -80 0 40 65 -10 -35 50 60 5 -5 0 95 0 -95 85 95 -85 -95 0 0 0 0 65 95 -5 -35 Median -5 -22,5

Table 10 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, MHQ Pain Score

31

Figure 18 Differences MHQ Pain Score In both groups pain get worse after two weeks with a median from the difference: MHQ Pain Score preoperative value – MHQ pain Score two weeks postoperative value, of -5. Six weeks after intervention in the Xiapex group the median of MHQ pain score pre-injection – MHQ pain score post-injection shows a value of 0. So there is no difference in preoperative MHQ Pain Score and six weeks postoperative Pain Score. Subjects treated with fasciectomy showed a six weeks median value of -22.5. So the MHQ Pain Score in this group was worse than the preoperative one.

32

Appearance Score Xiapex Xiapex values: 2 Xiapex values: 6 values: preweeks postweeks postinjection injection injection 25.00 31.25 37.50 43.75 12.50 75.00 100.00 31.25 25.00 43.75 87.50

81.25 43.75 75.00 37.50 43.75 75.00 75.00 31.25 100.00 87.50 100.00

100.00 75.00 100.00 75.00 12.50 75.00 43.75 50.00 68.75 68.75 100.00 Median

Pre- injection – 2 weeks postinjection -56.25 -12.50 -37.50 6.25 -31.25 0.00 25.00 0.00 -75.00 -43.75 -12.50 -12.50

Preoperative – 6 weeks postinjection -75.00 -43.75 -62.50 -31.25 0.00 0.00 56.25 -18.75 -43.75 -25.00 -12.50 -25.00

Table 11Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, MHQ Appearance Score

Fasciectomy Fasciectomy Fasciectomy Preoperative – Preoperative – values: values: 2 weeks values: 6 weeks 2 weeks 6 weeks preoperative postoperative postoperative postoperative postoperative 37.5 31.25 12.50 6.25 25.00 31.25 37.50 62.50 -6.25 -31.25 37.5 50 68.75 -12.50 -31.25 25 31.25 75.00 -6.25 -50.00 62.5 75.00 62.50 -12.50 0.00 68.75 100.00 68.75 -31.25 0.00 56.25 37.50 37.50 18.75 18.75 81.25 93.75 100.00 -12.50 -18.75 81.25 93.75 93.75 -12.50 -12.50 50 87.50 75.00 -37.50 -25.00 68.75 100.00 100.00 -31.25 -31.25 100 93.75 75.00 6.25 25.00 Median -12.50 -15.63

Table 12 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, Appearance Score

33

Figure 19 Differences MHQ Appearance Score Two weeks after intervention the median of differences, (Xiapex pre-injection – Xiapex two weeks post-injection, and fasciectomy preoperative – fasciectomy two weeks postoperative), has a value of -12.5. So the MHQ Appearance Score was in both groups better two weeks after operation than preoperative. Six weeks after treatment the median of the difference was -25 in the Xiapex group and – 15.63 in subjects treated with fasciectomy. So in both groups the MHQ Appearance Score became better after six weeks.

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MHQ Final Score Xiapex Xiapex values: 2 Xiapex values: 6 values: preweeks postweeks postinjection injection injection 54.16 12.50 95.83 87.50 33.33 75.00 70.83 25.00 45.83 29.17 79.16

83.33 50.00 100.00 83.33 66.67 0.00 66.67 41.67 87.50 70.83 91.67

66.67 41.67 91.67 100.00 0.00 0.00 79.17 70.83 100.00 100.00 95.83 Median

Pre- injection – 2 weeks postinjection -29.17 -37.50 -4.17 4.17 -33.33 75.00 4.16 -16.67 -41.67 -41.67 -12.51 -16.67

Preoperative – 6 weeks postinjection -12.51 -29.17 4.17 -12.50 33.33 75.00 -8.34 -45.83 -54.17 -70.83 -16.67 -12.51

Table 13 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, MHQ Final Score Fasciectomy Fasciectomy Fasciectomy Preoperative – Preoperative – values: values: 2 weeks values: 6 weeks 2 weeks 6 weeks preoperative postoperative postoperative postoperative postoperative 50.00 41.67 75.00 8.33 -25.00 25.00 50.00 33.33 -25.00 -8.33 12.50 66.67 20.83 -54.17 -8.33 41.67 37.50 54.17 4.17 -12.50 87.50 83.33 79.17 4.17 8.33 70.83 79.17 66.67 -8.33 4.17 25.00 33.33 66.67 -8.33 -41.67 41.67 75.00 20.83 -33.33 20.83 87.50 83.33 87.50 4.17 0.00 79.17 83.33 54.17 -4.17 25.00 100.00 91.67 91.67 8.33 8.33 83.33 79.17 79.17 4.17 4.17 Median 0 2.08

Table 14 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, MHQ Final Score

35

MHQ Final Score showed a better result for Xiapex two and six weeks after treatment. After two weeks the median was -16.67, and after 6 weeks -12.51. The fasciectomy group had a median of 0 two weeks after intervention, so there was no difference to the preoperative scores. Six weeks after treatment the MHQ Final Score became even worse in the fasciectomy group, than the preoperative one, with a median of 2.08.

36

MHOS Xiapex Xiapex values: 2 Xiapex values: 6 values: preweeks postweeks postinjection injection injection 69 39 78 73 49 76 80 60 63 50 89

83 46 82 78 74 68 72 49 91 70 94

86 70 84 84 39 68 78 70 94 83 97 Median

Pre- injection – 2 weeks postinjection

Preoperative – 6 weeks postinjection

-14 -7 -4 -5 -25 8 8 11 -28 -20 -5 -5

-17 -31 -6 -11 10 8 2 -10 -31 -33 -8 -10

Table 15 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, MHOS Fasciectomy values: preoperative 70 56 32 51 78 71 49 74 81 76 84 91

Fasciectomy Fasciectomy Preoperative – Preoperative – values: 2 weeks values: 6 weeks 2 weeks 6 weeks postoperative postoperative postoperative postoperative 52 61 18 9 49 56 7 0 47 55 -15 -23 57 72 -6 -21 75 88 3 -10 84 74 -13 -3 43 59 6 -10 72 76 2 -2 68 95 13 -14 90 82 -14 -6 75 84 9 0 72 89 19 2 Median 4,50 -4,50

Table 16 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, MHOS

37

Figure 20 Differences MHOS Subjects from the Xiapex group showed better results of MHOS two, and six weeks postoperative. The median of the difference was -5 after two weeks and -10 after six weeks. According to that patients treated with fasciectomy had a worse score two weeks postoperative with a median of the difference of 4.5. Six weeks after intervention the score was a little better than preoperative with a median of -4.5.

38

DASH (S) Xiapex Xiapex values: 2 Xiapex values: 6 values: preweeks postweeks postinjection injection injection 7.50 35.80 6.70 6.00 39.20 0.00 30.20 29.20 35.30 28.30 5.00

1.70 48.30 4.20 0.80 19.20 0.00 35.80 35.00 3.30 21.70 9.50

5.00 21.60 3.60 0.00 29.20 0.00 14.70 16.40 4.20 0.00 0.80 Median

Pre- injection – 2 weeks postinjection 5.80 -12.50 2.50 5.20 20.00 0.00 -5.60 -5.80 32.00 6.60 -4.50 2.50

Preoperative – 6 weeks postinjection 2.50 14.20 3.10 6.00 10.00 0.00 15.50 12.80 31.10 28.30 4.20 10.00

Table 17 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, DASH Score Fasciectomy Fasciectomy Fasciectomy Preoperative – Preoperative – values: values: 2 weeks values: 6 weeks 2 weeks 6 weeks preoperative postoperative postoperative postoperative postoperative 20 48.30 15 -28.30 5 26.9 24.20 29.5 2.70 -2.6 64.2 73.3 39.2 -9.10 25 40.5 49.2 32.5 -8.70 8 0 5.00 1.7 -5.00 -1.7 6.7 30.80 10.3 -24.10 -3.6 35.8 58.30 25.8 -22.50 10 6.7 33.30 11.7 -26.60 -5 0 19.20 0 -19.20 0 4.2 4.30 5.2 -0.10 -1 1.7 14.30 1.7 -12.60 0 8.3 31.70 11.7 -23.40 -3.4 Median -15.90 -0.50

Table 18 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, DASH Score

39

Figure 21 Differences DASH Score

DASH Score showed better results in the Xiapex group two and six weeks postinjection with medians of 2.5 and 10, while with a median of difference from -15.9 after two weeks and -0.5 after six weeks it was worse in the fasciectomy group at both points of evaluation according to the preoperative value.

40

TROM (S) Xiapex Xiapex values: 2 Xiapex values: 6 values: preweeks postweeks postinjection injection injection 170 80 155 235 155 170 126 70 90 205 170

245 185 265 290 250 235 212 150 215 245 250

240 225 275 280 255 250 250 190 205 280 235 Median

Pre- injection – 2 weeks postinjection -75 -105 -110 -55 -95 -65 -86 -80 -125 -40 -80 -80

Preoperative – 6 weeks postinjection -70 -145 -120 -45 -100 -80 -124 -120 -115 -75 -65 -100

Table 19 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, TROM Fasciectomy values: preoperative 190 250 135 155 230 195 130 185 230 145 210 260

Fasciectomy Fasciectomy Preoperative – Preoperative – values: 2 weeks values: 6 weeks 2 weeks 6 weeks postoperative postoperative postoperative postoperative 240 225 -50 -35 165 235 85 15 175 210 -40 -75 195 240 -40 -85 235 295 -5 -65 170 325 25 -130 160 215 -30 -85 170 225 15 -40 190 180 40 50 135 155 10 -10 195 270 15 -60 170 250 90 10 Median 12,5 -50

Table 20 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, TROM

41

Figure 22 Differences TROM Total Range of Motion showed better results in the Xiapex group two and six weeks after treatment, and in the fasciectomy group six weeks after treatment. Medians of difference were -80 two weeks post-injection, -100 six weeks postinjection and -50 six weeks postoperative. Two weeks after treatment with fasciectomy the median of differences was 12.5. So there were worse scores two weeks postoperative than preoperative in subjects treated with fasciectomy.

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Strength Level (S) Xiapex Xiapex values: 2 Xiapex values: 6 values: preweeks postweeks postinjection injection injection 27.00 49.67 48.00 44.33 46.67 29.33 40.67 24.33 20.00 22.67 40.00

32.67 28.00 42.67 40.33 45.00 28.00 36.33 31.67 19.33 22.67 47.00

33.67 39.33 42.00 42.33 50.00 28.00 45.00 34.67 22.00 24.00 48.33 Median

Pre- injection – 2 weeks postinjection -5.67 21.67 5.33 4.00 1.67 1.33 4.33 -7.33 0.67 0.00 -7.00 1.33

Preoperative – 6 weeks postinjection -6.67 10.33 6.00 2.00 -3.33 1.33 -4.33 -10.33 -2.00 -1.33 -8.33 -2.00

Table 21 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, Strength Level Fasciectomy Fasciectomy Fasciectomy Preoperative – Preoperative – values: values: 2 weeks values: 6 weeks 2 weeks 6 weeks preoperative postoperative postoperative postoperative postoperative 40.67 34.00 37.00 6.67 3.67 16.00 5.00 7.33 11.00 8.67 34.67 17.33 22.67 17.33 12.00 36.00 25.00 32.33 11.00 3.67 30.67 24.33 30.67 6.33 0.00 34.00 19.00 32.00 15.00 2.00 16.67 18.00 17.67 -1.33 -1.00 39.00 29.67 34.67 9.33 4.33 45.00 42.00 41.00 3.00 4.00 30.00 20.00 19.33 10.00 10.67 40.00 24.00 38.67 16.00 1.33 51.33 30.67 49.33 20.67 2.00 Median 10.50 3.67

Table 22 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, Strength Level

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Figure 23 Differences Strength Level Subjects only had better scores in Strength Level with a median of differences of preoperative - six weeks after Xiapex injection of -2. It was worse at all other points of time with a median of differences of 1.33 two weeks after injection, 10.5 two weeks after fasciectomy and 3.67 six weeks after operation.

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Semmes Weinstein Monofilaments Xiapex Xiapex values: 2 Xiapex values: 6 values: preweeks postweeks postinjection injection injection 2 3 1 3 2 1 3 3 1 3 2

1 2 1 2 2 1 4 2 1 1 2

2 4 2 2 2 1 2 2 1 1 2 Median

Pre- injection – 2 weeks postinjection

Preoperative – 6 weeks postinjection

1 1 0 1 0 0 -1 1 0 2 0 0

0 -1 -1 1 0 0 1 1 0 2 0 0

Table 23 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, Semmes Weinstein Monofilaments Fasciectomy values: preoperative 2 3 2 2 2 2 3 3 1 2 3 1

Fasciectomy Fasciectomy Preoperative – Preoperative – values: 2 weeks values: 6 weeks 2 weeks 6 weeks postoperative postoperative postoperative postoperative 5 3 -3 -1 1 1 2 2 2 4 0 -2 3 3 -1 -1 2 2 0 0 4 2 -2 0 2 2 1 1 4 1 -1 2 3 3 -2 -2 2 5 0 -3 2 2 1 1 1 1 0 0 Median 0 0

Table 24 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, Semmes Weinstein Monofilaments

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Figure 24 Differences Semmes Weinstein Monofilaments At all points of time, independent of treatment option medians of differences had a value of 0. So there is no differnece in this score to preoperative values.

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Progress of Contracture MCP joints Xiapex Xiapex values: 2 Xiapex values: 6 values: preweeks postweeks postinjection injection injection 50 40 40 25 25 0 70 80 25 10 30

10 0 0 0 15 0 10 50 0 0 0

5 0 0 0 20 0 0 45 0 0 0 Median

Pre- injection – 2 weeks postinjection

Preoperative – 6 weeks postinjection

40 40 40 25 10 0 60 30 25 10 30 30

45 40 40 25 5 0 70 35 25 10 30 35

Table 25 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, Progress of Contracture MCP joints Fasciectomy values: preoperative 45 10 45 55 0 30 25 0 0 25 35 0

Fasciectomy Fasciectomy Preoperative – Preoperative – values: 2 weeks values: 6 weeks 2 weeks 6 weeks postoperative postoperative postoperative postoperative 0 0 45 45 0 0 10 10 0 0 45 45 0 0 55 55 0 0 0 0 10 0 20 30 0 0 25 25 0 0 0 0 0 0 0 0 0 0 25 25 10 0 25 35 0 0 0 0 Median 22,50 25

Table 26 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, Progress of Contracture MCP joints

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Figure 25 Differences Progress of Contracture MCP Contracture of MCP joints was lower two and six weeks in subjects treated with Xiapex aswell in those treated with fasciectomy. The median of differences has been 30° two weeks post-injcetion and 35° six weeks post-injection. Medians of fasciectomy had values of 22.5 two weeks postoperative and 25 six weeks postoperative.

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Progress of Contracture PIP joint (S) Xiapex Xiapex values: 2 Xiapex values: 6 values: preweeks postweeks postinjection injection injection 15 90 45 0 30 45 18 60 30 35 45

0 45 20 0 5 0 5 20 20 20 20

0 40 15 0 5 0 5 5 10 15 20 Median

Pre- injection – 2 weeks postinjection

Preoperative – 6 weeks postinjection

15 45 25 0 25 45 13 40 10 15 25 25

15 50 30 0 25 45 13 55 20 20 25 25

Table 27 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, Progress of Contracture PIP joints

Fasciectomy values: preoperative 0 0 15 15 25 10 25 35 60 60 0 40

Fasciectomy Fasciectomy Preoperative – Preoperative – values: 2 weeks values: 6 weeks 2 weeks 6 weeks postoperative postoperative postoperative postoperative 0 0 0 0 0 0 0 0 10 10 5 5 5 0 10 15 20 5 5 20 10 10 0 0 10 10 15 15 0 10 35 25 35 45 25 15 35 35 25 25 5 0 -5 0 10 35 30 5 Median 7,50 10

Table 28 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, Progress of Contracture PIP joints

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Figure 26 Differences Progress of Contracture PIP Also PIP joint contracture showed better results in both treatment options two weeks, as well as six weeks post-treatment. Median of differences has been 25° in subjects treated with Xiapex two and six weeks post-injetion, 7.5° in subjects treated with fasciectomy two weeks postoperative, and 10° in the fasciectomy group six weeks postoperative.

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Progress of Contracture MCP + PIP (S) Xiapex Xiapex values: 2 Xiapex values: 6 values: preweeks postweeks postinjection injection injection 65 130 85 25 55 45 88 140 55 45 75

10 25 15 0 20 0 15 70 15 20 20

5 10 0 0 25 0 5 50 0 15 10 Median

Pre- injection – 2 weeks postinjection

Preoperative – 6 weeks postinjection

55 105 70 25 35 45 73 70 40 25 55 55

60 120 85 25 30 45 83 90 55 30 65 60

Table 29 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, Progress of contracture MCP + PIP joints

Fasciectomy values: preoperative 40 10 60 70 0 40 50 35 60 85 35 5

Fasciectomy Fasciectomy Preoperative – Preoperative – values: 2 weeks values: 6 weeks 2 weeks 6 weeks postoperative postoperative postoperative postoperative 0 0 40 40 0 0 10 10 10 10 50 50 5 0 65 70 0 0 0 0 20 10 20 30 10 10 40 40 0 10 35 25 35 45 25 15 25 35 60 50 15 0 20 35 10 15 -5 -10 Median 30 35

Table 30 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, Progress of contracture MCP + PIP joints

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Figure 27 Differences Progress of Contracture MCP + PIP In MCP + PIP joints with a median of differences of 55° two weeks after injection and 60° six weeks after injection contracture has shown better values than preinjection. Also in the fasciectomy group two and six weeks after intervention the values have been better then preoperative. (Median of differences: 30° two weeks postoperative, 35° six weeks postoperative)

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Pain Sensitivity in Rest Xiapex Xiapex values: 2 Xiapex values: 6 values: preweeks postweeks postinjection injection injection 0 6 0 0 0 0 0 0 0 8 0

0 0 0 0 0 0 0 0 0 1 0

0 0 0 0 2 0 0 2 0 0 0 Median

Pre- injection – 2 weeks postinjection

Preoperative – 6 weeks postinjection

0 6 0 0 0 0 0 0 0 7 0 0

0 6 0 0 -2 0 0 -2 0 8 0 0

Table 31 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, Pain Sensitivity in Rest Fasciectomy values: preoperative 2 0 4 0 0 0 3 0 0 0 0 0

Fasciectomy Fasciectomy Preoperative – Preoperative – values: 2 weeks values: 6 weeks 2 weeks 6 weeks postoperative postoperative postoperative postoperative 0 0 2 2 1 0 -1 0 0 2 4 2 0 0 0 0 0 0 0 0 0 0 0 0 0 2 3 1 1 0 -1 0 0 1 0 -1 0 0 0 0 0 0 0 0 0 0 0 0 Median 0 0

Table 32 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, Pain Sensitivity in Rest

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Figure 28 Differences Pain Sensitivity in Rest

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Pain Senitivity in Motion Xiapex Xiapex values: 2 Xiapex values: 6 values: preweeks postweeks postinjection injection injection 0 2 0 0 1 0 1 0 0 8 2

0 2 0 0 0 0 2 3 0 1 3

0 1 0 0 5 0 1 3 0 0 1 Median

Pre- injection – 2 weeks postinjection

Preoperative – 6 weeks postinjection

0 0 0 0 1 0 -1 -3 0 7 -1 0

0 1 0 0 -4 0 0 -3 0 8 1 0

Table 33 Xiapex values pre-injection, 2 and 6 weeks post-injection + differences, Pain Sensitivity in Motion Fasciectomy values: preoperative 2 0 3 0 0 0 3 4 0 0 0 6

Fasciectomy Fasciectomy Preoperative – Preoperative – values: 2 weeks values: 6 weeks 2 weeks 6 weeks postoperative postoperative postoperative postoperative 0 0 2 2 2 3 -2 -3 3 0 0 3 0 1 0 -1 0 1 0 -1 2 0 -2 0 2 2 1 1 6 3 -2 1 2 2 -2 -2 0 5 0 -5 0 0 0 0 2 0 4 6 Median 0 0

Table 34 Fasciectomy values preoperative, 2 and 6 weeks postoperative + differences, Pain Sensitivity in Motion

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Figure 29 Differences Pain Sensitivity in Motion In rest and in motion Pain Sensitivity had a value of 0 in the medians of differences, in both treatment options.

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4.3. Regression models MHQ General Score

Coefficients Estimate

Std. Error

t value

Pr(>|t|)

significance

(Intercept)

-9.977

3.124

-3.193

0.002631

**

factor(time)6

11.253

3.659

3.076

0.003644

**

Treatment

13.776

3.662

3.762

0.000506

***

Xiapex Table 35 Results: Regression Model MHQ General Score

The general score of the Michigan Hand outcome questionnaire depends on the factor time and Xiapex. Six weeks after intervention the score is on average 11.253 higher than after two weeks. This result is very significant with a p-value of 0.003644/2 = 0.001822. Patients treated with Xiapex have a 13.776 higher general MHQ than patients who underwent fasciectomy with a p-value of 0.000506/2 = 0.000253. MHQ Work Score

Coefficients Estimate

Std. Error

t value

Pr(>|t|)

significance

(Intercept)

-11.522

4.484

-2.57

0.0136

*

factor(time)6

16.739

6.341

2.64

0.0114

*

Table 36 Results: Regression Model MHQ Work Score

The work score of the MHQ only depends on the factor time. With a significant pvalue of 0.0114/2 = 0.00057 the score six weeks after intervention is higher by a factor of 16.739, than two weeks after it. MHQ Pain Score, Appearance Score, Final Score For these three scores the results are independent from all tested predictors.

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Michigan Hand Outcome Score (MHOS)

Coefficients Estimate

Std. Error

t value

Pr(>|t|)

significance

(Intercept)

-1.284

3.153

-0.407

0.6858

°

factor(time)6

6.652

3.692

1.802

0.0786

°

Treatment Xiapex

7.413

3.696

2.006

0.0512

°

Table 37 Results: Regression Model MHOS

The Michigan Hand outcome score is dependent on the factor time and treatment option. After 6 weeks the scores are on average 6.652 higher than after two weeks with a p-value of 0.0786/2 = 0.0393 and treated with Xiapex by 7.413 higher (pvalue 0.0512/2 = 0.0256) DASH

Coefficients: Estimate

Std. Error

t value

Pr(>|t|)

significance

(Intercept)

12.431

2.710

4.587

3.86e-05

***

factor(time)6

-12.678

3.174

-3.995

0.000249

***

Treatment Xiapex

-13.883

3.177

-4.370

7.71e-05

***

Table 38 Results: Regression Model DASH

The DASH score depends on time and the treatment option. After six weeks the score is on average 12.678 lower than after two weeks with a significant p-value of 0.000249/2 = 0.0001245. Also the treatment option becomes important at the DASH score. The score from patients who underwent Xiapex infiltration is on average 13.883 lower than the score from patients who underwent fasciectomy. (p-value = 7.71e-05/2 = 0.03)

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Total Range of Movement (TROM)

Coefficients:

(Intercept) factor(time)6 Treatment Xiapex Age

Estimate

Std. Error

t value

Pr(>|t|)

significance

-54.9313 33.3913 74.4306 0.8930

29.8044 11.7487 11.7737 0.4582

-1.843 2.842 6.322 1.949

0.07239 0.00689 1.37e-07 0.05802

° ** *** °

Table 39 Results: Regression Model TROM

After 6 weeks the TROM scores are on average 33.3913 higher than after two weeks. This difference is significant with a p-value of 0.00689/2 = 0.003445. The TROM score of patients with Xiapex treatment is 74.4306 higher than of patients treated with fasciotomy. This difference is also significant with a p-value near 0. (1.37e-07/2) Strength Level

Coefficients: (Intercept) factor(time)6 Treatment Xiapex

Estimate -9.724 4.754 7.241

Std. Error 1.565 1.832 1.834

t value -6.215 2.594 3.948

Pr(>|t|) 1.78e-07 0.012908 0.000287

Significance *** * ***

Table 40 Results: Regression Model Strength Level

Strength levels depend on the treatment option and the postoperative time. Six weeks after intervention with a p-value of 0.012908/2 = 0.006454 the strength measurements are on average 4.754 higher than after two weeks. The strength level is also higher in patients treated with Xiapex with an average of 7.241 and a significant p-value of 0.00287/2 = 0.0001435.

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Semmes Weinstein Monofilaments

Mf0 stands for the preoperative value of the Monofilament testing. Coefficients (Intercept) Treatment Xiapex Age

Estimate 1.106357 -0.392862

Std. Error 0.515009 0.205857

z value 2.148 -1.908

Pr(>|z|) 0.0317 0.0563

significance * °

-0.015090

0.008006

-1.885

0.0595

°

Table 41 Results: Regression Model Monofilament Testing

Both, Xiapex treatment and a higher age lead to better results at monofilament testing. Treatment with Xiapex lowers the results with 0.392862 and a p-value of 0.0563/2 = 0.02815. A higher age also affects lower results with the average factor 0.015090 and a p-value of 0.0595/2 = 0.02975. Progress of Dupuytren’s Contracture MCP

Coefficients (Intercept) Treatment Xiapex Age

Estimate 8.9071 -12.5473

Std. Error 15.6607 6.3103

t value 0.569 -1.988

Pr(>|t|) 0.5725 0.0532

significance °

-0.4924

0.2456

-2.005

0.0513

°

Table 42 Results: Regression Model Progress of Contracture MCP

Progress of Dupuytren´s Contracture in the MCP is dependent on treatment and age. Patients treated with Xiapex have on average a 12.5473 lower progress with a p-value of 0.0532/2 = 0.0266. The older the people are the better values they have. The results are 0.4924 lower than those of younger people with a significant p-value of 0.0513/2 = 0.02565.

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Progress of Dupuytren’s Contracture PIP

Coefficients (Intercept) Treatment Xiapex

Estimate -11.042 -14.231

Std. Error 2.818 4.075

t value -3.918 -3.493

Pr(>|t|) 0.000307 0.001102

significance *** **

Table 43 Results: Regression Model Progress of Contracture PIP

Progress of contracture in the PIP joint only depends on the treatment options. With Xiapex the results are lower by the factor 14.231 with a very significant pvalue of 0.001102/2 = 0.000551.

Progress of Dupuytren’s Contracture MCP + PIP

Coefficients Estimate -3.0601 -26.7594

Std. Error 16.8033 6.7707

t value -0.182 -3.952

Pr(>|t|) 0.856350 0.000284

significance

(Intercept) Treatment Xiapex Age

-0.4773

0.2635

-1.811

0.077099

°

***

Table 44 Results: Regression Model Progress of Contracture MCP + PIP

In both scores Xiapex as well as the age plays a role. With Xiapex the results are 26.7594 lower (p-value = 0.000284/2 = 0.000142) and the older the patients are the better results they have. It lowers the progress score with a value of 0.4773 and a significant p-value of 0.077099/2 = 0.0385495.

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Pain Sensitivity It was not possible to calculate a regression model for pain sensitivity, because of the different pain levels of every patient. The following tables show the pain sensitivity from all patients included, that were treated with Xiapex in rest and in motion, and underwent fasciotomy in rest and in motion.

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5. Discussion The boxplots in this thesis showed significant differences between the two treatment options in 6 out of 15 tested scores. Using regression models significantly better results appeared in 9 out of 15 tested scores in subjects treated with Xiapex compared to those, treated with fasciectomy. The findings of the study suggest that Xiapex offers a good alternative to limited fasciectomy. The CORDLESS study was designed as a prospective follow-up study for patients treated with CCH. The purpose was to assess long-term recurrence and safety during 5 years following treatment with CCH. Enrolled patients were followed up once annually for 4 years with 6 months or longer between the visits. At each visit, investigators examined and measured the MCP and PIP joints of each finger. 623 patients had been successfully treated. The cumulative 5-year 20° or greater recurrence rate for these joints was 47%. 39% of MCP joints and 66% of PIP joints. MCP joints of low baseline severity had a higher recurrence rate compared with those of high severity. Low severity PIP joints had a lower recurrence rate than high severity joints. The mean contracture at year 5 for recurrent MCP joints was 27°, which was lower than the pre-treatment baseline of 37°. Results for PIP joints were similar with a recurrent contracture of 35° after 5 years according to the preoperative baseline of 39°. Reported recurrence rates range from 12% to 73% for fasciectomy and aponeurectomy and from 33% to 100% for open or needle fasciotomy. The overall recurrence rate of 47% is comparable with published recurrence rates after surgical treatments. CCH treatment proved to be an effective and safe treatment for Dupuytren’s contracture (34). Chao Zhou et al. compared in their study the effectiveness of limited fasciectomy and injectable collagenase in actual clinical practice. The purpose was to directly compare the early clinical results. Injections were limited to 0.25 ml for MCP joints and 0.20 ml for PIP joints. Treated fingers were manipulated after 24 to 72 hours under local anaesthesia. Up to three injections were offered at 4-week intervals. In patients treated by limited fasciectomy cords were excised after Bruner type or longitudinal incisions with Z-plasties. The primary outcome of this study was the degree of residual contracture at follow-up visits between 6-12 weeks after

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treatment. After exclusion of some subjects a total of 218 patients remained, of whom 48% were treated with collagenase and 52% with fasciectomy. Results showed that for affected MCP joints the degree of residual contracture at follow-up and the proportion of joints achieving clinical improvement were not significantly different between the two groups. For affected PIP joints the degree of residual contracture was significantly worse in the collagenase group than in the fasciectomy group. In the scores satisfaction, activities of daily living and work performance of the Michigan Hand Outcomes Questionnaire, collagenase clostridium histolyticum subjects reported significantly larger improvements than did limited fasciectomy subjects(35). Also in my thesis results of MHOS and General Score were significantly better in subjects treated with Xiapex. Naam N. also reviewed data from patients with advanced Dupuytren’s contracture, who underwent either CCH injections or fasciectomy. DASH scores were compared between 13 CCH injection patients and 15 fasciectomy patients. In the first 3 month CCH injections leaded to significant better results in the DASH scores with p-values of 0.002 after 1 month, 0.007 after 2 month and 0.02 after 3 month. After one year, there was no longer a significant difference between the two groups in the DASH scores (36). According to that we were able to prove in this thesis, that patients treated with Xiapex had a better DASH score two and six weeks after intervention. Naam N. also reviewed ROM in the MCP, and PIP joints. There were 32 patients treated by CCH injection and 29 patients, who underwent fasciectomy. Out of 21 MCP joints in the CCH injection group and 29 MCP joints in the fasciectomy group there were significantly better post-treatment ROM values in the CCH injection group with a p-value from 0.02. The mean changes in both groups were nearly identical (36). In my thesis TROM also showed significantly better results in patients treated with Xiapex in both statistical methods. Further Strength Level, Semmes Weinstein Monofilaments, and Progress of Contracture in MCP and PIP had significantly better results in subjects treated with Xiapex.

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6. Conclusion Although the number of patients in my thesis was relatively low, the medians as well as regression models showed significantly better results in subjects treated with Xiapex. As Xiapex is the less invasive method, compared to fasciectomy, this is a very good outcome. Patients do not need to stay in hospital, the hand has only to be splinted at night, and fingers can be moved and trained as soon as the cord is disrupted. Because of the small number of patients in this analysis and the fact that the last examination was only 6 weeks after treatment it would be very interesting to conduct further long-term-studies, with a higher number of participants The factor “time” plays a big role in the treatment of Dupuytren’s disease. In 6 out of 15 scores patients reached significantly better results six weeks after treatment than two weeks after it. Wound-healing processes, effects of physiotherapy, and other contributing factors should be the subject of further long-term-studies in this field.

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