Original Article
Treatment of Dupuytren's disease using collagenase from Clostridium histolyticum
Tratamiento de la enfermedad de Dupuytren mediante la colagenasa del Clostridium histolyticum
M.Á. Martín-Ferrero, C. Simón-Pérez
, J.I. Rodríguez-Mateos, B. García-Medrano, R. Hernández-Ramajo, M. Brotat-García
Corresponding author
Servicio de Cirugía ortopédica y Traumatología, Hospital Clínico Universitario de Valladolid, Valladolid, Spain
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Martín-Ferrero, C. Simón-Pérez, J.I. Rodríguez-Mateos, B. García-Medrano, R. Hernández-Ramajo, M. Brotat-García" "autores" => array:6 [ 0 => array:2 [ "nombre" => "M.Á." "apellidos" => "Martín-Ferrero" ] 1 => array:4 [ "nombre" => "C." "apellidos" => "Simón-Pérez" "email" => array:1 [ 0 => "simonclarisa@yahoo.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 2 => array:2 [ "nombre" => "J.I." "apellidos" => "Rodríguez-Mateos" ] 3 => array:2 [ "nombre" => "B." "apellidos" => "García-Medrano" ] 4 => array:2 [ "nombre" => "R." "apellidos" => "Hernández-Ramajo" ] 5 => array:2 [ "nombre" => "M." "apellidos" => "Brotat-García" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Cirugía ortopédica y Traumatología, Hospital Clínico Universitario de Valladolid, Valladolid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento de la enfermedad de Dupuytren mediante la colagenasa del <span class="elsevierStyleItalic">Clostridium histolyticum</span>" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1226 "Ancho" => 1599 "Tamanyo" => 81734 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Levels of contracture prior and after administration of CH collagenase, according to the Tubiana classification.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Dupuytren's disease is a progressive fibroproliferative disorder characterized by the development of collagen bands and nodules at the level of the superficial palmar aponeurosis, which causes progressive closure of the fingers.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Recurrence of Dupuytren's disease is common after surgical treatment,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> especially in young patients.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The recurrence rate after surgery is highly variable according to different publications, going from 0% to 85% depending on the characteristics of each patient, disease and type of surgery performed.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In addition, surgical treatment of Dupuytren's disease entails significant morbidity, with a complication rate of about 17%, which includes skin problems, hematomas, nerve lesions and reflex sympathetic dystrophy.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Some published series report a 39% rate of complications, both during surgery and in the postoperative period.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Collagenase from <span class="elsevierStyleItalic">Clostridium histolyticum</span> (CH collagenase) is the only approved pharmaceutical treatment for the treatment of Dupuytren's disease. This is a molecular compound formed by mixing fixed percentages of 2 purified collagenolytic enzymes (AUX-I and AUX-II) isolated from a culture of <span class="elsevierStyleItalic">Clostridium histolyticum</span>.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The purpose of this study was to establish injection of collagenase as a safe and effective treatment modality to reduce the level of contracture in Dupuytren's disease and to assess the rate of recurrence of the disease within a short follow-up period.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and Methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">We conducted a prospective study in the period from 2011 to the present, which included 35 patients suffering Dupuytren's disease. All were male, aged between 45 and 89 years with a mean age of 68.14 years, and treated at the University Hospital of Valladolid. A total of 15 patients participated in a phase IV, multicenter clinical trial.</p><p id="par0035" class="elsevierStylePara elsevierViewall">All 35 patients included in the study were right-handed. In 15 patients we treated the left hand (42.8%) and in 20 patients we treated the right hand (57.1%).</p><p id="par0040" class="elsevierStylePara elsevierViewall">We used the Tubiana classification to determine the severity of the disease, as reflected in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">A total of 22 patients (62.8%) were injected in a single and palpable band at the level of the metacarpophalangeal (MCP) joint (1 patient in the third radius, 15 patients in the fourth radius and 6 in the fifth radius), 6 patients (17.1%) in a Y-shaped band affecting 2 fingers, 5 patients (14.2%) were treated by injection in the band at the level of the proximal interphalangeal (PIP) joint and 2 patients (5.7%) underwent a double injection: at the levels of the MCP and PIP.</p><p id="par0050" class="elsevierStylePara elsevierViewall">A total of 3 patients (8.7%) had undergone a previous intervention for Dupuytren's disease in the affected hand. Moreover, 22 patients (62.8%) presented concomitant diseases and risk factors for surgical treatment.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Inclusion criteria were adult patients with Dupuytren's disease, ensuring that the age was over 60 years except in cases in which the patient expressly requested this treatment option, with a palpable band in at least 1 finger, excluding the thumb, and contraction of at least 20–90° at the level of the MCP and 80° at the PIP.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Exclusion criteria were patients with hemorrhagic disorders or recent stroke, with other neuromuscular hand disorders, patients who had received treatment including surgery for Dupuytren's contracture in the previous 90 days, allergy to collagenase or excipients, use of doxycycline in the previous 14 days and anticoagulant drugs in the previous 7 days.</p><p id="par0065" class="elsevierStylePara elsevierViewall">All patients signed a specific consent document for the treatment prior to the injection of collagenase.</p><p id="par0070" class="elsevierStylePara elsevierViewall">All patients were treated in an outpatient surgery regime, taking into account the specific doses necessary, both of collagenase and solvent, depending on the joints to be treated according to the recommendations of the product.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Collagenase was administered by local injection directly into the palpable band, with EMLA (numbing cream) being topically administered in the injection area, half an hour earlier in an outpatient surgery room. After the injection, patients were applied compression bandage and recommended to avoid movement.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Extension of the finger and breakage of the band took place after 24<span class="elsevierStyleHsp" style=""></span>h in an outpatient operating room, with local anesthesia or sedation and subsequent compressive bandaging of the hand.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Follow-up consultations were conducted at 1 week, 2 weeks, 1 month, 3 months, 6 months and 1 year to assess local complications (hematoma, dehiscence of the skin, etc.), decrease of joint contracture and increase of range of motion as measured by a goniometer.</p><p id="par0090" class="elsevierStylePara elsevierViewall">We evaluated patient satisfaction and drug safety by assessing possible complications and performing a blood test 1 month after the injection to seek possible abnormalities, mainly in hepato-renal function.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0095" class="elsevierStylePara elsevierViewall">All patients treated with CH collagenase were administered a single injection in the palpable band. In 2 patients the dose was divided between the MCP and the PIP joints, using the maximum recommended dosage of the product, adding the corresponding solvent for the MCP joint and administering the result at 2 levels according to the indicated doses.</p><p id="par0100" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, the finger contracture rate in the MCP group prior to injection was 64° and after injection it was 8° at 2 weeks and 4° in the reviews conducted after 2, 3 and 6 months. The finger contracture rate in the PIP group prior to injection was 83.3° and after injection it was 20° at 2 weeks and 15° in the reviews conducted at 2, 3 and 6 months. The finger contracture rate in the MCP/PIP group prior to injection was 140° and after injection it was 30° at 2 weeks, 25° in the review conducted after 2 months and 20° after 3 and 6 months.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">In patients with dual MCP/PIP injection we observed a lower efficiency of the stretching at the level of the PIP.</p><p id="par0110" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>, the final result became worse as the degree of contracture was more severe.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">Skin dehiscence appeared during finger stretching in 9 patients (25.7%). This was resolved by cures and without complications (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). A total of 13 patients (37%) presented hematoma and/or phlyctenas at the site of injection. There were no local, vascular, tendinous or neural complications or infections.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">In 2 patients (5.7%) we detected axillary lymphadenopathy hours after injection, which disappeared within the first 48<span class="elsevierStyleHsp" style=""></span>h. One patient (2.85%) reported axillary pain with no palpable lymphadenopathy.</p><p id="par0125" class="elsevierStylePara elsevierViewall">Two patients (5.7%) presented an increase in transaminases without clinical consequences in the analytical study conducted 1 month after the injection.</p><p id="par0130" class="elsevierStylePara elsevierViewall">We observed no recurrences of the disease during the follow-up period.</p><p id="par0135" class="elsevierStylePara elsevierViewall">Functional recovery was fast and painless. Only 3 patients (8.5%) required physiotherapy treatment.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0140" class="elsevierStylePara elsevierViewall">Therapeutic options for the treatment of Dupuytren's disease are multiple depending on the characteristics of the patient and the disease itself. They include surgery: fasciectomies, dermofasciectomies, fasciotomies, etc., and pharmaceutical treatment: local injection of collagenase from <span class="elsevierStyleItalic">Clostridium histolyticum</span>.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Collagenase from <span class="elsevierStyleItalic">Clostridium histolyticum</span> is a new therapeutic alternative and the first pharmaceutical option approved for the treatment of adult patients with Dupuytren's disease which avoids the complications associated with surgery.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">In order to obtain good results and minimize risks it is essential to follow the recommendations to ensure a proper use of the product, as explained in the technical data sheet.</p><p id="par0155" class="elsevierStylePara elsevierViewall">The study revealed efficacy of CH collagenase in Dupuytren's disease with clinical and functional improvement in all patients who were administered the treatment and with rapid recovery, as in other published studies.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,3,5</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">The best results were obtained in patients in whom the injection was administered at the level of a palpable band in the MCP joint (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>) and in those patients with lower levels of contracture, as reported in other series.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,3–5</span></a></p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0165" class="elsevierStylePara elsevierViewall">We established the safety of CH collagenase administration through the observation of a scarce number of low-severity, local and easily resolved complications. We did not observe severe local (tendinous, vascular, nerve lesions, etc.) or general complications,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> although there are some reports documenting severe complications caused by intratendinous injection with ruptured tendons and major skin necrosis.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,10</span></a> Comparing the overall complication rates after surgery, different series reached between 4% and 39%.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">The treatment was minimally invasive and with few complications, representing an alternative to the treatment of Dupuytren's disease, especially in elderly patients and those with multiple associated pathologies, with limitations in daily activities and in whom surgery represented an increase in the rate of local and general complications.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">This alternative pharmaceutical treatment for Dupuytren's disease has surgical indications comparable to those of percutaneous fasciotomy, a technique with a low economic cost, but with high recurrence rates, between 33% and 100%, according to different series.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> It would be interesting to compare these during longer monitoring periods in order to determine whether or not the pharmaceutical treatment of Dupuytren's disease offers greater effectiveness.</p><p id="par0180" class="elsevierStylePara elsevierViewall">Due to the follow-up period of our patients, we cannot report on long-term recurrence rates. Nevertheless, studies with longer follow-up periods have reported recurrences, especially in cases affecting the PIP group.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,3</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Further research is required to clarify the recurrence rate of the disease, possible adverse reactions and to compare the efficacy and durability with those offered by other treatment alternatives.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Level of Evidence</span><p id="par0190" class="elsevierStylePara elsevierViewall">Level of evidence <span class="elsevierStyleSmallCaps">iv</span>.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflict of Interests</span><p id="par0195" class="elsevierStylePara elsevierViewall">The authors have no conflict of interests to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:2 [ "identificador" => "xres298317" "titulo" => array:5 [ 0 => "Abstract" 1 => "Objective" 2 => "Material and methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec281556" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres298318" "titulo" => array:5 [ 0 => "Resumen" 1 => "Objetivo" 2 => "Material y métodos" 3 => "Resultados" 4 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec281555" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Material and Methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Level of Evidence" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflict of Interests" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-06-10" "fechaAceptado" => "2013-07-17" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec281556" "palabras" => array:4 [ 0 => "Collagenase" 1 => "Clostridium" 2 => "Histolyticum" 3 => "Dupuytren" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec281555" "palabras" => array:4 [ 0 => "Colagenasa" 1 => "Clostridium" 2 => "Histolyticum" 3 => "Dupuytren" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The collagenase from <span class="elsevierStyleItalic">Clostridium histolyticum</span> is a new therapeutic option, and the first pharmacological one, in the treatment of Dupuytren's disease.</p> <span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A prospective study was conducted on 35 patients with Dupuytren's disease. The clinical and functional variables, as well as patient satisfaction and drug safety were evaluated.</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The functional and clinical results after its administration were good, with a rapid recovery, especially at the metacarpophalangeal (MCP) joint. The index finger contracture prior to MCP puncture was 64° and after puncture it was 4°. In the proximal interphalangeal (PIP) prior to puncture it was 83.3° and after puncture it was 15°; In the MCP/PIP prior to puncture it was 140°, and after puncture it 25°.</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Collagenase from <span class="elsevierStyleItalic">Clostridium histolyticum</span> an alternative of treatment of Dupuytren's disease, mainly in the elderly. More research is required in order to clarify the rate of recurrence of the disease, the possible adverse reactions, and to compare the efficiency and permanence with other treatment options.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La colagenasa del <span class="elsevierStyleItalic">Clostridium histolyticum</span> es una nueva opción terapéutica y el primer tratamiento farmacológico en el tratamiento de la enfermedad de Dupuytren.</p> <span class="elsevierStyleSectionTitle" id="sect0040">Material y métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio prospectivo de 35 pacientes afectos de la enfermedad de Dupuytren. Se evaluó los resultados clínicos, funcionales, la satisfacción del paciente y la seguridad del fármaco.</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Los resultados funcionales y clínicos tras su administración son buenos sobre todo en la articulación metacarpofalángica, con una recuperación rápida. El índice de contractura del dedo MCF previo a la punción fue de 64° y tras la punción de 4°; en las IFP previo a la punción fue de 83,3 grados y tras la punción de 15°; en MCF/IFP previo a la punción fue de 140° y tras la punción de 25°.</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Es una alternativa de tratamiento de la enfermedad de Dupuytren, fundamentalmente en los ancianos. La investigación es necesaria para clarificar el índice de recurrencia de la enfermedad, las posibles reacciones adversas y comparar la eficacia y durabilidad con otras alternativas de tratamiento.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Martín-Ferrero MÁ, Simón-Pérez C, Rodríguez-Mateos JI, García-Medrano B, Hernández-Ramajo R, Brotat-García M. Tratamiento de la enfermedad de Dupuytren mediante la colagenasa del <span class="elsevierStyleItalic">Clostridium histolyticum</span>. Rev Esp Cir Ortop Traumatol. 2013;57:398–402.</p>" ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 839 "Ancho" => 1613 "Tamanyo" => 62118 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Levels of contracture prior to injection of CH collagenase and at 2 weeks, 2, 3 and 6 months after the injection.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1226 "Ancho" => 1599 "Tamanyo" => 81734 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Levels of contracture prior and after administration of CH collagenase, according to the Tubiana classification.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1500 "Ancho" => 463 "Tamanyo" => 143907 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Skin dehiscence after finger stretching, at 15 and 25 days (healing by secondary intention).</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 937 "Ancho" => 1400 "Tamanyo" => 233519 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Dupuytren's disease in fourth finger prior to the administration of CH collagenase and at 1 month after administration.</p>" ] ] 4 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Grades \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Angles \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Percentage \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleSmallCaps">i</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1–45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleSmallCaps">ii</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46–90 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleSmallCaps">iii</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">91–135 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25.7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleSmallCaps">iv</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>135 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab436087.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Classification of the Patients in the Study According to the Tubiana Classification.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:11 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dupuytren contracture recurrence following treatment with collagenase <span class="elsevierStyleItalic">clostridium histolyticum</span> (CORDLESS Study): 3-year data" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.A. Peimer" 1 => "P. Blazar" 2 => "S. Coleman" 3 => "T.D. Kaplan" 4 => "T. Smith" 5 => "J. Tursi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhsa.2012.09.028" "Revista" => array:6 [ "tituloSerie" => "J Hand Surg Am" "fecha" => "2013" "volumen" => "38" "paginaInicial" => "12" "paginaFinal" => "22" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23200951" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Correction of contracture and recurrence rates of Dupuytren contracture following invasive treatment: the importance of clear definitions" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "P.M. Werker" 1 => "G.M. Pess" 2 => "A.L. van Rijssen" 3 => "K. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 6 | 0 | 6 |
| 2024 October | 44 | 1 | 45 |
| 2024 September | 55 | 3 | 58 |
| 2024 August | 34 | 6 | 40 |
| 2024 July | 30 | 2 | 32 |
| 2024 June | 31 | 2 | 33 |
| 2024 May | 40 | 0 | 40 |
| 2024 April | 39 | 8 | 47 |
| 2024 March | 31 | 2 | 33 |
| 2024 February | 32 | 7 | 39 |
| 2024 January | 54 | 4 | 58 |
| 2023 December | 53 | 8 | 61 |
| 2023 November | 58 | 3 | 61 |
| 2023 October | 73 | 9 | 82 |
| 2023 September | 38 | 1 | 39 |
| 2023 August | 40 | 4 | 44 |
| 2023 July | 60 | 5 | 65 |
| 2023 June | 46 | 8 | 54 |
| 2023 May | 77 | 3 | 80 |
| 2023 April | 60 | 1 | 61 |
| 2023 March | 50 | 0 | 50 |
| 2023 February | 41 | 8 | 49 |
| 2023 January | 56 | 6 | 62 |
| 2022 December | 50 | 2 | 52 |
| 2022 November | 41 | 5 | 46 |
| 2022 October | 34 | 6 | 40 |
| 2022 September | 47 | 6 | 53 |
| 2022 August | 55 | 8 | 63 |
| 2022 July | 30 | 13 | 43 |
| 2022 June | 34 | 9 | 43 |
| 2022 May | 25 | 16 | 41 |
| 2022 April | 21 | 10 | 31 |
| 2022 March | 21 | 8 | 29 |
| 2022 February | 11 | 4 | 15 |
| 2022 January | 10 | 4 | 14 |
| 2021 December | 17 | 12 | 29 |
| 2021 November | 11 | 9 | 20 |
| 2021 October | 26 | 9 | 35 |
| 2021 September | 11 | 10 | 21 |
| 2021 August | 15 | 5 | 20 |
| 2021 July | 22 | 7 | 29 |
| 2021 June | 13 | 3 | 16 |
| 2021 May | 13 | 7 | 20 |
| 2021 April | 21 | 9 | 30 |
| 2021 March | 22 | 13 | 35 |
| 2021 February | 12 | 8 | 20 |
| 2021 January | 5 | 4 | 9 |
| 2020 December | 1 | 0 | 1 |
| 2018 February | 15 | 1 | 16 |
| 2018 January | 9 | 0 | 9 |
| 2017 December | 10 | 0 | 10 |
| 2017 November | 6 | 1 | 7 |
| 2017 October | 11 | 1 | 12 |
| 2017 September | 10 | 2 | 12 |
| 2017 August | 5 | 4 | 9 |
| 2017 July | 16 | 4 | 20 |
| 2017 June | 14 | 3 | 17 |
| 2017 May | 14 | 0 | 14 |
| 2017 April | 11 | 5 | 16 |
| 2017 March | 11 | 54 | 65 |
| 2017 February | 7 | 0 | 7 |
| 2017 January | 16 | 3 | 19 |
| 2016 December | 17 | 5 | 22 |
| 2016 November | 11 | 5 | 16 |
| 2016 October | 28 | 3 | 31 |
| 2016 September | 15 | 8 | 23 |
| 2016 August | 7 | 1 | 8 |
| 2016 July | 6 | 1 | 7 |
| 2016 June | 12 | 5 | 17 |
| 2016 May | 11 | 9 | 20 |
| 2016 April | 14 | 15 | 29 |
| 2016 March | 9 | 14 | 23 |
| 2016 February | 10 | 15 | 25 |
| 2016 January | 5 | 18 | 23 |
| 2015 December | 8 | 7 | 15 |
| 2015 November | 12 | 13 | 25 |
| 2015 September | 0 | 1 | 1 |
| 2015 August | 0 | 3 | 3 |
| 2015 July | 0 | 1 | 1 |
| 2015 April | 0 | 1 | 1 |
| 2015 March | 1 | 0 | 1 |
| 2015 February | 1 | 0 | 1 |
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