Is Botulinum Toxin Useful in Systemic Sclerosis Related Peripheral Vasculopathy? A Literature Review

array:23 ["pii" => "S2173574321001039" "issn" => "21735743" "doi" => "10.1016/j.reumae.2020.04.013" "estado" => "S300" "fechaPublicacion" => "2021-06-01" "aid" => "1417" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología" "copyrightAnyo" => "2020" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Reumatol Clin. 2021;17:357-63" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:18 [ "pii" => "S2173574321001040" "issn" => "21735743" "doi" => "10.1016/j.reumae.2020.04.014" "estado" => "S300" "fechaPublicacion" => "2021-06-01" "aid" => "1427" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Reumatol Clin. 2021;17:364-5" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "Case Report" "titulo" => "Remission of Rheumatoid Arthritis and Primary Biliary Cholangitis After Treatment With Tocilizumab" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "364" "paginaFinal" => "365" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Remisión de artritis reumatoide y colangitis biliar primaria tras tratamiento con tocilizumab" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Soraia Azevedo, Joana Sousa-Neves, Joana Ramos Rodrigues, Daniela Peixoto, José Tavares-Costa, Filipa Teixeira" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Soraia" "apellidos" => "Azevedo" ] 1 => array:2 [ "nombre" => "Joana" "apellidos" => "Sousa-Neves" ] 2 => array:2 [ "nombre" => "Joana" "apellidos" => "Ramos Rodrigues" ] 3 => array:2 [ "nombre" => "Daniela" "apellidos" => "Peixoto" ] 4 => array:2 [ "nombre" => "José" "apellidos" => "Tavares-Costa" ] 5 => array:2 [ "nombre" => "Filipa" "apellidos" => "Teixeira" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574321001040?idApp=UINPBA00004M" "url" => "/21735743/0000001700000006/v1_202105240506/S2173574321001040/v1_202105240506/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S2173574321000988" "issn" => "21735743" "doi" => "10.1016/j.reumae.2019.09.005" "estado" => "S300" "fechaPublicacion" => "2021-06-01" "aid" => "1371" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Reumatol Clin. 2021;17:351-6" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Original Article" "titulo" => "Clinical and sociodemographic factors associated with lupus nephritis in Colombian patients: A cross-sectional study" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "351" "paginaFinal" => "356" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Factores clínicos y sociodemográficos asociados a nefritis lúpica en pacientes colombianos: resultados de un estudio transversal" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:6 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 847 "Ancho" => 1673 "Tamanyo" => 75469 ] ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Juan C. Díaz-Coronado, Adriana Rojas-Villarraga, Deicy Hernandez-Parra, Laura Betancur-Vásquez, Jorge Lacouture-Fierro, Daniel Gonzalez-Hurtado, Juanita González-Arango, Laura Uribe-Arango, Maria C. Gaviria-Aguilar, Ricardo A. Pineda-Tamayo" "autores" => array:10 [ 0 => array:2 [ "nombre" => "Juan C." "apellidos" => "Díaz-Coronado" ] 1 => array:2 [ "nombre" => "Adriana" "apellidos" => "Rojas-Villarraga" ] 2 => array:2 [ "nombre" => "Deicy" "apellidos" => "Hernandez-Parra" ] 3 => array:2 [ "nombre" => "Laura" "apellidos" => "Betancur-Vásquez" ] 4 => array:2 [ "nombre" => "Jorge" "apellidos" => "Lacouture-Fierro" ] 5 => array:2 [ "nombre" => "Daniel" "apellidos" => "Gonzalez-Hurtado" ] 6 => array:2 [ "nombre" => "Juanita" "apellidos" => "González-Arango" ] 7 => array:2 [ "nombre" => "Laura" "apellidos" => "Uribe-Arango" ] 8 => array:2 [ "nombre" => "Maria C." "apellidos" => "Gaviria-Aguilar" ] 9 => array:2 [ "nombre" => "Ricardo A." "apellidos" => "Pineda-Tamayo" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574321000988?idApp=UINPBA00004M" "url" => "/21735743/0000001700000006/v1_202105240506/S2173574321000988/v1_202105240506/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Review Article" "titulo" => "Is Botulinum Toxin Useful in Systemic Sclerosis Related Peripheral Vasculopathy? A Literature Review" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "357" "paginaFinal" => "363" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Miguel Gomes Guerra, Diogo Guimarães da Fonseca, Beatriz Samões, Taciana Videira, Patrícia Pinto" "autores" => array:5 [ 0 => array:4 [ "nombre" => "Miguel Gomes" "apellidos" => "Guerra" "email" => array:1 [ 0 => "mlgomesg@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Diogo Guimarães da" "apellidos" => "Fonseca" ] 2 => array:2 [ "nombre" => "Beatriz" "apellidos" => "Samões" ] 3 => array:2 [ "nombre" => "Taciana" "apellidos" => "Videira" ] 4 => array:2 [ "nombre" => "Patrícia" "apellidos" => "Pinto" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Rheumatology Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Rua Conceição Fernandes, 4434-502 Vila Nova de Gaia, Portugal" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "¿Es la toxina botulínica útil en la vasculopatía periférica de la esclerosis sistémica? Una revisión sistemática" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1664 "Ancho" => 1500 "Tamanyo" => 130154 ] ] "descripcion" => array:1 [ "en" => "Flowchart of systematic review according to PRISMA guidelines." ] ] ] "textoCompleto" => "IntroductionSystemic sclerosis (SSc) is an orphan connective tissue disease where diffuse microangiopathy and immune system dysregulation result in collagen hyperproduction with skin and internal organs fibrosis.<a class="elsevierStyleCrossRef" href="#bib0115">1</a> Raynaud Phenomenon (RP) is a consequence of peripheral microvasculopathy, triggered by endothelium dysfunction.<a class="elsevierStyleCrossRefs" href="#bib0115">1,2</a> It is highly prevalent in SSc (95% of patients) and consists on an episodic colour change of the extremities in response to cold exposure.<a class="elsevierStyleCrossRef" href="#bib0125">3</a> Moreover, it is typically the initial manifestation and precedes by years major organ involvement.<a class="elsevierStyleCrossRef" href="#bib0115">1</a> Digital ulcers (DU) are a serious consequence of SSc related vasculopathy. They occur in up to 58% of patients, either in the diffuse or limited subtype. With an extended time to healing, DU may result in critical ischaemia and soft tissue/bone infections, thus demanding aggressive treatment. Moreover, they also point to a worse prognosis.<a class="elsevierStyleCrossRef" href="#bib0130">4</a>As vascular injury performs a major role in SSc pathogenesis, several treatment options focuses on it, not only for RP and DU, but also pulmonary arterial hypertension. Nowadays, calcium channel blockers, prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase inhibitors are the main pharmacologic representatives to target this pathway.<a class="elsevierStyleCrossRef" href="#bib0135">5</a> Nevertheless, in daily clinical practice, RP and DU still pose a challenge for both physicians and patients.In the last two decades, botulinum toxin (BT) has emerged as a nonsurgical treatment for vasospastic disease.<a class="elsevierStyleCrossRef" href="#bib0140">6</a>Through local hand injections, numerous reports showed an improvement in RP severity and DU healing,<a class="elsevierStyleCrossRefs" href="#bib0140">6,7</a> including in patients with SSc.The aim of this review was to evaluate the available evidence concerning the use of BT in the treatment of SSc related RP/DU.Materials and methodsData source and search strategyA literature review was devised, fitting the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines in order to identify all full-text manuscripts that focused on the use of BT in the treatment of SSc related RP/DU. The search was performed on Pubmed, with the following MeSH terms: ‘systemic sclerosis’ and ‘botulinum toxin’, with the boolean term “AND”. No other keywords were added, in order to avoid an excessively restrictive search string that would exclude studies of interest and result in an extremely low number of results.The search was performed from database inception up to the 31st of May 2019. No filters were added.Screening process and selection criteriaAfter the search, MG and DF screened the records on 3 steps – title, abstract and full-text level – to assess for inclusion. A manual search through the references of the retained manuscripts was also performed in order to detect additional reports. Records were considered eligible when both reviewers included them for the next step. When opinions differed, consensus was reached by discussion with the remaining investigators (BS, TV, PP).Manuscripts were selected considering the Population, Intervention, Comparison, Outcome (PICO) strategy:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">-Population: Patients aged 18 or more years old, with SSc related RP or DU refractory to standard of care. Ideally, studies should follow the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) and/or 1980 ACR classification criteria. Cohorts with broader samples that included SSc patients were also considered for inclusion;</li><li class="elsevierStyleListItem" id="lsti0010">-Intervention: BT hand injection;</li><li class="elsevierStyleListItem" id="lsti0015">-Comparison: Ideally, randomized control group of patients maintaining standard of care. In the absence of a control group, a statistical analysis comparing with baseline was considered the minimum;</li><li class="elsevierStyleListItem" id="lsti0020">-Outcome: for DU, ulcer healing and development of new ulcers. For RP, Raynaud's Condition Score (RCS) or, in alternative, at least 1 Visual Analogue Scale (VAS). Occurrence and description of complications.</li></ul>Reviews, letters, editorials, abstracts of scientific reunions and case series (CS) with less than 5 patients were rejected. English, French and Portuguese were the only 3 idioms accepted. After screening, manuscripts’ data was systematized in a standardized electronic spreadsheet that included: author, year, country, study design, SSc classification criteria, sample size, type of BT used, injection protocol used (including injection points and dose administered), evaluated outcomes, follow-up length, adverse reactions, statistical analysis performed and results.Quality appraisalThe studies selected through the screening process were assessed for quality appraisal by MG and DF using the National Institute of Health (NIH) tools for randomized control trials (RCT), case–control (CC) studies and CS.ResultsThirty results were obtained from the search through Pubmed. No article was obtained by reference checking. After the screening phase, 5 reports were considered for the qualitative analysis (see <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Ratings according to the NIH are presented in supplement 1. Only 1 was considered as Good Quality.<a class="elsevierStyleCrossRef" href="#bib0150">8</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Study design, population and exclusion criteriaTwo of the retained articles were RCT and presented the largest samples, 40<a class="elsevierStyleCrossRef" href="#bib0150">8</a> and 45<a class="elsevierStyleCrossRef" href="#bib0155">9</a> patients (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Both used the American College of Rheumatology (ACR) 1980 and/or ACR/European League Against Rheumatism (EULAR) 2013 classification criteria. Bello et al.<a class="elsevierStyleCrossRef" href="#bib0150">8</a> applied the most rigorous exclusion criteria. In comparison to Motegi et al., 2017,<a class="elsevierStyleCrossRef" href="#bib0155">9</a> the first authors also selected a more suitable control group – the contralateral hand of each patient, in a double-blinded design.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The CC study<a class="elsevierStyleCrossRef" href="#bib0160">10</a> failed to report on classification and exclusion criteria. Despite this, it followed a methodology similar to the one adopted by Bello et al.<a class="elsevierStyleCrossRef" href="#bib0150">8</a> concerning the control group, by using the patient's dominant hand, but with no blinding process.The 2 CS presented the smallest samples (Motegi et al., 2016<a class="elsevierStyleCrossRef" href="#bib0165">11</a> with 10 patients, Serri et al.<a class="elsevierStyleCrossRef" href="#bib0170">12</a> with 18 patients), thus under-powering even more their conclusions. One of them also didn’t report on classification criteria.<a class="elsevierStyleCrossRef" href="#bib0170">12</a>As for current treatment, there was disparity between studies. All authors implemented BT as adjuvant treatment. In 3 of them, patients were included only if there were unsatisfying results with standard of care.<a class="elsevierStyleCrossRefs" href="#bib0155">9–11</a> Serri et al.<a class="elsevierStyleCrossRef" href="#bib0170">12</a> and Bello et al.,<a class="elsevierStyleCrossRef" href="#bib0150">8</a> on the contrary, included patients irrespective of treatment response. None of the 5 described clearly the previous treatment, specifically which associations of vasodilators were used. The same was verified concerning extra-articular manifestations.Outcome measures<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarizes the evaluated outcome measures. RCS is a validated tool to assess the severity of RP; however, it was only applied in 3 studies.<a class="elsevierStyleCrossRefs" href="#bib0150">8,9,11</a> Other tools used to evaluate this outcome were: VAS of pain (Pain-VAS), skin temperature recovery time, McCabe cold sensitivity score, re-colouration time, colour change VAS and cold intolerance VAS.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Laser Doppler imaging and Oxygen Saturation were performed by Bello et al.<a class="elsevierStyleCrossRef" href="#bib0150">8</a> to objectively evaluate perfusion. Serri et al.,<a class="elsevierStyleCrossRef" href="#bib0170">12</a> on the other hand, only used Oxygen Partial Pressure. All included manuscripts evaluated the presence/number of DU.As for hand function, a high variety of measures were applied. Motegi et al.<a class="elsevierStyleCrossRefs" href="#bib0155">9,11</a> was the only that did not include hand function evaluation. The “Disabilities of the Arm, Shoulder and Hand” questionnaire (DASH) is a validated tool that evaluates upper limbs daily functionality, and was used by Uppal et al.<a class="elsevierStyleCrossRef" href="#bib0160">10</a> Bello et al.<a class="elsevierStyleCrossRef" href="#bib0150">8</a> and Serri et al.<a class="elsevierStyleCrossRef" href="#bib0170">12</a> opted for a simpler version, the “Quick Disabilities of the Arm, Shoulder and Hand” questionnaire (QuickDASH). Uppal et al.<a class="elsevierStyleCrossRef" href="#bib0160">10</a> also reported on pinch and power grip strength, ranges of movement of hand joints, hand span and Kapandji thumb opposition test.Injection protocolInjection protocols differed between studies, and even within the same study<a class="elsevierStyleCrossRef" href="#bib0170">12</a> (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). From the 7 serotypes of BT existent, 2 were used: type A (BT-A) and type B (BT-B). Motegi et al., 2017<a class="elsevierStyleCrossRef" href="#bib0155">9</a> were the only ones that used BT-B (NeuroBloc®). As for the remaining 4 investigation groups, all chose BT-A (BOTOX®); Serri et al.,<a class="elsevierStyleCrossRef" href="#bib0170">12</a> however, used BT-A from 2 different suppliers (BOTOX® and Xéomin®).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Injection sites and units (U) administered were also highly heterogeneous. Bello et al.<a class="elsevierStyleCrossRef" href="#bib0150">8</a> was the only to adopt a dorsal side approach, with the lowest dose of BT-A (50U per hand). Motegi et al., 2016<a class="elsevierStyleCrossRef" href="#bib0165">11</a> opted to inject only the most symptomatic finger, through the palmar side, with a total of 20U of BT-A. Remaining authors followed a multiple injection procedure, in the palmar side of hand.<a class="elsevierStyleCrossRefs" href="#bib0155">9,10,12</a> Uppal et al. and Serri et al. (in one protocol) also injected the palmar crease besides fingers’ bases.<a class="elsevierStyleCrossRefs" href="#bib0160">10,12</a>Follow-upTimings of follow-up were heterogeneous. Considering the potential time of effect of BT, only the two RCT and 1 CS adopted a sufficient time lapse – up to 16 weeks.<a class="elsevierStyleCrossRefs" href="#bib0150">8,9,11</a>Studies’ findings<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a> resumes the main findings of each report on RP, perfusion, DU, hand function and complications.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Raynaud phenomenonBello et al. reported a statistically significant faster decline in RCS in the treatment group.<a class="elsevierStyleCrossRef" href="#bib0150">8</a> In Motegi et al., 2016,<a class="elsevierStyleCrossRef" href="#bib0165">11</a> RSC significantly reduced from 4 to 16 weeks after injection. In Motegi et al., 2017,<a class="elsevierStyleCrossRef" href="#bib0155">9</a> RCS in the group treated with 250U was significantly lower than in the control group at week 4; in the groups treated with 1000 and 2000U BT-B, values were significantly lower than those in control group and the group treated with 250U BT-B at every follow-up check-point; groups treated with 1000 and 2000U BTX-B were comparable.Peripheral perfusionSurprisingly, the RCT with the largest sample<a class="elsevierStyleCrossRef" href="#bib0150">8</a> reported a statistically significant worse blood flow in BT treated arm from baseline to 1 month; however, this result was not verified in the period from baseline to 4 months. No difference was found between groups on Oxygen Saturation.Distinctly, Serri et al. reported an improvement on Oxygen Partial Pressure (p=0.003) at the end of follow-up.<a class="elsevierStyleCrossRef" href="#bib0170">12</a>Digital ulcersBello et al.<a class="elsevierStyleCrossRef" href="#bib0150">8</a> found no significant differences between treatment and control groups, neither concerning the risk of new ulcers, nor changes over time in number of new ulcers. In Motegi et al., 2016,<a class="elsevierStyleCrossRef" href="#bib0165">11</a> half the sample (n=5) presented DU at the beginning of follow-up; after 16 weeks, every patients’ DUs had healed. In Motegi et al., 2017,<a class="elsevierStyleCrossRef" href="#bib0155">9</a> the numbers of DUs in the groups treated with 1000 and 2000U were significantly lower than those in the control group 4–16 weeks after injection; the same 2 groups had no new DU, in comparison to 2 DU in the group treated with 250U and 7 in the control group. As for Serri et al.,<a class="elsevierStyleCrossRef" href="#bib0170">12</a> 10 out of 18 patients had active DU at baseline (median 4 DU per patient); at the end of follow-up, 100% had healed. In Uppal et al.,<a class="elsevierStyleCrossRef" href="#bib0160">10</a> 75% of the patients with DU (3 out of 4) had complete lesions’ healing at the end of follow-up.Hand functionOf the 3 studies that evaluated hand function,<a class="elsevierStyleCrossRefs" href="#bib0150">8,10,12</a> 2 reported positive results.<a class="elsevierStyleCrossRefs" href="#bib0160">10,12</a> Serri et al.<a class="elsevierStyleCrossRef" href="#bib0170">12</a> found a significant improvement in the QuickDASH score. In Uppal et al.,<a class="elsevierStyleCrossRef" href="#bib0160">10</a> objective measures of hand functionality also showed improvement (pinch grip, power grip, 2nd/3rd metacarpophalangeal joint flexion).ComplicationsBT administration was mostly safe through all studies. The only adverse reaction reported was weakness of hand's intrinsic muscles, with a prevalence ranging between 0 and 16.7% (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). Considering all 5 studies, only 8 out of 133 patients reported this adverse effect (6.0%). Moreover, this was a transitory effect, which reverted completely after the local effect of BT wore of.DiscussionBT first emerged in the 1970s in the treatment of strabismus, as it prevents muscular contraction by inhibiting the release of acetylcholine in the neuromuscular junctions.<a class="elsevierStyleCrossRef" href="#bib0175">13</a> This mechanism justifies most of the clinical indications of this neurotoxin.<a class="elsevierStyleCrossRefs" href="#bib0180">14,15</a> However, evidence suggests the additional role of pain transmission blockage (for example, substance P).<a class="elsevierStyleCrossRefs" href="#bib0190">16–18</a> BT also inhibits sympathetic adrenergic vasoconstriction and endothelial exocytosis of endothelin-1,<a class="elsevierStyleCrossRef" href="#bib0205">19</a> through a dose-dependent mechanism, hence justifying the increasing interest in vasospastic disorders.Our search identified 2 RCT focusing on SSc-related RP/DU. Bello et al.<a class="elsevierStyleCrossRef" href="#bib0150">8</a> presented the most precise study. Unfortunately, it showed the least impressive results and reported a worse blood flow in the treated arm. However, when comparing the units of BT, lower values were administered (versus (10–12)). Considering that the vasodilating effects of BT are shown to be dose-dependent, this might have contributed to the absence of positive results. Despite this, it still reported encouraging findings, with faster decline in RCS in the BT treated arm.A direct comparison between RCT is unfeasible due to the use of different BT subtypes. Motegi et al., 2017<a class="elsevierStyleCrossRef" href="#bib0155">9</a> opted for BT-B instead of BT-A. If one considers an equivalency of 1:40, the highest dose administered of BT-B in Motegi et al., 2017<a class="elsevierStyleCrossRef" href="#bib0155">9</a> equalled the 50U of BT-A in Bello et al.<a class="elsevierStyleCrossRef" href="#bib0150">8</a> and still reported significantly better RCS/pain/skin temperature recovery. However, this equivalency ratio is not applicable to the vasodilator effect.<a class="elsevierStyleCrossRef" href="#bib0175">13</a>The only CC included failed to report the selection criteria (Both SSc classification criteria and exclusion criteria).<a class="elsevierStyleCrossRef" href="#bib0160">10</a> It focused mainly on hand function, besides RP and DU, and showed statistically significant improvements in pinch grip, power grip, DASH score and 2nd/3rd metacarpophalangeal joints’ flexion. The 2 CS,<a class="elsevierStyleCrossRefs" href="#bib0165">11,12</a> despite the limitations, showed significant improvement of numerous outcomes: RCS,<a class="elsevierStyleCrossRef" href="#bib0165">11</a> pain,<a class="elsevierStyleCrossRefs" href="#bib0165">11,12</a> skin temperature recovery time,<a class="elsevierStyleCrossRef" href="#bib0165">11</a> hand function,<a class="elsevierStyleCrossRef" href="#bib0170">12</a> O2 partial pressure<a class="elsevierStyleCrossRef" href="#bib0170">12</a> and DU complete healing.<a class="elsevierStyleCrossRefs" href="#bib0165">11,12</a>Concerning DU healing, Motegi et al., 2017<a class="elsevierStyleCrossRef" href="#bib0155">9</a> showed statistically significant results, for 1000 and 2000U of BT-B. Bello et al.<a class="elsevierStyleCrossRef" href="#bib0150">8</a> did not support this finding, but all other studies reported positive results, with complete DU healing in 75%<a class="elsevierStyleCrossRef" href="#bib0160">10</a> to 100%<a class="elsevierStyleCrossRefs" href="#bib0165">11,12</a> of patients.Future investigation in this area needs improvement. For example, BT achieves its maximal effect after 2 weeks and then gradually decreases for 2–3 months.<a class="elsevierStyleCrossRef" href="#bib0175">13</a> Thus, follow up time is of crucial importance when reporting results. Only the 2 RCT and 1 CS included a sufficient time-period in their study.<a class="elsevierStyleCrossRefs" href="#bib0150">8,9,11</a> This aspect needs to be consistent while evaluating BT in SSc-related peripheral vasculopathy. Environmental conditions must also be reported, specifically daily minimum temperature. Only Bello et al.<a class="elsevierStyleCrossRef" href="#bib0150">8</a> adjusted statistical analysis to this confounding factor. Other studies were performed during the Winter,<a class="elsevierStyleCrossRefs" href="#bib0155">9,11</a> when RP/DU are more common and severe.Another limitation is sample's selection. Some authors did not report the classification criteria applied for patient selection,<a class="elsevierStyleCrossRefs" href="#bib0160">10,12</a> and one failed to present the exclusion criteria.<a class="elsevierStyleCrossRef" href="#bib0160">10</a> All of them administered BT as adjuvant measure. This aspect greatly compromises the conclusions drawn, especially because none of the 5 studies included a satisfactory description of baseline vasodilator medications. Moreover, none of the authors performed a description of systemic manifestations with enough accuracy.The injection protocol was also highly variable. BT-A doses varied between 20U/finger and 100U/hand,<a class="elsevierStyleCrossRefs" href="#bib0150">8,10–12</a> and one study opted for BT-B.<a class="elsevierStyleCrossRef" href="#bib0155">9</a> Injection sites differed markedly, with 1 group using a dorsal approach<a class="elsevierStyleCrossRef" href="#bib0150">8</a> and 2 injecting the palmar creases.<a class="elsevierStyleCrossRefs" href="#bib0160">10,12</a> In the future, researchers should focus mainly on only one BT type, and perform similar injection procedures (for example, using the palmar approach, but avoiding injecting the palmar crease, because of a possible higher risk of muscle weakness<a class="elsevierStyleCrossRef" href="#bib0170">12</a>).Outcome measures must also be uniformized. RCS is the only tool validated for RP assessment.<a class="elsevierStyleCrossRef" href="#bib0210">20</a> Other possibilities to include are frequency/duration of RF attacks and VAS of patient's and physician's assessment of RP activity. DU, namely the number of ulcers and development of new ulcers, should be systematically reported. Hand function assessment is a secondary outcome that can be included – DASH or QuickDASH questionnaires showed validity in SSc<a class="elsevierStyleCrossRef" href="#bib0215">21</a> but other tools are available.<a class="elsevierStyleCrossRef" href="#bib0220">22</a>Previous reviews focusing on this subject have been performed, with promising findings.<a class="elsevierStyleCrossRef" href="#bib0145">7</a> However, the studies included primary and secondary FP of different aetiologies, thus invaliding conclusions concerning only SSc. This has impact in daily clinical practice, because the most severe cases of peripheral vasculopathy are typically associated to SSc. In light to this scenario, this review clarifies that BT can also claim a role in this population.ConclusionDespite not conclusive, evidence suggests that BT has a position to claim in the treatment of SSc-related vasculopathy – it may not be necessarily an anchor therapy, but an effective and safe adjuvant to the vasodilating drugs presently recommended in the treatment of RP/DU. However, in face of conflicting results of one RCT, more robust studies are needed to clarify its true efficacy, as well as the optimal dose and injection protocol.Key points<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025">•Treatment of peripheral vasculopathy (RP/DU) in SSc can pose a difficult challenge in clinical practice.</li><li class="elsevierStyleListItem" id="lsti0030">•BT, through inhibition of sympathetic adrenergic vasoconstriction and endothelin-1, has emerged as an alternative treatment in this scenario.</li><li class="elsevierStyleListItem" id="lsti0035">•Current evidence supports a positive effect of BT on RP severity and DU healing, but is held back by several methodological limitations of the studies performed to date.</li><li class="elsevierStyleListItem" id="lsti0040">•Future investigation is required to further clarify the findings of this review, especially the conflicting results of 1 RCT.</li><li class="elsevierStyleListItem" id="lsti0045">•For the moment, BT can be considered an adjunctive in the treatment of refractory RP/DU, but not an anchor therapy.</li></ul>ContributionsMG – Ideation of the study, substantial contributions to the design of the study, acquisition of data, analysis and interpretation of data, drafting of the article, critical revision of the intellectual content, final approval of the version to be published.DF – Acquisition of data, substantial contributions to the design of the study, acquisition of data, analysis and interpretation of data, critical revision of the intellectual content, final approval of the version to be published.BS – Substantial contributions to the design of the study, analysis and interpretation of data, critical revision of the intellectual content, final approval of the version to be published.TV – Ideation of the study, substantial contributions to the design of the study, critical revision of the intellectual content, final approval of the version to be published.PP – Ideation of the study, substantial contributions to the design of the study, critical revision of the intellectual content, final approval of the version to be published.FundingNo funding received.Conflict of interestNone to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1515133" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1373939" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1515134" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Materiales y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1373938" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Data source and search strategy" ] 1 => array:2 [ "identificador" => "sec0120" "titulo" => "Screening process and selection criteria" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "Quality appraisal" ] ] ] 6 => array:3 [ "identificador" => "sec0025" "titulo" => "Results" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Study design, population and exclusion criteria" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Outcome measures" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Injection protocol" ] 3 => array:2 [ "identificador" => "sec0045" "titulo" => "Follow-up" ] 4 => array:3 [ "identificador" => "sec0050" "titulo" => "Studies’ findings" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Raynaud phenomenon" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Peripheral perfusion" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Digital ulcers" ] 3 => array:2 [ "identificador" => "sec0070" "titulo" => "Hand function" ] 4 => array:2 [ "identificador" => "sec0075" "titulo" => "Complications" ] ] ] ] ] 7 => array:2 [ "identificador" => "sec0080" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0085" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "sec0090" "titulo" => "Key points" ] 10 => array:2 [ "identificador" => "sec0095" "titulo" => "Contributions" ] 11 => array:2 [ "identificador" => "sec0100" "titulo" => "Funding" ] 12 => array:2 [ "identificador" => "sec0105" "titulo" => "Conflict of interest" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-06-28" "fechaAceptado" => "2020-04-02" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1373939" "palabras" => array:4 [ 0 => "Systemic sclerosis" 1 => "Raynaud phenomenon" 2 => "Digital ulcer" 3 => "Botulinum toxin" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1373938" "palabras" => array:4 [ 0 => "Esclerosis sistémica" 1 => "Fenómeno de Raynaud" 2 => "Úlcera digital" 3 => "Toxina botulínica" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "IntroductionIn systemic sclerosis (SSc), peripheral vasculopathy presents typically as Raynaud Phenomenon (RP) and Digital Ulceration (DU). Over the last decade, botulinum toxin (BT) has been reported effective in this scenario. Our goal was to review existing literature evaluating the efficacy of BT on RP/DU in SSc. Materials and methodsWe performed a search in Pubmed with the MeSH terms “systemic sclerosis” and “botulinum toxin”. Original studies evaluating BT in the treatment of SSc-associated RP/DU were considered for inclusion. Results were screened by title, abstract and full-text. ResultsWe identified 30 results, of which 5 original papers were included: 2 randomized controlled trials (RCT), 2 case series and 1 case control study, from a total of 133 patients. Only one RCT showed negative results, with worse blood flow in treated arm, but with lower dose of BT. Despite this, all 5 included studies reported improvement of at least 1 RP/hand function outcome measure. Concerning DU healing, resolution of baseline DU at the end of follow-up was reported in 75–100% of the patients, with 1 RCT showing superiority over placebo. The only reported adverse effect was transient hand weakness, affecting only 0–16.7% of patients. BT injection protocols were highly heterogeneous. ConclusionDespite conflicting results in 1 RCT, evidence points BT as an option in the treatment of SSc-related peripheral vasculopathy. However, future larger prospective trials are necessary to corroborate this hypothesis." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "IntroducciónEn la esclerosis sistémica (ES), la vasculopatía periférica se presenta normalmente como fenómeno de Raynaud (FR) y ulceración digital (UD). En el último decenio se ha reportado la efectividad de la toxina botulínica (TB) en este escenario. Nuestro objetivo fue revisar la literatura existente que evalúa la eficacia de la TB en el FR/UD en la ES. Materiales y métodosRealizamos una búsqueda en Pubmed con los términos MeSH «esclerosis sistémica» y «toxina botulínica». Se consideraron para inclusión los estudios originales que evaluaban la TB en el tratamiento del FR/UD asociados a ES. Se cribaron los resultados por título, resumen y texto completo. ResultadosIdentificamos 30 resultados, de los cuales se incluyeron 5 documentos originales: 2 ensayos controlados aleatorizados (ECA), 2 series de casos y un estudio de control de caso, de un total de 133 pacientes. Únicamente un ECA reflejó resultados negativos con peor flujo sanguíneo en el brazo tratado, aunque con menor dosis de TB. A pesar de ello, los 5 estudios incluidos reportaron una mejora de al menos una medida del resultado FR/función de la mano. En cuanto a la sanación de la UD, la resolución de la UD basal al final del seguimiento se reportó en el 75-100% de los pacientes, y un ECA reflejó superioridad con respecto al placebo. El único efecto adverso reportado fue debilidad transitoria en la mano, que afectó únicamente al 0-16,7% de los pacientes. Los protocolos de inyección de la TB fueron altamente homogéneos. ConclusiónA pesar de los resultados conflictivos en un ECA, la evidencia apunta a la TB como opción para el tratamiento de la vasculopatía periférica asociada a la ES. Sin embargo, son necesarios ensayos prospectivos futuros más amplios para corroborar esta hipótesis." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Materiales y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "The following are the supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia><elsevierMultimedia ident="upi0010"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0115" ] ] ] ] "multimedia" => array:7 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1664 "Ancho" => 1500 "Tamanyo" => 130154 ] ] "descripcion" => array:1 [ "en" => "Flowchart of systematic review according to PRISMA guidelines." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ACR, American College of Rheumatology; BT, Botulinum toxin; CC, Case control; CS, Case series; EULAR, European League Against Rheumatism; RCT, Randomized controlled trial." "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"><th 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" scope="col" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Country \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Study design \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Classification criteria \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Exclusion criteria \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Sample size \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Control group \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bello et al., 2017<a class="elsevierStyleCrossRef" href="#bib0150">8</a> \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">United States of America \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">Double blinded RCT \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">ACR 1980 or ACR/EULAR 2013 \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">Active infection, acute digit ischaemia, myasthenia gravis, hypersensitivity to BT, previous BT vaccine, current use of aminoglycoside antibiotics, prior upper extremity vascular surgery, pregnancy, lactation \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">40 \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">Contralateral hand \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Motegi et al., 2016<a class="elsevierStyleCrossRef" href="#bib0165">11</a> \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">Japan \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">CS \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">ACR 1980 or ACR/EULAR 2013 \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">Previous treatment with BT, pregnancy \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">10 \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">Not applicable \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Motegi et al., 2017<a class="elsevierStyleCrossRef" href="#bib0155">9</a> \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">Japan \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">Single blinded RCT \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">ACR 1980 or ACR/EULAR 2013 \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">Previous treatment with BT, pregnancy \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">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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 randomly selected patients \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Serri et al., 2013<a class="elsevierStyleCrossRef" href="#bib0170">12</a> \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">France \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">CS \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">Not reported \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">Hypersensitivity to BT, pregnancy, lactation, radial/ulnar artery occlusion \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not applicable \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uppal et al., 2014<a class="elsevierStyleCrossRef" href="#bib0160">10</a> \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">United Kingdom \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">CC \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">Not reported \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">Not reported \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><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">Dominant hand \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2601084.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Demographic characteristics of studies included in the systematic review." ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "DASH, disability of arm, shoulder and hand questionnaire; QuickDASH, Quick Disabilities of the Arm, Shoulder and Hand questionnaire; DU, digital ulcer; RCS, Raynaud's condition score; VAS, visual analogue scale." "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"><th 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" scope="col" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Raynaud's phenomenon \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Digital ulcers \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Hand function \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Perfusion \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Follow-up visit \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bello et al., 2017<a class="elsevierStyleCrossRef" href="#bib0150">8</a> \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">RCS, Pain-VAS, McCabe cold sensitivity score \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">Number of DU \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">QuickDASH \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">Change in blood flow measured with Laser Doppler Imaging; pulse oximetry \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">Week 4 & 16 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Motegi et al., 2016<a class="elsevierStyleCrossRef" href="#bib0165">11</a> \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">RCS, Pain-VAS, skin temperature recovery time after cold water stimulus \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">Number of DU \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">Not evaluated \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">Not evaluated \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">Week 2, 4, 8, 12 & 16 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Motegi et al., 2017<a class="elsevierStyleCrossRef" href="#bib0155">9</a> \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">RCS, Pain/numbness-VAS, skin temperature recovery time after cold water stimulus \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">Number of DU \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">Not evaluated \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">Not evaluated \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">Week 4, 8, 12 & 16 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Serri et al., 2013<a class="elsevierStyleCrossRef" href="#bib0170">12</a> \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">Pain VAS, patient satisfaction scale, re-colouration time \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">Number of DU \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">QuickDASH \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">Oxygen partial pressure \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">Week 4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uppal et al., 2014<a class="elsevierStyleCrossRef" href="#bib0160">10</a> \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">Pain VAS, colour change VAS, cold intolerance VAS \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">Presence of DU \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">Pinch/power grip strength, range of movement of hand joints, hand span, Kapandji thumb opposition test, DASH \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">Not evaluated \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">Week 8 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2601086.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Outcome measures of studies included in the systematic review." ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "BT, Botulinum toxin." "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"><th 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" scope="col" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Type of BT \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Injection sites \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Units injected \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bello et al., 2017<a class="elsevierStyleCrossRef" href="#bib0150">8</a> \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">A (Botox®) \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">Dorsal surface in 7 points of hand: 2nd, 3rd, and 4th web spaces, radial side of the index finger base, ulnar side of the small finger base, and each side of the thumb base \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">50U/hand \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Motegi et al., 2016<a class="elsevierStyleCrossRef" href="#bib0165">11</a> \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">A (Botox®) \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">2 injections proximally to A1 pulley of the most symptomatic finger of each hand \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">20U/finger \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Motegi et al., 2017<a class="elsevierStyleCrossRef" href="#bib0155">9</a> \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">B (NeuroBloc®) \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">Palmar surface in 6 points of hand: web spaces, radial side of the thumb base and ulnar side of the small finger base \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">3 groups: 250U/hand; 1000U/hand; 2000U/hand \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Serri et al., 2013<a class="elsevierStyleCrossRef" href="#bib0170">12</a> \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">A (Botox, Xéomin®) \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">2 protocols: A with 14 palmar points of hand: 2 at the base of each finger plus 4 in the palmar creases; B with 18 palmar points of hand: 2 at the base of each finger and 2 at the proximal extremity of second phalange of 2nd to 5th finger \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">100U/hand \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uppal et al., 2014<a class="elsevierStyleCrossRef" href="#bib0160">10</a> \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">A (Botox®) \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">Palmar surface, at distal palmar crease, in web spaces, around digital neurovascular bundles of all 5 digits of the non-dominant hand (number of points not reported) \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">100U/hand \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2601087.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Injection protocols performed by each study." ] ] 4 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "BT, Botulinum toxin; DASH, disability of arm, shoulder and hand questionnaire; DU, digital ulcer; MCPJ, Metacarpophalangeal joint; RCS, Raynaud's condition score; VAS, visual analogue scale." "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"><th 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" scope="col" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Raynaud's phenomenon \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Digital ulcers \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Hand function \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Perfusion \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Complications \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bello et al., 2017<a class="elsevierStyleCrossRef" href="#bib0150">8</a> \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">Faster decline of RCS in BT treated arm \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">No significant results \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">No significant results \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">Worse blood flow in BT treated arm at 4 weeks \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">Transient weakness of intrinsic muscles of hand in 5% of sample (n=2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Motegi et al., 2016<a class="elsevierStyleCrossRef" href="#bib0165">11</a> \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">Improvement in RCS, pain-VAS and skin temperature recovery time \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">Complete healing of DU \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">Not evaluated \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">Not evaluated \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">Not found \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Motegi et al., 2017<a class="elsevierStyleCrossRef" href="#bib0155">9</a> \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">RCS:Lower in the 250U-arm vs control at week 4;Lower in the 1000U and 2000U arms vs control group and 250U arm, at weeks 4/8/12/16.Pain VAS:Lower in the 250U-arm vs control at week 8/12;Lower in the 1000U and 2000U arms vs control group, at weeks 4/8/12/16.Skin temperature recovery:Lower in the 2000U-arm vs control and 250U-arm at week 4. \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">Lower number of DU in the 1000U and 2000U arms vs control group, at week 4/8/12/16 \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">Not evaluated \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">Not evaluated \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">Transient weakness of intrinsic muscles of hand in 2.2% of sample (n=1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Serri et al., 2013<a class="elsevierStyleCrossRef" href="#bib0170">12</a> \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">Improvement in Pain-VAS \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">Complete healing of all DU, without new ones \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">Improvement in QuickDASH score \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">Improvement in oxygen partial pressure \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">Transient weakness of intrinsic muscles of hand in 16.7% of sample (n=3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uppal et al., 2014<a class="elsevierStyleCrossRef" href="#bib0160">10</a> \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">No significant results \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">75% of patients with DU with complete lesions’ healing \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">Improvement in pinch grip, power grip, 2nd MCPJ flexion and 3rd MCPJ flexion \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">Not evaluated \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">Transient weakness of intrinsic muscles of hand in 10% of sample (n=2) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2601085.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Main findings reported by the studies included in the systematic review." ] ] 5 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.pdf" "ficheroTamanyo" => 58591 ] ] 6 => array:5 [ "identificador" => "upi0010" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc2.pdf" "ficheroTamanyo" => 138924 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:22 [ 0 => array:3 [ "identificador" => "bib0115" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pathophysiology of systemic sclerosis: current understanding and new insights" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M. Cutolo" 1 => "S. Soldano" 2 => "V. Smith" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Expert Rev Clin Immunol" "fecha" => "2019" "paginaInicial" => "1" "paginaFinal" => "12" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0120" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The role of endothelial cells in the vasculopathy of systemic sclerosis: a systematic review" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Mostmans" 1 => "M. Cutolo" 2 => "C. Giddelo" 3 => "S. Decuman" 4 => "K. Melsens" 5 => "H. Declercq" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.autrev.2017.05.024" "Revista" => array:6 [ "tituloSerie" => "Autoimmun Rev" "fecha" => "2017" "volumen" => "16" "paginaInicial" => "774" "paginaFinal" => "786" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28572048" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0125" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Raynaud's phenomenon" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "F.M. Wigley" 1 => "N.A. Flavahan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMra1507638" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2016" "volumen" => "375" "paginaInicial" => "556" "paginaFinal" => "565" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27509103" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0130" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Systemic sclerosis: current concepts of skin and systemic manifestations" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "D.R. Pearson" 1 => "V.P. Werth" 2 => "L. Pappas-Taffer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.clindermatol.2018.04.004" "Revista" => array:6 [ "tituloSerie" => "Clin Dermatol" "fecha" => "2018" "volumen" => "36" "paginaInicial" => "459" "paginaFinal" => "474" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30047430" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0135" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Emerging targets of disease-modifying therapy for systemic sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "E.R. Volkmann" 1 => "J. Varga" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41584-019-0184-z" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Rheumatol" "fecha" => "2019" "volumen" => "15" "paginaInicial" => "208" "paginaFinal" => "224" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30796362" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0140" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Botulinum toxin A treatment of Raynaud's phenomenon: a review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M.L. Iorio" 1 => "D.L. Masden" 2 => "J.P. Higgins" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.semarthrit.2011.07.006" "Revista" => array:6 [ "tituloSerie" => "Semin Arthritis Rheum" "fecha" => "2012" "volumen" => "41" "paginaInicial" => "599" "paginaFinal" => "603" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21868066" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0145" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Botulinum toxin A in the treatment of Raynaud's phenomenon: a systematic review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "P. Zebryk" 1 => "M.J. Puszczewicz" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "AMS" "fecha" => "2016" "volumen" => "12" "paginaInicial" => "864" "paginaFinal" => "870" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0150" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The therapeutic efficacy of botulinum toxin in treating scleroderma-associated raynaud's phenomenon: a randomized, double-blind, placebo-controlled clinical trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.J. Bello" 1 => "C.M. Cooney" 2 => "E. Melamed" 3 => "K. Follmar" 4 => "G. Yenokyan" 5 => "G. Leatherman" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Arthritis Rheumatol (Hoboken, NJ)" "fecha" => "2017" "volumen" => "69" "paginaInicial" => "1661" "paginaFinal" => "1669" ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0155" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy of botulinum toxin b injection for Raynaud's phenomenon and digital ulcers in patients with systemic sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.I. Motegi" 1 => "A. Uehara" 2 => "K. Yamada" 3 => "A. Sekiguchi" 4 => "C. Fujiwara" 5 => "S. Toki" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2340/00015555-2665" "Revista" => array:6 [ "tituloSerie" => "Acta Derm Venereol" "fecha" => "2017" "volumen" => "97" "paginaInicial" => "843" "paginaFinal" => "850" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28358168" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0160" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A prospective study of the use of botulinum toxin injections in the treatment of Raynaud's syndrome associated with scleroderma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "L. Uppal" 1 => "K. Dhaliwal" 2 => "P.E. Butler" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/1753193413516242" "Revista" => array:6 [ "tituloSerie" => "J Hand Surg Eur Vol" "fecha" => "2014" "volumen" => "39" "paginaInicial" => "876" "paginaFinal" => "880" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24369360" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0165" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Beneficial effect of botulinum toxin A on Raynaud's phenomenon in Japanese patients with systemic sclerosis: a prospective, case series study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Motegi" 1 => "K. Yamada" 2 => "S. Toki" 3 => "A. Uchiyama" 4 => "Y. Kubota" 5 => "T. Nakamura" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/1346-8138.13030" "Revista" => array:6 [ "tituloSerie" => "J Dermatol" "fecha" => "2016" "volumen" => "43" "paginaInicial" => "56" "paginaFinal" => "62" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26173902" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0170" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Botulinum toxin type A contribution in the treatment of Raynaud's phenomenon due to systemic sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "J. Serri" 1 => "R. Legre" 2 => "V. Veit" 3 => "C. Guardia" 4 => "A.M. Gay" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.anplas.2011.11.001" "Revista" => array:6 [ "tituloSerie" => "Ann Chir Plast Esthet" "fecha" => "2013" "volumen" => "58" "paginaInicial" => "658" "paginaFinal" => "662" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22204894" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0175" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical applications of botulinum toxin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "D. Dressler" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.mib.2012.05.012" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Microbiol" "fecha" => "2012" "volumen" => "15" "paginaInicial" => "325" "paginaFinal" => "336" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22770659" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0180" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Botulinum toxin in the management of head and neck disorders" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "R. Nagi" 1 => "D.J. Patil" 2 => "S. Sahu" 3 => "S. Jain" 4 => "G.S. Naidu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.oooo.2016.11.009" "Revista" => array:6 [ "tituloSerie" => "Oral Surg Oral Med Oral Pathol Oral Radiol" "fecha" => "2017" "volumen" => "123" "paginaInicial" => "419" "paginaFinal" => "428" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28159584" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0185" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The therapeutic usage of botulinum toxin (Botox) in non-cosmetic head and neck conditions – an evidence based review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "K.H. Awan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jsps.2016.04.024" "Revista" => array:6 [ "tituloSerie" => "Saudi Pharm J" "fecha" => "2017" "volumen" => "25" "paginaInicial" => "18" "paginaFinal" => "24" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28223858" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0190" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Botulinum toxin: pharmacology and therapeutic roles in pain states" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Patil" 1 => "O. Willett" 2 => "T. Thompkins" 3 => "R. Hermann" 4 => "S. Ramanathan" 5 => "E.M. Cornett" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s11916-016-0545-0" "Revista" => array:5 [ "tituloSerie" => "Curr Pain Headache Rep" "fecha" => "2016" "volumen" => "20" "paginaInicial" => "15" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26879873" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0195" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Botulinum toxin for the treatment of neuropathic pain" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J. Park" 1 => "H.J. Park" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Toxins (Basel)" "fecha" => "2017" "volumen" => "9" "numero" => "9." ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0200" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Botulinum toxin for chronic pain conditions" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R. Kermen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.disamonth.2016.05.011" "Revista" => array:6 [ "tituloSerie" => "Dis Mon" "fecha" => "2016" "volumen" => "62" "paginaInicial" => "353" "paginaFinal" => "357" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27426886" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0205" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A vascular mechanistic approach to understanding Raynaud phenomenon" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "N.A. Flavahan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nrrheum.2014.195" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Rheumatol" "fecha" => "2015" "volumen" => "11" "paginaInicial" => "146" "paginaFinal" => "158" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25536485" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0210" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Points to consider-Raynaud's phenomenon in systemic sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M. Cutolo" 1 => "V. Smith" 2 => "D.E. Furst" 3 => "D. Khanna" 4 => "A.L. Herrick" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rheumatology (Oxford)" "fecha" => "2017" "volumen" => "56" "numero" => "Suppl. 5" "paginaInicial" => "v45" "paginaFinal" => "v48" ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0215" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cross-cultural adaptation of the disabilities of the arm, shoulder, and hand (DASH) questionnaire into Hungarian and investigation of its validity in patients with systemic sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Varju" 1 => "Z. Balint" 2 => "A.I. Solyom" 3 => "H. Farkas" 4 => "E. Karpati" 5 => "B. Berta" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Clin Exp Rheumatol" "fecha" => "2008" "volumen" => "26" "paginaInicial" => "776" "paginaFinal" => "783" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19032808" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0220" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Measures of hand function: Arthritis Hand Function Test (AHFT), Australian Canadian Osteoarthritis Hand Index (AUSCAN), Cochin Hand Function Scale, Functional Index for Hand Osteoarthritis (FIHOA), Grip Ability Test (GAT), Jebsen Hand Function Test (JHFT), and Michigan Hand Outcomes Questionnaire (MHQ)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J.L. Poole" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arthritis Care Res (Hoboken)" "fecha" => "2011" "volumen" => "63" "numero" => "Suppl. 11" "paginaInicial" => "S189" "paginaFinal" => "S199" ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/21735743/0000001700000006/v1_202105240506/S2173574321001039/v1_202105240506/en/main.assets" "Apartado" => array:4 [ "identificador" => "8383" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Review Article" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21735743/0000001700000006/v1_202105240506/S2173574321001039/v1_202105240506/en/main.pdf?idApp=UINPBA00004M&text.app=https://reumatologiaclinica.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574321001039?idApp=UINPBA00004M"]

Statistics

Review Article

Is Botulinum Toxin Useful in Systemic Sclerosis Related Peripheral Vasculopathy? A Literature Review

¿Es la toxina botulínica útil en la vasculopatía periférica de la esclerosis sistémica? Una revisión sistemática

Miguel Gomes Guerra

Corresponding author

mlgomesg@gmail.com

Corresponding author.

, Diogo Guimarães da Fonseca, Beatriz Samões, Taciana Videira, Patrícia Pinto

Rheumatology Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Rua Conceição Fernandes, 4434-502 Vila Nova de Gaia, Portugal

Read

2800

Times
was read the article

1162

Total PDF

1638

Total HTML

Share statistics

 array:23 [
  "pii" => "S2173574321001039"
  "issn" => "21735743"
  "doi" => "10.1016/j.reumae.2020.04.013"
  "estado" => "S300"
  "fechaPublicacion" => "2021-06-01"
  "aid" => "1417"
  "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46; and Sociedad Espa&#241;ola de Reumatolog&#237;a y Colegio Mexicano de Reumatolog&#237;a"
  "copyrightAnyo" => "2020"
  "documento" => "article"
  "crossmark" => 1
  "subdocumento" => "rev"
  "cita" => "Reumatol Clin. 2021;17:357-63"
  "abierto" => array:3 [
    "ES" => false
    "ES2" => false
    "LATM" => false
  ]
  "gratuito" => false
  "lecturas" => array:1 [
    "total" => 0
  ]
  "itemSiguiente" => array:18 [
    "pii" => "S2173574321001040"
    "issn" => "21735743"
    "doi" => "10.1016/j.reumae.2020.04.014"
    "estado" => "S300"
    "fechaPublicacion" => "2021-06-01"
    "aid" => "1427"
    "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46; and Sociedad Espa&#241;ola de Reumatolog&#237;a y Colegio Mexicano de Reumatolog&#237;a"
    "documento" => "simple-article"
    "crossmark" => 1
    "subdocumento" => "crp"
    "cita" => "Reumatol Clin. 2021;17:364-5"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:12 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Case Report</span>"
      "titulo" => "Remission of Rheumatoid Arthritis and Primary Biliary Cholangitis After Treatment With Tocilizumab"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "364"
          "paginaFinal" => "365"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Remisi&#243;n de artritis reumatoide y colangitis biliar primaria tras tratamiento con tocilizumab"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "es" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Soraia Azevedo, Joana Sousa-Neves, Joana Ramos Rodrigues, Daniela Peixoto, Jos&#233; Tavares-Costa, Filipa Teixeira"
          "autores" => array:6 [
            0 => array:2 [
              "nombre" => "Soraia"
              "apellidos" => "Azevedo"
            ]
            1 => array:2 [
              "nombre" => "Joana"
              "apellidos" => "Sousa-Neves"
            ]
            2 => array:2 [
              "nombre" => "Joana"
              "apellidos" => "Ramos Rodrigues"
            ]
            3 => array:2 [
              "nombre" => "Daniela"
              "apellidos" => "Peixoto"
            ]
            4 => array:2 [
              "nombre" => "Jos&#233;"
              "apellidos" => "Tavares-Costa"
            ]
            5 => array:2 [
              "nombre" => "Filipa"
              "apellidos" => "Teixeira"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574321001040?idApp=UINPBA00004M"
    "url" => "/21735743/0000001700000006/v1_202105240506/S2173574321001040/v1_202105240506/en/main.assets"
  ]
  "itemAnterior" => array:18 [
    "pii" => "S2173574321000988"
    "issn" => "21735743"
    "doi" => "10.1016/j.reumae.2019.09.005"
    "estado" => "S300"
    "fechaPublicacion" => "2021-06-01"
    "aid" => "1371"
    "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46; and Sociedad Espa&#241;ola de Reumatolog&#237;a y Colegio Mexicano de Reumatolog&#237;a"
    "documento" => "article"
    "crossmark" => 1
    "subdocumento" => "fla"
    "cita" => "Reumatol Clin. 2021;17:351-6"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:13 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>"
      "titulo" => "Clinical and sociodemographic factors associated with lupus nephritis in Colombian patients&#58; A cross-sectional study"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "351"
          "paginaFinal" => "356"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Factores cl&#237;nicos y sociodemogr&#225;ficos asociados a nefritis l&#250;pica en pacientes colombianos&#58; resultados de un estudio transversal"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "es" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:6 [
          "identificador" => "fig0005"
          "etiqueta" => "Fig&#46; 1"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr1.jpeg"
              "Alto" => 847
              "Ancho" => 1673
              "Tamanyo" => 75469
            ]
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Juan C&#46; D&#237;az-Coronado, Adriana Rojas-Villarraga, Deicy Hernandez-Parra, Laura Betancur-V&#225;squez, Jorge Lacouture-Fierro, Daniel Gonzalez-Hurtado, Juanita Gonz&#225;lez-Arango, Laura Uribe-Arango, Maria C&#46; Gaviria-Aguilar, Ricardo A&#46; Pineda-Tamayo"
          "autores" => array:10 [
            0 => array:2 [
              "nombre" => "Juan C&#46;"
              "apellidos" => "D&#237;az-Coronado"
            ]
            1 => array:2 [
              "nombre" => "Adriana"
              "apellidos" => "Rojas-Villarraga"
            ]
            2 => array:2 [
              "nombre" => "Deicy"
              "apellidos" => "Hernandez-Parra"
            ]
            3 => array:2 [
              "nombre" => "Laura"
              "apellidos" => "Betancur-V&#225;squez"
            ]
            4 => array:2 [
              "nombre" => "Jorge"
              "apellidos" => "Lacouture-Fierro"
            ]
            5 => array:2 [
              "nombre" => "Daniel"
              "apellidos" => "Gonzalez-Hurtado"
            ]
            6 => array:2 [
              "nombre" => "Juanita"
              "apellidos" => "Gonz&#225;lez-Arango"
            ]
            7 => array:2 [
              "nombre" => "Laura"
              "apellidos" => "Uribe-Arango"
            ]
            8 => array:2 [
              "nombre" => "Maria C&#46;"
              "apellidos" => "Gaviria-Aguilar"
            ]
            9 => array:2 [
              "nombre" => "Ricardo A&#46;"
              "apellidos" => "Pineda-Tamayo"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574321000988?idApp=UINPBA00004M"
    "url" => "/21735743/0000001700000006/v1_202105240506/S2173574321000988/v1_202105240506/en/main.assets"
  ]
  "en" => array:20 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Review Article</span>"
    "titulo" => "Is Botulinum Toxin Useful in Systemic Sclerosis Related Peripheral Vasculopathy&#63; A Literature Review"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "357"
        "paginaFinal" => "363"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Miguel Gomes Guerra, Diogo Guimar&#227;es da Fonseca, Beatriz Sam&#245;es, Taciana Videira, Patr&#237;cia Pinto"
        "autores" => array:5 [
          0 => array:4 [
            "nombre" => "Miguel Gomes"
            "apellidos" => "Guerra"
            "email" => array:1 [
              0 => "mlgomesg@gmail.com"
            ]
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor0005"
              ]
            ]
          ]
          1 => array:2 [
            "nombre" => "Diogo Guimar&#227;es da"
            "apellidos" => "Fonseca"
          ]
          2 => array:2 [
            "nombre" => "Beatriz"
            "apellidos" => "Sam&#245;es"
          ]
          3 => array:2 [
            "nombre" => "Taciana"
            "apellidos" => "Videira"
          ]
          4 => array:2 [
            "nombre" => "Patr&#237;cia"
            "apellidos" => "Pinto"
          ]
        ]
        "afiliaciones" => array:1 [
          0 => array:2 [
            "entidad" => "Rheumatology Department&#44; Centro Hospitalar Vila Nova de Gaia&#47;Espinho&#44; Rua Concei&#231;&#227;o Fernandes&#44; 4434-502 Vila Nova de Gaia&#44; Portugal"
            "identificador" => "aff0005"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author&#46;"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "&#191;Es la toxina botul&#237;nica &#250;til en la vasculopat&#237;a perif&#233;rica de la esclerosis sist&#233;mica&#63; Una revisi&#243;n sistem&#225;tica"
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 0
      "multimedia" => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1664
            "Ancho" => 1500
            "Tamanyo" => 130154
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flowchart of systematic review according to PRISMA guidelines&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Systemic sclerosis &#40;SSc&#41; is an orphan connective tissue disease where diffuse microangiopathy and immune system dysregulation result in collagen hyperproduction with skin and internal organs fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">1</span></a> Raynaud Phenomenon &#40;RP&#41; is a consequence of peripheral microvasculopathy&#44; triggered by endothelium dysfunction&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">1&#44;2</span></a> It is highly prevalent in SSc &#40;95&#37; of patients&#41; and consists on an episodic colour change of the extremities in response to cold exposure&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">3</span></a> Moreover&#44; it is typically the initial manifestation and precedes by years major organ involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">1</span></a> Digital ulcers &#40;DU&#41; are a serious consequence of SSc related vasculopathy&#46; They occur in up to 58&#37; of patients&#44; either in the diffuse or limited subtype&#46; With an extended time to healing&#44; DU may result in critical ischaemia and soft tissue&#47;bone infections&#44; thus demanding aggressive treatment&#46; Moreover&#44; they also point to a worse prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">As vascular injury performs a major role in SSc pathogenesis&#44; several treatment options focuses on it&#44; not only for RP and DU&#44; but also pulmonary arterial hypertension&#46; Nowadays&#44; calcium channel blockers&#44; prostacyclin analogues&#44; endothelin receptor antagonists and phosphodiesterase inhibitors are the main pharmacologic representatives to target this pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">5</span></a> Nevertheless&#44; in daily clinical practice&#44; RP and DU still pose a challenge for both physicians and patients&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">In the last two decades&#44; botulinum toxin &#40;BT&#41; has emerged as a nonsurgical treatment for vasospastic disease&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">6</span></a>Through local hand injections&#44; numerous reports showed an improvement in RP severity and DU healing&#44;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">6&#44;7</span></a> including in patients with SSc&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The aim of this review was to evaluate the available evidence concerning the use of BT in the treatment of SSc related RP&#47;DU&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Data source and search strategy</span><p id="par0025" class="elsevierStylePara elsevierViewall">A literature review was devised&#44; fitting the Preferred Reporting Items for Systematic reviews and Meta-Analyses &#40;PRISMA&#41; guidelines in order to identify all full-text manuscripts that focused on the use of BT in the treatment of SSc related RP&#47;DU&#46; The search was performed on Pubmed&#44; with the following MeSH terms&#58; &#8216;systemic sclerosis&#8217; and &#8216;botulinum toxin&#8217;&#44; with the boolean term &#8220;AND&#8221;&#46; No other keywords were added&#44; in order to avoid an excessively restrictive search string that would exclude studies of interest and result in an extremely low number of results&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The search was performed from database inception up to the 31st of May 2019&#46; No filters were added&#46;</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Screening process and selection criteria</span><p id="par0035" class="elsevierStylePara elsevierViewall">After the search&#44; MG and DF screened the records on 3 steps &#8211; title&#44; abstract and full-text level &#8211; to assess for inclusion&#46; A manual search through the references of the retained manuscripts was also performed in order to detect additional reports&#46; Records were considered eligible when both reviewers included them for the next step&#46; When opinions differed&#44; consensus was reached by discussion with the remaining investigators &#40;BS&#44; TV&#44; PP&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Manuscripts were selected considering the Population&#44; Intervention&#44; Comparison&#44; Outcome &#40;PICO&#41; strategy&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0045" class="elsevierStylePara elsevierViewall">Population&#58; Patients aged 18 or more years old&#44; with SSc related RP or DU refractory to standard of care&#46; Ideally&#44; studies should follow the 2013 American College of Rheumatology &#40;ACR&#41;&#47;European League Against Rheumatism &#40;EULAR&#41; and&#47;or 1980 ACR classification criteria&#46; Cohorts with broader samples that included SSc patients were also considered for inclusion&#59;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall">Intervention&#58; BT hand injection&#59;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0055" class="elsevierStylePara elsevierViewall">Comparison&#58; Ideally&#44; randomized control group of patients maintaining standard of care&#46; In the absence of a control group&#44; a statistical analysis comparing with baseline was considered the minimum&#59;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0060" class="elsevierStylePara elsevierViewall">Outcome&#58; for DU&#44; ulcer healing and development of new ulcers&#46; For RP&#44; Raynaud&#39;s Condition Score &#40;RCS&#41; or&#44; in alternative&#44; at least 1 Visual Analogue Scale &#40;VAS&#41;&#46; Occurrence and description of complications&#46;</p></li></ul></p><p id="par0065" class="elsevierStylePara elsevierViewall">Reviews&#44; letters&#44; editorials&#44; abstracts of scientific reunions and case series &#40;CS&#41; with less than 5 patients were rejected&#46; English&#44; French and Portuguese were the only 3 idioms accepted&#46; After screening&#44; manuscripts&#8217; data was systematized in a standardized electronic spreadsheet that included&#58; author&#44; year&#44; country&#44; study design&#44; SSc classification criteria&#44; sample size&#44; type of BT used&#44; injection protocol used &#40;including injection points and dose administered&#41;&#44; evaluated outcomes&#44; follow-up length&#44; adverse reactions&#44; statistical analysis performed and results&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Quality appraisal</span><p id="par0070" class="elsevierStylePara elsevierViewall">The studies selected through the screening process were assessed for quality appraisal by MG and DF using the National Institute of Health &#40;NIH&#41; tools for randomized control trials &#40;RCT&#41;&#44; case&#8211;control &#40;CC&#41; studies and CS&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><p id="par0075" class="elsevierStylePara elsevierViewall">Thirty results were obtained from the search through Pubmed&#46; No article was obtained by reference checking&#46; After the screening phase&#44; 5 reports were considered for the qualitative analysis &#40;see <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Ratings according to the NIH are presented in supplement 1&#46; Only 1 was considered as Good Quality&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Study design&#44; population and exclusion criteria</span><p id="par0080" class="elsevierStylePara elsevierViewall">Two of the retained articles were RCT and presented the largest samples&#44; 40<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> and 45<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a> patients &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Both used the American College of Rheumatology &#40;ACR&#41; 1980 and&#47;or ACR&#47;European League Against Rheumatism &#40;EULAR&#41; 2013 classification criteria&#46; Bello et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> applied the most rigorous exclusion criteria&#46; In comparison to Motegi et al&#46;&#44; 2017&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a> the first authors also selected a more suitable control group &#8211; the contralateral hand of each patient&#44; in a double-blinded design&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">The CC study<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a> failed to report on classification and exclusion criteria&#46; Despite this&#44; it followed a methodology similar to the one adopted by Bello et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> concerning the control group&#44; by using the patient&#39;s dominant hand&#44; but with no blinding process&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The 2 CS presented the smallest samples &#40;Motegi et al&#46;&#44; 2016<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a> with 10 patients&#44; Serri et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a> with 18 patients&#41;&#44; thus under-powering even more their conclusions&#46; One of them also didn&#8217;t report on classification criteria&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">As for current treatment&#44; there was disparity between studies&#46; All authors implemented BT as adjuvant treatment&#46; In 3 of them&#44; patients were included only if there were unsatisfying results with standard of care&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">9&#8211;11</span></a> Serri et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a> and Bello et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> on the contrary&#44; included patients irrespective of treatment response&#46; None of the 5 described clearly the previous treatment&#44; specifically which associations of vasodilators were used&#46; The same was verified concerning extra-articular manifestations&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Outcome measures</span><p id="par0100" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarizes the evaluated outcome measures&#46; RCS is a validated tool to assess the severity of RP&#59; however&#44; it was only applied in 3 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">8&#44;9&#44;11</span></a> Other tools used to evaluate this outcome were&#58; VAS of pain &#40;Pain-VAS&#41;&#44; skin temperature recovery time&#44; McCabe cold sensitivity score&#44; re-colouration time&#44; colour change VAS and cold intolerance VAS&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Laser Doppler imaging and Oxygen Saturation were performed by Bello et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> to objectively evaluate perfusion&#46; Serri et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a> on the other hand&#44; only used Oxygen Partial Pressure&#46; All included manuscripts evaluated the presence&#47;number of DU&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">As for hand function&#44; a high variety of measures were applied&#46; Motegi et al&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">9&#44;11</span></a> was the only that did not include hand function evaluation&#46; The &#8220;Disabilities of the Arm&#44; Shoulder and Hand&#8221; questionnaire &#40;DASH&#41; is a validated tool that evaluates upper limbs daily functionality&#44; and was used by Uppal et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a> Bello et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> and Serri et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a> opted for a simpler version&#44; the &#8220;Quick Disabilities of the Arm&#44; Shoulder and Hand&#8221; questionnaire &#40;QuickDASH&#41;&#46; Uppal et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a> also reported on pinch and power grip strength&#44; ranges of movement of hand joints&#44; hand span and Kapandji thumb opposition test&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Injection protocol</span><p id="par0115" class="elsevierStylePara elsevierViewall">Injection protocols differed between studies&#44; and even within the same study<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; From the 7 serotypes of BT existent&#44; 2 were used&#58; type A &#40;BT-A&#41; and type B &#40;BT-B&#41;&#46; Motegi et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a> were the only ones that used BT-B &#40;NeuroBloc&#174;&#41;&#46; As for the remaining 4 investigation groups&#44; all chose BT-A &#40;BOTOX&#174;&#41;&#59; Serri et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a> however&#44; used BT-A from 2 different suppliers &#40;BOTOX&#174; and X&#233;omin&#174;&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">Injection sites and units &#40;U&#41; administered were also highly heterogeneous&#46; Bello et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> was the only to adopt a dorsal side approach&#44; with the lowest dose of BT-A &#40;50<span class="elsevierStyleHsp" style=""></span>U per hand&#41;&#46; Motegi et al&#46;&#44; 2016<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a> opted to inject only the most symptomatic finger&#44; through the palmar side&#44; with a total of 20<span class="elsevierStyleHsp" style=""></span>U of BT-A&#46; Remaining authors followed a multiple injection procedure&#44; in the palmar side of hand&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">9&#44;10&#44;12</span></a> Uppal et al&#46; and Serri et al&#46; &#40;in one protocol&#41; also injected the palmar crease besides fingers&#8217; bases&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">10&#44;12</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Follow-up</span><p id="par0125" class="elsevierStylePara elsevierViewall">Timings of follow-up were heterogeneous&#46; Considering the potential time of effect of BT&#44; only the two RCT and 1 CS adopted a sufficient time lapse &#8211; up to 16 weeks&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">8&#44;9&#44;11</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Studies&#8217; findings</span><p id="par0130" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a> resumes the main findings of each report on RP&#44; perfusion&#44; DU&#44; hand function and complications&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Raynaud phenomenon</span><p id="par0135" class="elsevierStylePara elsevierViewall">Bello et al&#46; reported a statistically significant faster decline in RCS in the treatment group&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> In Motegi et al&#46;&#44; 2016&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a> RSC significantly reduced from 4 to 16 weeks after injection&#46; In Motegi et al&#46;&#44; 2017&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a> RCS in the group treated with 250<span class="elsevierStyleHsp" style=""></span>U was significantly lower than in the control group at week 4&#59; in the groups treated with 1000 and 2000<span class="elsevierStyleHsp" style=""></span>U BT-B&#44; values were significantly lower than those in control group and the group treated with 250<span class="elsevierStyleHsp" style=""></span>U BT-B at every follow-up check-point&#59; groups treated with 1000 and 2000<span class="elsevierStyleHsp" style=""></span>U BTX-B were comparable&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Peripheral perfusion</span><p id="par0140" class="elsevierStylePara elsevierViewall">Surprisingly&#44; the RCT with the largest sample<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> reported a statistically significant worse blood flow in BT treated arm from baseline to 1 month&#59; however&#44; this result was not verified in the period from baseline to 4 months&#46; No difference was found between groups on Oxygen Saturation&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Distinctly&#44; Serri et al&#46; reported an improvement on Oxygen Partial Pressure &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41; at the end of follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Digital ulcers</span><p id="par0150" class="elsevierStylePara elsevierViewall">Bello et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> found no significant differences between treatment and control groups&#44; neither concerning the risk of new ulcers&#44; nor changes over time in number of new ulcers&#46; In Motegi et al&#46;&#44; 2016&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a> half the sample &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41; presented DU at the beginning of follow-up&#59; after 16 weeks&#44; every patients&#8217; DUs had healed&#46; In Motegi et al&#46;&#44; 2017&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a> the numbers of DUs in the groups treated with 1000 and 2000<span class="elsevierStyleHsp" style=""></span>U were significantly lower than those in the control group 4&#8211;16 weeks after injection&#59; the same 2 groups had no new DU&#44; in comparison to 2 DU in the group treated with 250<span class="elsevierStyleHsp" style=""></span>U and 7 in the control group&#46; As for Serri et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a> 10 out of 18 patients had active DU at baseline &#40;median 4 DU per patient&#41;&#59; at the end of follow-up&#44; 100&#37; had healed&#46; In Uppal et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a> 75&#37; of the patients with DU &#40;3 out of 4&#41; had complete lesions&#8217; healing at the end of follow-up&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Hand function</span><p id="par0155" class="elsevierStylePara elsevierViewall">Of the 3 studies that evaluated hand function&#44;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">8&#44;10&#44;12</span></a> 2 reported positive results&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">10&#44;12</span></a> Serri et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a> found a significant improvement in the QuickDASH score&#46; In Uppal et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a> objective measures of hand functionality also showed improvement &#40;pinch grip&#44; power grip&#44; 2nd&#47;3rd metacarpophalangeal joint flexion&#41;&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Complications</span><p id="par0160" class="elsevierStylePara elsevierViewall">BT administration was mostly safe through all studies&#46; The only adverse reaction reported was weakness of hand&#39;s intrinsic muscles&#44; with a prevalence ranging between 0 and 16&#46;7&#37; &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; Considering all 5 studies&#44; only 8 out of 133 patients reported this adverse effect &#40;6&#46;0&#37;&#41;&#46; Moreover&#44; this was a transitory effect&#44; which reverted completely after the local effect of BT wore of&#46;</p></span></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Discussion</span><p id="par0165" class="elsevierStylePara elsevierViewall">BT first emerged in the 1970s in the treatment of strabismus&#44; as it prevents muscular contraction by inhibiting the release of acetylcholine in the neuromuscular junctions&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">13</span></a> This mechanism justifies most of the clinical indications of this neurotoxin&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">14&#44;15</span></a> However&#44; evidence suggests the additional role of pain transmission blockage &#40;for example&#44; substance P&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">16&#8211;18</span></a> BT also inhibits sympathetic adrenergic vasoconstriction and endothelial exocytosis of endothelin-1&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">19</span></a> through a dose-dependent mechanism&#44; hence justifying the increasing interest in vasospastic disorders&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Our search identified 2 RCT focusing on SSc-related RP&#47;DU&#46; Bello et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> presented the most precise study&#46; Unfortunately&#44; it showed the least impressive results and reported a worse blood flow in the treated arm&#46; However&#44; when comparing the units of BT&#44; lower values were administered &#40;<span class="elsevierStyleItalic">versus</span> &#40;10&#8211;12&#41;&#41;&#46; Considering that the vasodilating effects of BT are shown to be dose-dependent&#44; this might have contributed to the absence of positive results&#46; Despite this&#44; it still reported encouraging findings&#44; with faster decline in RCS in the BT treated arm&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">A direct comparison between RCT is unfeasible due to the use of different BT subtypes&#46; Motegi et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a> opted for BT-B instead of BT-A&#46; If one considers an equivalency of 1&#58;40&#44; the highest dose administered of BT-B in Motegi et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a> equalled the 50<span class="elsevierStyleHsp" style=""></span>U of BT-A in Bello et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> and still reported significantly better RCS&#47;pain&#47;skin temperature recovery&#46; However&#44; this equivalency ratio is not applicable to the vasodilator effect&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">13</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">The only CC included failed to report the selection criteria &#40;Both SSc classification criteria and exclusion criteria&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a> It focused mainly on hand function&#44; besides RP and DU&#44; and showed statistically significant improvements in pinch grip&#44; power grip&#44; DASH score and 2nd&#47;3rd metacarpophalangeal joints&#8217; flexion&#46; The 2 CS&#44;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">11&#44;12</span></a> despite the limitations&#44; showed significant improvement of numerous outcomes&#58; RCS&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a> pain&#44;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">11&#44;12</span></a> skin temperature recovery time&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a> hand function&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a> O<span class="elsevierStyleInf">2</span> partial pressure<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a> and DU complete healing&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">11&#44;12</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Concerning DU healing&#44; Motegi et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a> showed statistically significant results&#44; for 1000 and 2000<span class="elsevierStyleHsp" style=""></span>U of BT-B&#46; Bello et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> did not support this finding&#44; but all other studies reported positive results&#44; with complete DU healing in 75&#37;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a> to 100&#37;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">11&#44;12</span></a> of patients&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Future investigation in this area needs improvement&#46; For example&#44; BT achieves its maximal effect after 2 weeks and then gradually decreases for 2&#8211;3 months&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">13</span></a> Thus&#44; follow up time is of crucial importance when reporting results&#46; Only the 2 RCT and 1 CS included a sufficient time-period in their study&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">8&#44;9&#44;11</span></a> This aspect needs to be consistent while evaluating BT in SSc-related peripheral vasculopathy&#46; Environmental conditions must also be reported&#44; specifically daily minimum temperature&#46; Only Bello et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> adjusted statistical analysis to this confounding factor&#46; Other studies were performed during the Winter&#44;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">9&#44;11</span></a> when RP&#47;DU are more common and severe&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Another limitation is sample&#39;s selection&#46; Some authors did not report the classification criteria applied for patient selection&#44;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">10&#44;12</span></a> and one failed to present the exclusion criteria&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a> All of them administered BT as adjuvant measure&#46; This aspect greatly compromises the conclusions drawn&#44; especially because none of the 5 studies included a satisfactory description of baseline vasodilator medications&#46; Moreover&#44; none of the authors performed a description of systemic manifestations with enough accuracy&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">The injection protocol was also highly variable&#46; BT-A doses varied between 20<span class="elsevierStyleHsp" style=""></span>U&#47;finger and 100<span class="elsevierStyleHsp" style=""></span>U&#47;hand&#44;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">8&#44;10&#8211;12</span></a> and one study opted for BT-B&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a> Injection sites differed markedly&#44; with 1 group using a dorsal approach<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> and 2 injecting the palmar creases&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">10&#44;12</span></a> In the future&#44; researchers should focus mainly on only one BT type&#44; and perform similar injection procedures &#40;for example&#44; using the palmar approach&#44; but avoiding injecting the palmar crease&#44; because of a possible higher risk of muscle weakness<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a>&#41;&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Outcome measures must also be uniformized&#46; RCS is the only tool validated for RP assessment&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">20</span></a> Other possibilities to include are frequency&#47;duration of RF attacks and VAS of patient&#39;s and physician&#39;s assessment of RP activity&#46; DU&#44; namely the number of ulcers and development of new ulcers&#44; should be systematically reported&#46; Hand function assessment is a secondary outcome that can be included &#8211; DASH or QuickDASH questionnaires showed validity in SSc<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">21</span></a> but other tools are available&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">22</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">Previous reviews focusing on this subject have been performed&#44; with promising findings&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">7</span></a> However&#44; the studies included primary and secondary FP of different aetiologies&#44; thus invaliding conclusions concerning only SSc&#46; This has impact in daily clinical practice&#44; because the most severe cases of peripheral vasculopathy are typically associated to SSc&#46; In light to this scenario&#44; this review clarifies that BT can also claim a role in this population&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conclusion</span><p id="par0215" class="elsevierStylePara elsevierViewall">Despite not conclusive&#44; evidence suggests that BT has a position to claim in the treatment of SSc-related vasculopathy &#8211; it may not be necessarily an anchor therapy&#44; but an effective and safe adjuvant to the vasodilating drugs presently recommended in the treatment of RP&#47;DU&#46; However&#44; in face of conflicting results of one RCT&#44; more robust studies are needed to clarify its true efficacy&#44; as well as the optimal dose and injection protocol&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Key points</span><p id="par0220" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0225" class="elsevierStylePara elsevierViewall">Treatment of peripheral vasculopathy &#40;RP&#47;DU&#41; in SSc can pose a difficult challenge in clinical practice&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0230" class="elsevierStylePara elsevierViewall">BT&#44; through inhibition of sympathetic adrenergic vasoconstriction and endothelin-1&#44; has emerged as an alternative treatment in this scenario&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0235" class="elsevierStylePara elsevierViewall">Current evidence supports a positive effect of BT on RP severity and DU healing&#44; but is held back by several methodological limitations of the studies performed to date&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8226;</span><p id="par0240" class="elsevierStylePara elsevierViewall">Future investigation is required to further clarify the findings of this review&#44; especially the conflicting results of 1 RCT&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8226;</span><p id="par0245" class="elsevierStylePara elsevierViewall">For the moment&#44; BT can be considered an adjunctive in the treatment of refractory RP&#47;DU&#44; but not an anchor therapy&#46;</p></li></ul></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Contributions</span><p id="par0250" class="elsevierStylePara elsevierViewall">MG &#8211; Ideation of the study&#44; substantial contributions to the design of the study&#44; acquisition of data&#44; analysis and interpretation of data&#44; drafting of the article&#44; critical revision of the intellectual content&#44; final approval of the version to be published&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">DF &#8211; Acquisition of data&#44; substantial contributions to the design of the study&#44; acquisition of data&#44; analysis and interpretation of data&#44; critical revision of the intellectual content&#44; final approval of the version to be published&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">BS &#8211; Substantial contributions to the design of the study&#44; analysis and interpretation of data&#44; critical revision of the intellectual content&#44; final approval of the version to be published&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">TV &#8211; Ideation of the study&#44; substantial contributions to the design of the study&#44; critical revision of the intellectual content&#44; final approval of the version to be published&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">PP &#8211; Ideation of the study&#44; substantial contributions to the design of the study&#44; critical revision of the intellectual content&#44; final approval of the version to be published&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Funding</span><p id="par0275" class="elsevierStylePara elsevierViewall">No funding received&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Conflict of interest</span><p id="par0280" class="elsevierStylePara elsevierViewall">None to declare&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:14 [
        0 => array:3 [
          "identificador" => "xres1515133"
          "titulo" => "Abstract"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "abst0005"
              "titulo" => "Introduction"
            ]
            1 => array:2 [
              "identificador" => "abst0010"
              "titulo" => "Materials and methods"
            ]
            2 => array:2 [
              "identificador" => "abst0015"
              "titulo" => "Results"
            ]
            3 => array:2 [
              "identificador" => "abst0020"
              "titulo" => "Conclusion"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec1373939"
          "titulo" => "Keywords"
        ]
        2 => array:3 [
          "identificador" => "xres1515134"
          "titulo" => "Resumen"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "abst0025"
              "titulo" => "Introducci&#243;n"
            ]
            1 => array:2 [
              "identificador" => "abst0030"
              "titulo" => "Materiales y m&#233;todos"
            ]
            2 => array:2 [
              "identificador" => "abst0035"
              "titulo" => "Resultados"
            ]
            3 => array:2 [
              "identificador" => "abst0040"
              "titulo" => "Conclusi&#243;n"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec1373938"
          "titulo" => "Palabras clave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Materials and methods"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Data source and search strategy"
            ]
            1 => array:2 [
              "identificador" => "sec0120"
              "titulo" => "Screening process and selection criteria"
            ]
            2 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Quality appraisal"
            ]
          ]
        ]
        6 => array:3 [
          "identificador" => "sec0025"
          "titulo" => "Results"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Study design&#44; population and exclusion criteria"
            ]
            1 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Outcome measures"
            ]
            2 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Injection protocol"
            ]
            3 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Follow-up"
            ]
            4 => array:3 [
              "identificador" => "sec0050"
              "titulo" => "Studies&#8217; findings"
              "secciones" => array:5 [
                0 => array:2 [
                  "identificador" => "sec0055"
                  "titulo" => "Raynaud phenomenon"
                ]
                1 => array:2 [
                  "identificador" => "sec0060"
                  "titulo" => "Peripheral perfusion"
                ]
                2 => array:2 [
                  "identificador" => "sec0065"
                  "titulo" => "Digital ulcers"
                ]
                3 => array:2 [
                  "identificador" => "sec0070"
                  "titulo" => "Hand function"
                ]
                4 => array:2 [
                  "identificador" => "sec0075"
                  "titulo" => "Complications"
                ]
              ]
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0080"
          "titulo" => "Discussion"
        ]
        8 => array:2 [
          "identificador" => "sec0085"
          "titulo" => "Conclusion"
        ]
        9 => array:2 [
          "identificador" => "sec0090"
          "titulo" => "Key points"
        ]
        10 => array:2 [
          "identificador" => "sec0095"
          "titulo" => "Contributions"
        ]
        11 => array:2 [
          "identificador" => "sec0100"
          "titulo" => "Funding"
        ]
        12 => array:2 [
          "identificador" => "sec0105"
          "titulo" => "Conflict of interest"
        ]
        13 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2019-06-28"
    "fechaAceptado" => "2020-04-02"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1373939"
          "palabras" => array:4 [
            0 => "Systemic sclerosis"
            1 => "Raynaud phenomenon"
            2 => "Digital ulcer"
            3 => "Botulinum toxin"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1373938"
          "palabras" => array:4 [
            0 => "Esclerosis sist&#233;mica"
            1 => "Fen&#243;meno de Raynaud"
            2 => "&#218;lcera digital"
            3 => "Toxina botul&#237;nica"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">In systemic sclerosis &#40;SSc&#41;&#44; peripheral vasculopathy presents typically as Raynaud Phenomenon &#40;RP&#41; and Digital Ulceration &#40;DU&#41;&#46; Over the last decade&#44; botulinum toxin &#40;BT&#41; has been reported effective in this scenario&#46; Our goal was to review existing literature evaluating the efficacy of BT on RP&#47;DU in SSc&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We performed a search in Pubmed with the MeSH terms &#8220;systemic sclerosis&#8221; and &#8220;botulinum toxin&#8221;&#46; Original studies evaluating BT in the treatment of SSc-associated RP&#47;DU were considered for inclusion&#46; Results were screened by title&#44; abstract and full-text&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We identified 30 results&#44; of which 5 original papers were included&#58; 2 randomized controlled trials &#40;RCT&#41;&#44; 2 case series and 1 case control study&#44; from a total of 133 patients&#46; Only one RCT showed negative results&#44; with worse blood flow in treated arm&#44; but with lower dose of BT&#46; Despite this&#44; all 5 included studies reported improvement of at least 1 RP&#47;hand function outcome measure&#46; Concerning DU healing&#44; resolution of baseline DU at the end of follow-up was reported in 75&#8211;100&#37; of the patients&#44; with 1 RCT showing superiority over placebo&#46; The only reported adverse effect was transient hand weakness&#44; affecting only 0&#8211;16&#46;7&#37; of patients&#46; BT injection protocols were highly heterogeneous&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Despite conflicting results in 1 RCT&#44; evidence points BT as an option in the treatment of SSc-related peripheral vasculopathy&#46; However&#44; future larger prospective trials are necessary to corroborate this hypothesis&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Materials and methods"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusion"
          ]
        ]
      ]
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">En la esclerosis sist&#233;mica &#40;ES&#41;&#44; la vasculopat&#237;a perif&#233;rica se presenta normalmente como fen&#243;meno de Raynaud &#40;FR&#41; y ulceraci&#243;n digital &#40;UD&#41;&#46; En el &#250;ltimo decenio se ha reportado la efectividad de la toxina botul&#237;nica &#40;TB&#41; en este escenario&#46; Nuestro objetivo fue revisar la literatura existente que eval&#250;a la eficacia de la TB en el FR&#47;UD en la ES&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Materiales y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Realizamos una b&#250;squeda en Pubmed con los t&#233;rminos MeSH &#171;esclerosis sist&#233;mica&#187; y &#171;toxina botul&#237;nica&#187;&#46; Se consideraron para inclusi&#243;n los estudios originales que evaluaban la TB en el tratamiento del FR&#47;UD asociados a ES&#46; Se cribaron los resultados por t&#237;tulo&#44; resumen y texto completo&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Identificamos 30 resultados&#44; de los cuales se incluyeron 5 documentos originales&#58; 2 ensayos controlados aleatorizados &#40;ECA&#41;&#44; 2 series de casos y un estudio de control de caso&#44; de un total de 133 pacientes&#46; &#218;nicamente un ECA reflej&#243; resultados negativos con peor flujo sangu&#237;neo en el brazo tratado&#44; aunque con menor dosis de TB&#46; A pesar de ello&#44; los 5 estudios incluidos reportaron una mejora de al menos una medida del resultado FR&#47;funci&#243;n de la mano&#46; En cuanto a la sanaci&#243;n de la UD&#44; la resoluci&#243;n de la UD basal al final del seguimiento se report&#243; en el 75-100&#37; de los pacientes&#44; y un ECA reflej&#243; superioridad con respecto al placebo&#46; El &#250;nico efecto adverso reportado fue debilidad transitoria en la mano&#44; que afect&#243; &#250;nicamente al 0-16&#44;7&#37; de los pacientes&#46; Los protocolos de inyecci&#243;n de la TB fueron altamente homog&#233;neos&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A pesar de los resultados conflictivos en un ECA&#44; la evidencia apunta a la TB como opci&#243;n para el tratamiento de la vasculopat&#237;a perif&#233;rica asociada a la ES&#46; Sin embargo&#44; son necesarios ensayos prospectivos futuros m&#225;s amplios para corroborar esta hip&#243;tesis&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Introducci&#243;n"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Materiales y m&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusi&#243;n"
          ]
        ]
      ]
    ]
    "apendice" => array:1 [
      0 => array:1 [
        "seccion" => array:1 [
          0 => array:4 [
            "apendice" => "<p id="par0290" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia><elsevierMultimedia ident="upi0010"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0115"
          ]
        ]
      ]
    ]
    "multimedia" => array:7 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1664
            "Ancho" => 1500
            "Tamanyo" => 130154
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flowchart of systematic review according to PRISMA guidelines&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">ACR&#44; American College of Rheumatology&#59; BT&#44; Botulinum toxin&#59; CC&#44; Case control&#59; CS&#44; Case series&#59; EULAR&#44; European League Against Rheumatism&#59; RCT&#44; Randomized controlled trial&#46;</p>"
          "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"><th 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" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Country&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Study design&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Classification criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Exclusion criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Sample size&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Control group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bello et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a>&nbsp;\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">United States of America&nbsp;\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">Double blinded RCT&nbsp;\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">ACR 1980 or ACR&#47;EULAR 2013&nbsp;\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">Active infection&#44; acute digit ischaemia&#44; myasthenia gravis&#44; hypersensitivity to BT&#44; previous BT vaccine&#44; current use of aminoglycoside antibiotics&#44; prior upper extremity vascular surgery&#44; pregnancy&#44; lactation&nbsp;\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">40&nbsp;\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">Contralateral hand&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Motegi et al&#46;&#44; 2016<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a>&nbsp;\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">Japan&nbsp;\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">CS&nbsp;\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">ACR 1980 or ACR&#47;EULAR 2013&nbsp;\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">Previous treatment with BT&#44; pregnancy&nbsp;\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">10&nbsp;\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">Not applicable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Motegi et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a>&nbsp;\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">Japan&nbsp;\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">Single blinded RCT&nbsp;\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">ACR 1980 or ACR&#47;EULAR 2013&nbsp;\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">Previous treatment with BT&#44; pregnancy&nbsp;\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">45&nbsp;\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">8 randomly selected patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serri et al&#46;&#44; 2013<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a>&nbsp;\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">France&nbsp;\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">CS&nbsp;\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">Not reported&nbsp;\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">Hypersensitivity to BT&#44; pregnancy&#44; lactation&#44; radial&#47;ulnar artery occlusion&nbsp;\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&nbsp;\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">Not applicable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Uppal et al&#46;&#44; 2014<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a>&nbsp;\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">United Kingdom&nbsp;\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">CC&nbsp;\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">Not reported&nbsp;\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">Not reported&nbsp;\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&nbsp;\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">Dominant hand&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2601084.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Demographic characteristics of studies included in the systematic review&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">DASH&#44; disability of arm&#44; shoulder and hand questionnaire&#59; QuickDASH&#44; Quick Disabilities of the Arm&#44; Shoulder and Hand questionnaire&#59; DU&#44; digital ulcer&#59; RCS&#44; Raynaud&#39;s condition score&#59; VAS&#44; visual analogue scale&#46;</p>"
          "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"><th 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" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Raynaud&#39;s phenomenon&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Digital ulcers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Hand function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Perfusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Follow-up visit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bello et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a>&nbsp;\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">RCS&#44; Pain-VAS&#44; McCabe cold sensitivity score&nbsp;\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">Number of DU&nbsp;\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">QuickDASH&nbsp;\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">Change in blood flow measured with Laser Doppler Imaging&#59; pulse oximetry&nbsp;\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">Week 4 &#38; 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Motegi et al&#46;&#44; 2016<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a>&nbsp;\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">RCS&#44; Pain-VAS&#44; skin temperature recovery time after cold water stimulus&nbsp;\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">Number of DU&nbsp;\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">Not evaluated&nbsp;\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">Not evaluated&nbsp;\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">Week 2&#44; 4&#44; 8&#44; 12 &#38; 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Motegi et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a>&nbsp;\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">RCS&#44; Pain&#47;numbness-VAS&#44; skin temperature recovery time after cold water stimulus&nbsp;\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">Number of DU&nbsp;\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">Not evaluated&nbsp;\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">Not evaluated&nbsp;\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">Week 4&#44; 8&#44; 12 &#38; 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serri et al&#46;&#44; 2013<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a>&nbsp;\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">Pain VAS&#44; patient satisfaction scale&#44; re-colouration time&nbsp;\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">Number of DU&nbsp;\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">QuickDASH&nbsp;\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">Oxygen partial pressure&nbsp;\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">Week 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Uppal et al&#46;&#44; 2014<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a>&nbsp;\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">Pain VAS&#44; colour change VAS&#44; cold intolerance VAS&nbsp;\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">Presence of DU&nbsp;\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">Pinch&#47;power grip strength&#44; range of movement of hand joints&#44; hand span&#44; Kapandji thumb opposition test&#44; DASH&nbsp;\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">Not evaluated&nbsp;\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">Week 8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2601086.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Outcome measures of studies included in the systematic review&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">BT&#44; Botulinum toxin&#46;</p>"
          "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"><th 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" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Type of BT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Injection sites&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Units injected&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bello et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a>&nbsp;\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">A &#40;Botox&#174;&#41;&nbsp;\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">Dorsal surface in 7 points of hand&#58; 2nd&#44; 3rd&#44; and 4th web spaces&#44; radial side of the index finger base&#44; ulnar side of the small finger base&#44; and each side of the thumb base&nbsp;\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">50<span class="elsevierStyleHsp" style=""></span>U&#47;hand&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Motegi et al&#46;&#44; 2016<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a>&nbsp;\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">A &#40;Botox&#174;&#41;&nbsp;\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">2 injections proximally to A1 pulley of the most symptomatic finger of each hand&nbsp;\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">20<span class="elsevierStyleHsp" style=""></span>U&#47;finger&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Motegi et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a>&nbsp;\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">B &#40;NeuroBloc&#174;&#41;&nbsp;\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">Palmar surface in 6 points of hand&#58; web spaces&#44; radial side of the thumb base and ulnar side of the small finger base&nbsp;\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">3 groups&#58; 250<span class="elsevierStyleHsp" style=""></span>U&#47;hand&#59; 1000<span class="elsevierStyleHsp" style=""></span>U&#47;hand&#59; 2000<span class="elsevierStyleHsp" style=""></span>U&#47;hand&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serri et al&#46;&#44; 2013<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a>&nbsp;\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">A &#40;Botox&#44; X&#233;omin&#174;&#41;&nbsp;\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">2 protocols&#58; A with 14 palmar points of hand&#58; 2 at the base of each finger plus 4 in the palmar creases&#59; B with 18 palmar points of hand&#58; 2 at the base of each finger and 2 at the proximal extremity of second phalange of 2nd to 5th finger&nbsp;\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">100<span class="elsevierStyleHsp" style=""></span>U&#47;hand&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Uppal et al&#46;&#44; 2014<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a>&nbsp;\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">A &#40;Botox&#174;&#41;&nbsp;\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">Palmar surface&#44; at distal palmar crease&#44; in web spaces&#44; around digital neurovascular bundles of all 5 digits of the non-dominant hand &#40;number of points not reported&#41;&nbsp;\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">100<span class="elsevierStyleHsp" style=""></span>U&#47;hand&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2601087.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Injection protocols performed by each study&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">BT&#44; Botulinum toxin&#59; DASH&#44; disability of arm&#44; shoulder and hand questionnaire&#59; DU&#44; digital ulcer&#59; MCPJ&#44; Metacarpophalangeal joint&#59; RCS&#44; Raynaud&#39;s condition score&#59; VAS&#44; visual analogue scale&#46;</p>"
          "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"><th 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" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Raynaud&#39;s phenomenon&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Digital ulcers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Hand function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Perfusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Complications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bello et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a>&nbsp;\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">Faster decline of RCS in BT treated arm&nbsp;\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">No significant results&nbsp;\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">No significant results&nbsp;\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">Worse blood flow in BT treated arm at 4 weeks&nbsp;\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">Transient weakness of intrinsic muscles of hand in 5&#37; of sample &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Motegi et al&#46;&#44; 2016<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a>&nbsp;\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">Improvement in RCS&#44; pain-VAS and skin temperature recovery time&nbsp;\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">Complete healing of DU&nbsp;\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">Not evaluated&nbsp;\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">Not evaluated&nbsp;\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">Not found&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Motegi et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a>&nbsp;\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">RCS&#58;Lower in the 250<span class="elsevierStyleHsp" style=""></span>U-arm <span class="elsevierStyleItalic">vs</span> control at week 4&#59;Lower in the 1000<span class="elsevierStyleHsp" style=""></span>U and 2000<span class="elsevierStyleHsp" style=""></span>U arms <span class="elsevierStyleItalic">vs</span> control group and 250<span class="elsevierStyleHsp" style=""></span>U arm&#44; at weeks 4&#47;8&#47;12&#47;16&#46;Pain VAS&#58;Lower in the 250<span class="elsevierStyleHsp" style=""></span>U-arm <span class="elsevierStyleItalic">vs</span> control at week 8&#47;12&#59;Lower in the 1000<span class="elsevierStyleHsp" style=""></span>U and 2000<span class="elsevierStyleHsp" style=""></span>U arms <span class="elsevierStyleItalic">vs</span> control group&#44; at weeks 4&#47;8&#47;12&#47;16&#46;Skin temperature recovery&#58;Lower in the 2000<span class="elsevierStyleHsp" style=""></span>U-arm <span class="elsevierStyleItalic">vs</span> control and 250<span class="elsevierStyleHsp" style=""></span>U-arm at week 4&#46;&nbsp;\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">Lower number of DU in the 1000<span class="elsevierStyleHsp" style=""></span>U and 2000<span class="elsevierStyleHsp" style=""></span>U arms <span class="elsevierStyleItalic">vs</span> control group&#44; at week 4&#47;8&#47;12&#47;16&nbsp;\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">Not evaluated&nbsp;\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">Not evaluated&nbsp;\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">Transient weakness of intrinsic muscles of hand in 2&#46;2&#37; of sample &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serri et al&#46;&#44; 2013<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a>&nbsp;\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">Improvement in Pain-VAS&nbsp;\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">Complete healing of all DU&#44; without new ones&nbsp;\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">Improvement in QuickDASH score&nbsp;\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">Improvement in oxygen partial pressure&nbsp;\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">Transient weakness of intrinsic muscles of hand in 16&#46;7&#37; of sample &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Uppal et al&#46;&#44; 2014<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a>&nbsp;\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">No significant results&nbsp;\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">75&#37; of patients with DU with complete lesions&#8217; healing&nbsp;\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">Improvement in pinch grip&#44; power grip&#44; 2nd MCPJ flexion and 3rd MCPJ flexion&nbsp;\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">Not evaluated&nbsp;\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">Transient weakness of intrinsic muscles of hand in 10&#37; of sample &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2601085.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Main findings reported by the studies included in the systematic review&#46;</p>"
        ]
      ]
      5 => array:5 [
        "identificador" => "upi0005"
        "tipo" => "MULTIMEDIAECOMPONENTE"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Ecomponente" => array:2 [
          "fichero" => "mmc1.pdf"
          "ficheroTamanyo" => 58591
        ]
      ]
      6 => array:5 [
        "identificador" => "upi0010"
        "tipo" => "MULTIMEDIAECOMPONENTE"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Ecomponente" => array:2 [
          "fichero" => "mmc2.pdf"
          "ficheroTamanyo" => 138924
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:22 [
            0 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pathophysiology of systemic sclerosis&#58; current understanding and new insights"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "M&#46; Cutolo"
                            1 => "S&#46; Soldano"
                            2 => "V&#46; Smith"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Expert Rev Clin Immunol"
                        "fecha" => "2019"
                        "paginaInicial" => "1"
                        "paginaFinal" => "12"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The role of endothelial cells in the vasculopathy of systemic sclerosis&#58; a systematic review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46; Mostmans"
                            1 => "M&#46; Cutolo"
                            2 => "C&#46; Giddelo"
                            3 => "S&#46; Decuman"
                            4 => "K&#46; Melsens"
                            5 => "H&#46; Declercq"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.autrev.2017.05.024"
                      "Revista" => array:6 [
                        "tituloSerie" => "Autoimmun Rev"
                        "fecha" => "2017"
                        "volumen" => "16"
                        "paginaInicial" => "774"
                        "paginaFinal" => "786"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28572048"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0125"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Raynaud&#39;s phenomenon"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "F&#46;M&#46; Wigley"
                            1 => "N&#46;A&#46; Flavahan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMra1507638"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2016"
                        "volumen" => "375"
                        "paginaInicial" => "556"
                        "paginaFinal" => "565"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27509103"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Systemic sclerosis&#58; current concepts of skin and systemic manifestations"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "D&#46;R&#46; Pearson"
                            1 => "V&#46;P&#46; Werth"
                            2 => "L&#46; Pappas-Taffer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.clindermatol.2018.04.004"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Dermatol"
                        "fecha" => "2018"
                        "volumen" => "36"
                        "paginaInicial" => "459"
                        "paginaFinal" => "474"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30047430"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Emerging targets of disease-modifying therapy for systemic sclerosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "E&#46;R&#46; Volkmann"
                            1 => "J&#46; Varga"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/s41584-019-0184-z"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Rheumatol"
                        "fecha" => "2019"
                        "volumen" => "15"
                        "paginaInicial" => "208"
                        "paginaFinal" => "224"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30796362"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Botulinum toxin A treatment of Raynaud&#39;s phenomenon&#58; a review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "M&#46;L&#46; Iorio"
                            1 => "D&#46;L&#46; Masden"
                            2 => "J&#46;P&#46; Higgins"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.semarthrit.2011.07.006"
                      "Revista" => array:6 [
                        "tituloSerie" => "Semin Arthritis Rheum"
                        "fecha" => "2012"
                        "volumen" => "41"
                        "paginaInicial" => "599"
                        "paginaFinal" => "603"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21868066"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Botulinum toxin A in the treatment of Raynaud&#39;s phenomenon&#58; a systematic review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "P&#46; Zebryk"
                            1 => "M&#46;J&#46; Puszczewicz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "AMS"
                        "fecha" => "2016"
                        "volumen" => "12"
                        "paginaInicial" => "864"
                        "paginaFinal" => "870"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The therapeutic efficacy of botulinum toxin in treating scleroderma-associated raynaud&#39;s phenomenon&#58; a randomized&#44; double-blind&#44; placebo-controlled clinical trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;J&#46; Bello"
                            1 => "C&#46;M&#46; Cooney"
                            2 => "E&#46; Melamed"
                            3 => "K&#46; Follmar"
                            4 => "G&#46; Yenokyan"
                            5 => "G&#46; Leatherman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Arthritis Rheumatol &#40;Hoboken&#44; NJ&#41;"
                        "fecha" => "2017"
                        "volumen" => "69"
                        "paginaInicial" => "1661"
                        "paginaFinal" => "1669"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Efficacy of botulinum toxin b injection for Raynaud&#39;s phenomenon and digital ulcers in patients with systemic sclerosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;I&#46; Motegi"
                            1 => "A&#46; Uehara"
                            2 => "K&#46; Yamada"
                            3 => "A&#46; Sekiguchi"
                            4 => "C&#46; Fujiwara"
                            5 => "S&#46; Toki"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2340/00015555-2665"
                      "Revista" => array:6 [
                        "tituloSerie" => "Acta Derm Venereol"
                        "fecha" => "2017"
                        "volumen" => "97"
                        "paginaInicial" => "843"
                        "paginaFinal" => "850"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28358168"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A prospective study of the use of botulinum toxin injections in the treatment of Raynaud&#39;s syndrome associated with scleroderma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "L&#46; Uppal"
                            1 => "K&#46; Dhaliwal"
                            2 => "P&#46;E&#46; Butler"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/1753193413516242"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hand Surg Eur Vol"
                        "fecha" => "2014"
                        "volumen" => "39"
                        "paginaInicial" => "876"
                        "paginaFinal" => "880"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24369360"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Beneficial effect of botulinum toxin A on Raynaud&#39;s phenomenon in Japanese patients with systemic sclerosis&#58; a prospective&#44; case series study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Motegi"
                            1 => "K&#46; Yamada"
                            2 => "S&#46; Toki"
                            3 => "A&#46; Uchiyama"
                            4 => "Y&#46; Kubota"
                            5 => "T&#46; Nakamura"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/1346-8138.13030"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Dermatol"
                        "fecha" => "2016"
                        "volumen" => "43"
                        "paginaInicial" => "56"
                        "paginaFinal" => "62"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26173902"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Botulinum toxin type A contribution in the treatment of Raynaud&#39;s phenomenon due to systemic sclerosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "J&#46; Serri"
                            1 => "R&#46; Legre"
                            2 => "V&#46; Veit"
                            3 => "C&#46; Guardia"
                            4 => "A&#46;M&#46; Gay"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.anplas.2011.11.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Chir Plast Esthet"
                        "fecha" => "2013"
                        "volumen" => "58"
                        "paginaInicial" => "658"
                        "paginaFinal" => "662"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22204894"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical applications of botulinum toxin"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "D&#46; Dressler"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.mib.2012.05.012"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Microbiol"
                        "fecha" => "2012"
                        "volumen" => "15"
                        "paginaInicial" => "325"
                        "paginaFinal" => "336"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22770659"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Botulinum toxin in the management of head and neck disorders"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "R&#46; Nagi"
                            1 => "D&#46;J&#46; Patil"
                            2 => "S&#46; Sahu"
                            3 => "S&#46; Jain"
                            4 => "G&#46;S&#46; Naidu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.oooo.2016.11.009"
                      "Revista" => array:6 [
                        "tituloSerie" => "Oral Surg Oral Med Oral Pathol Oral Radiol"
                        "fecha" => "2017"
                        "volumen" => "123"
                        "paginaInicial" => "419"
                        "paginaFinal" => "428"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28159584"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The therapeutic usage of botulinum toxin &#40;Botox&#41; in non-cosmetic head and neck conditions &#8211; an evidence based review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "K&#46;H&#46; Awan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jsps.2016.04.024"
                      "Revista" => array:6 [
                        "tituloSerie" => "Saudi Pharm J"
                        "fecha" => "2017"
                        "volumen" => "25"
                        "paginaInicial" => "18"
                        "paginaFinal" => "24"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28223858"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Botulinum toxin&#58; pharmacology and therapeutic roles in pain states"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Patil"
                            1 => "O&#46; Willett"
                            2 => "T&#46; Thompkins"
                            3 => "R&#46; Hermann"
                            4 => "S&#46; Ramanathan"
                            5 => "E&#46;M&#46; Cornett"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s11916-016-0545-0"
                      "Revista" => array:5 [
                        "tituloSerie" => "Curr Pain Headache Rep"
                        "fecha" => "2016"
                        "volumen" => "20"
                        "paginaInicial" => "15"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26879873"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Botulinum toxin for the treatment of neuropathic pain"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46; Park"
                            1 => "H&#46;J&#46; Park"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Toxins &#40;Basel&#41;"
                        "fecha" => "2017"
                        "volumen" => "9"
                        "numero" => "9&#46;"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Botulinum toxin for chronic pain conditions"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "R&#46; Kermen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.disamonth.2016.05.011"
                      "Revista" => array:6 [
                        "tituloSerie" => "Dis Mon"
                        "fecha" => "2016"
                        "volumen" => "62"
                        "paginaInicial" => "353"
                        "paginaFinal" => "357"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27426886"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A vascular mechanistic approach to understanding Raynaud phenomenon"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "N&#46;A&#46; Flavahan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nrrheum.2014.195"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Rheumatol"
                        "fecha" => "2015"
                        "volumen" => "11"
                        "paginaInicial" => "146"
                        "paginaFinal" => "158"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25536485"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Points to consider-Raynaud&#39;s phenomenon in systemic sclerosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "M&#46; Cutolo"
                            1 => "V&#46; Smith"
                            2 => "D&#46;E&#46; Furst"
                            3 => "D&#46; Khanna"
                            4 => "A&#46;L&#46; Herrick"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Rheumatology &#40;Oxford&#41;"
                        "fecha" => "2017"
                        "volumen" => "56"
                        "numero" => "Suppl&#46; 5"
                        "paginaInicial" => "v45"
                        "paginaFinal" => "v48"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cross-cultural adaptation of the disabilities of the arm&#44; shoulder&#44; and hand &#40;DASH&#41; questionnaire into Hungarian and investigation of its validity in patients with systemic sclerosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Varju"
                            1 => "Z&#46; Balint"
                            2 => "A&#46;I&#46; Solyom"
                            3 => "H&#46; Farkas"
                            4 => "E&#46; Karpati"
                            5 => "B&#46; Berta"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Rheumatol"
                        "fecha" => "2008"
                        "volumen" => "26"
                        "paginaInicial" => "776"
                        "paginaFinal" => "783"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19032808"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Measures of hand function&#58; Arthritis Hand Function Test &#40;AHFT&#41;&#44; Australian Canadian Osteoarthritis Hand Index &#40;AUSCAN&#41;&#44; Cochin Hand Function Scale&#44; Functional Index for Hand Osteoarthritis &#40;FIHOA&#41;&#44; Grip Ability Test &#40;GAT&#41;&#44; Jebsen Hand Function Test &#40;JHFT&#41;&#44; and Michigan Hand Outcomes Questionnaire &#40;MHQ&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "J&#46;L&#46; Poole"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Care Res &#40;Hoboken&#41;"
                        "fecha" => "2011"
                        "volumen" => "63"
                        "numero" => "Suppl&#46; 11"
                        "paginaInicial" => "S189"
                        "paginaFinal" => "S199"
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/21735743/0000001700000006/v1_202105240506/S2173574321001039/v1_202105240506/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "8383"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Review Article"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/21735743/0000001700000006/v1_202105240506/S2173574321001039/v1_202105240506/en/main.pdf?idApp=UINPBA00004M&text.app=https://reumatologiaclinica.org/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574321001039?idApp=UINPBA00004M"
]

Article information

ISSN: 21735743
Original language: English

DOI:10.1016/j.reumae.2020.04.013

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	4	5	9
2024 October	34	25	59
2024 September	36	22	58
2024 August	65	49	114
2024 July	41	39	80
2024 June	55	35	90
2024 May	66	15	81
2024 April	45	26	71
2024 March	36	27	63
2024 February	46	23	69
2024 January	46	22	68
2023 December	25	31	56
2023 November	49	38	87
2023 October	34	35	69
2023 September	118	39	157
2023 August	104	19	123
2023 July	25	38	63
2023 June	31	45	76
2023 May	37	24	61
2023 April	33	20	53
2023 March	66	37	103
2023 February	37	33	70
2023 January	32	35	67
2022 December	57	36	93
2022 November	38	33	71
2022 October	67	39	106
2022 September	34	27	61
2022 August	33	31	64
2022 July	47	48	95
2022 June	38	36	74
2022 May	55	46	101
2022 April	39	29	68
2022 March	46	43	89
2022 February	39	42	81
2022 January	49	33	82
2021 December	30	34	64
2021 November	1	3	4

Show all

Indexed in:

Follow us:

Subscribe:

Statistics

Indexed in:

Follow us:

Subscribe:

Statistics

Subscribe to our newsletter