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    "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; 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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>"
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            ]
            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" => "xpalclavsec1372445"
          "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" => "xpalclavsec1372444"
          "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>
                  """
              ]
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                0 => "xTab2598329.png"
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          ]
        ]
        "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"
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        "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>
                  """
              ]
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                0 => "xTab2598327.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Outcome measures of studies included in the systematic review&#46;</p>"
        ]
      ]
      3 => array:8 [
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        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Table "
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        "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>
                  """
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          "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>"
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              "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>
                  """
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    "bibliografia" => array:2 [
      "titulo" => "References"
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          "identificador" => "bibs0015"
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                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"
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                      ]
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                        "paginaFinal" => "12"
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                    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:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Autoimmun Rev"
                        "fecha" => "2017"
                        "volumen" => "16"
                        "paginaInicial" => "774"
                        "paginaFinal" => "786"
                      ]
                    ]
                  ]
                ]
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                    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 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27509103"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
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                ]
              ]
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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
Autor para correspondencia
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
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    "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>"
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              "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" => "xpalclavsec1372445"
          "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" => "xpalclavsec1372444"
          "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>
                  """
              ]
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                0 => "xTab2598329.png"
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        ]
        "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"
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        "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>
                  """
              ]
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                0 => "xTab2598327.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Outcome measures of studies included in the systematic review&#46;</p>"
        ]
      ]
      3 => array:8 [
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        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Table "
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        "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