Large vessels vasculopathy in systemic sclerosis | Medicina Clínica (English Edition)

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"documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Med Clin. 2015;145:485-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "Editorial" "titulo" => "New therapeutic approaches in type 2 diabetes mellitus" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "485" "paginaFinal" => "487" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Nuevos planteamientos terapéuticos en la diabetes mellitus tipo 2" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Carles Zafon" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Carles" "apellidos" => "Zafon" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775315003012" "doi" => "10.1016/j.medcli.2015.05.008" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775315003012?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020616300250?idApp=UINPBA00004N" "url" => "/23870206/0000014500000011/v1_201604300039/S2387020616300250/v1_201604300039/en/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Large vessels vasculopathy in systemic sclerosis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "488" "paginaFinal" => "492" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Beatriz Tejera Segura, Iván Ferraz-Amaro" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Beatriz" "apellidos" => "Tejera Segura" "email" => array:1 [ 0 => "btejerasegura@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Iván" "apellidos" => "Ferraz-Amaro" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Reumatología, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Vasculopatía de grandes vasos en la esclerosis sistémica" ] ] "textoCompleto" => "IntroductionSystemic sclerosis (SSc) is a connective tissue disease characterized by excessive collagen and other extracellular matrix components deposition on different organs. In general, 3 components are involved in the pathogenesis of SSc: vascular, in which the endothelium plays a major role; fibrotic, fibroblasts and myofibroblasts dependent; and the immune system, in which lymphocytes and their mediators play a main role. Somehow, these 3 components are interconnected and are responsible for the disease development.<a class="elsevierStyleCrossRefs" href="#bib0295">1,2</a>Vascular involvement in SSc is a challenge for clinicians due to its high morbidity and mortality and the lack of effective treatment options when vasculopathy is present. It is important to distinguish the concept of vascular disease and vasculitis: vasculopathy encompasses any disease that affects a vessel, while vasculitis is the inflammatory disease of a vessel due to an impaired immune system. In this review we will focus primarily on two uncommon manifestations of scleroderma, such as the involvement of large vessels and non-digital ulcers. The rarity of large vessel involvement and the importance of a correct differential diagnosis justifies this review.Pathogenesis of vascular involvement in systemic sclerosisCurrently it is not known exactly what stimulus triggers vasculopathy in SSc. It is thought that different infectious agents could be involved, such as free radicals related to nitric oxide, endothelial cells antibodies or cytotoxic T cells. The point is that, from a precipitating factor a series of processes that result in changes that start in microcirculation and eventually end up in fibrosis are activated.<a class="elsevierStyleCrossRefs" href="#bib0295">1–3</a>This series of alterations can be summarized as follows: microcirculation impairment, endothelial dysfunction and pericyte involvement, abnormal angiogenesis and vasculogenesis, chronic activation of platelets and maintained vasoconstriction.Impairment of microcirculationThe earliest, most frequent and severe SSc clinical manifestations, with increased morbidity and mortality, are the ones that result from changes in microcirculation. Hair loss and altered capillary structure: the basement membrane is thickened, the endothelial cells of the capillary wall increase in size and there is a loss of intercellular junctions so gaps are formed, vacuolization of the cytoplasm occurs and plasmalemma vesicles are lost. Parallel to all this process, intimal proliferation occurs by accumulation of proteoglycans in arteries and arterioles.<a class="elsevierStyleCrossRefs" href="#bib0305">3–7</a>Endothelial dysfunction and impaired pericytesEndothelial damage occurs early in the SSc. Endothelial dysfunction triggers such an imbalance of vasoactive molecules that vasoconstrictors increase and vasodilators decrease. Increased von Willebrand factor in plasma as well as endothelin-1 point to endothelial dysfunction indicators. The increase in both results in platelet aggregation and vasoconstriction, which in turn produces continuous platelet adhesion and fibrin accumulation.<a class="elsevierStyleCrossRef" href="#bib0300">2</a> This contributes to an intravascular thrombus formation.<a class="elsevierStyleCrossRefs" href="#bib0295">1,8–10</a> On the other hand, it is not clear that this process is associated to an apoptotic phenomenon affecting the endothelial cell, resulting in phagocytosis by antigen presenting cells and cytotoxic T lymphocytes exposure. Thus, an alternative complement and coagulation pathway favouring thrombus formation would be activated.<a class="elsevierStyleCrossRefs" href="#bib0340">10–12</a>Pericytes are contractile cells that wrap around the endothelial cells of capillaries and venules. They regulate vascular maturation and stabilization during angiogenesis. They express cytokines such as the β receptor of the platelet-derived growth factor and the melanoma associated antigen of high molecular weight. Elevated levels of these cytokines have been observed in patients with SSc, Raynaud's phenomenon and vascular lesions. In addition, pericytes can be differentiated to smooth muscle cells, fibroblasts and myofibroblasts, contributing to increase the thickness of the capillary.<a class="elsevierStyleCrossRefs" href="#bib0355">13,14</a>Impaired angiogenesis and vasculogenesisAngiogenesis is the formation of new blood vessels from pre-existing vessels. It depends on the activation, proliferation and migration of endothelial cells. It is caused by a stimulus that induces proteolytic enzymes that break the extracellular matrix. The loss of capillaries and small vessels in scleroderma patients suggests a defect in the angiogenesis process, due to the increase of proangiogenic and antiangiogenic agents.<a class="elsevierStyleCrossRefs" href="#bib0295">1,15</a>Vasculogenesis is the formation of a vessel from stem cells and its role in SSc is not so clear. Stem cells migrate to where there has been endothelial damage, but there is no optimal differentiation mechanism for these new endothelial cells to repair the damage.<a class="elsevierStyleCrossRefs" href="#bib0370">16–19</a> This fact shows that there may be a defect in these patients vasculogenesis.Chronic platelet activation and impaired platelet aggregationA release of vasoactive agents that induce permanent vasoconstriction occurs. This leads to a proliferation of intimal and smooth muscle cells and, eventually, fibrosis.<a class="elsevierStyleCrossRef" href="#bib0390">20</a> In summary, obliterative vasculopathy combined with progressive fibrosis occurs in the SSc. It can affect capillaries, arterioles and, less frequently, medium and large calibre vessels.Clinical manifestations of vasculopathy in systemic sclerosisRaynaud's phenomenon and digital ulcersThe typical clinical manifestations of impaired microcirculation include Raynaud's phenomenon, telangiectasia, linear subungual bleeding or “splinter” haemorrhage and ulcer, as the most severe manifestation.Raynaud's phenomenon is a transient, reversible vasospasm, triggered by cold, stress or spontaneous appearance. It is characterized by three phases: pallor, cyanosis and hyperaemia. It affects the acral areas and can be asymmetrical. Its prevalence in the general population is less than 10%, however, in patients with SSc, the prevalence increases to 90%.<a class="elsevierStyleCrossRef" href="#bib0300">2</a> If Raynaud's phenomenon is maintained over time, digital ulcer appears.The digital ulcer in SSc is defined as an ischaemic-necrotic lesion with loss of dermoepidermal tissue substance located in the palmar surface of the fingers, distal to the proximal interphalangeal joint.<a class="elsevierStyleCrossRefs" href="#bib0395">21,22</a> These ulcers can be active (less than 6 months) or chronic (more than 6 months). It is essential to consider certain aspects such as edges, size, bed, tissue exposure and the presence of subcutaneous calcinosis. The most important risk factor for its development is a maintained and refractory to treatment Raynaud.<a class="elsevierStyleCrossRef" href="#bib0300">2</a> In different studies with cohorts of SSc patients, it has been observed that other risk factors for developing digital ulcers are: male sex, presence of pulmonary hypertension and/or decreased diffusion, diffuse type systemic scleroderma, long term disease progression, presence of scl-70 antibody and smoking.<a class="elsevierStyleCrossRefs" href="#bib0405">23,24</a>The association between anticardiolipin antibodies and digital ischaemia has been researched, with conflicting data. Herrick et al.,<a class="elsevierStyleCrossRef" href="#bib0415">25</a> found no difference in the prevalence of anticardiolipin antibodies in patients with SSc and ischaemic ulcers (11/31) compared with those who did not present these conditions (16/31).Nor did they find any differences among patients who required amputation (5/13) and those that didn’t (22/55). However, in the Boin et al.<a class="elsevierStyleCrossRef" href="#bib0420">26</a> study, a positive correlation between anti-beta2-glycoprotein antibodies (specifically IgA subtype) and digital ischaemia was observed.Almost 60% of the patients with SSc develop an ulcer throughout their illness. 30% of cases correspond to ulcers with loss of soft tissue or bone and 11% of cases have digital gangrene at 7 years of follow-up. It is noteworthy that 25% of patients with SSc have 2 or more digital ulcers in the first visit, that is, even before being diagnosed.<a class="elsevierStyleCrossRefs" href="#bib0300">2,27–29</a>Non digital ulcersAlthough the prevalence of digital ulcers is well documented, this is not the case with non-digital ulcers. However, since the last century, case series highlighting the impact of these on morbidity and mortality of patients with SSc have been published.<a class="elsevierStyleCrossRef" href="#bib0440">30</a>In the general population, the most frequent causes are non-digital ulcers with venous involvement (70%), followed by arterial (15%) and mixed cause (10%), for example by diabetes. Instead, the aetiology of non-digital ulcers in patients with SSc are mostly by arterial involvement and appear on extensor surfaces and bony prominences (metacarpophalangeal joints, proximal interphalangeal joints, elbows, ankles, pretibial and forefoot regions). Lower extremity ulcers are often extensive, making it necessary to perform a differential diagnosis in those of vasculitic origin.<a class="elsevierStyleCrossRef" href="#bib0300">2</a> Also, areas where there is subcutaneous calcinosis are more likely to ulcerate.While vasospasm plays a fundamental role in the digital ulcers themselves, in the case of non-digital ulcers, repeated microtrauma is the main risk factor in areas of chronic contracture and atrophic skin. Others are thinning of the skin, loss of elasticity and peripheral neurological impairment that hinders tissue regeneration and repair, which results in chronic ulcers, making them more vulnerable to infection. These ulcers respond less well to treatment with vasodilating agents compared to distal location ones.In a recent publication by Shanmugam et al.,<a class="elsevierStyleCrossRef" href="#bib0440">30</a> 249 cases of patients with limited and diffuse SSc were reviewed. Non digital ulcer was defined as a lower extremity dermoepidermal lesion, of more than 3 months’ progression, which has not improved despite standard treatment. The prevalence of non-digital and lower limbs ulcers was 4% (n=10). Seven patients had bilateral ulcers and 3 unilateral. Ulcer biopsy was performed in 50% of cases and fibrosis stood out histologically. None was compatible with vasculitis. An autoimmune genetic study was requested and it was observed that patients with non-digital ulcer had heterozygous or homozygous mutation for gene MTHFR-C677T (methylene tetrahydrofolate reductase gene, enzyme involved in clotting) and positive antiphospholipid antibodies (without meeting the criteria for antiphospholipid syndrome). However, it is a study with only a few patients and would require a larger sample size to confirm this finding.Furthermore, Youssef et al.,<a class="elsevierStyleCrossRef" href="#bib0445">31</a> compared the prevalence of large vessel involvement (diagnosed by the absence of peripheral pulses in the physical examination, angiography or ultrasound Doppler) of 31 patients with limited SSc relative to a control group adjusted for age, sex and cardiovascular risk factors, observing that the prevalence of macrovascular disease was higher in the group of patients with limited SSc (58% versus 9%). However, no differences were found in the prevalence of coronary and cerebrovascular disease in any of the 2 groups.In turn, there are also cases of proximal vessel involvement in upper limbs, mainly the ulnar artery. Through arteriography, Hasegawa et al.,<a class="elsevierStyleCrossRef" href="#bib0450">32</a> evaluated the prevalence of large vessel involvement in the upper and lower limbs in 8 patients with SSc and ulcers. Macrovascular upper limb involvement was higher than the lower limbs (7/5). The vessels affected in the upper limbs were the ulnar and radial arteries, while in the lower they were the posterior tibial, the arcuate and the pedia arteries. The palmar and plantar arches were also affected. In another study,<a class="elsevierStyleCrossRef" href="#bib0455">33</a> with a larger sample size (20 patients with SSc), a Doppler ultrasound was performed, with the ulnar artery showing a narrower arterial lumen and an increased wall thickness compared to the control group, although no significant differences were found with other vessels.In short, virtually all the vascular system of patients with SSc may be affected. All the studies conducted advocate the use of angiography for the diagnosis and early revascularization, if possible.<a class="elsevierStyleCrossRefs" href="#bib0460">34,35</a>Arteriosclerosis and systemic sclerosisIn recent years, in other autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, an increase in ischaemic macrovascular diseases has been described, probably related to accelerated atherosclerosis connected to the underlying inflammation. It seems that this very fact may occur in patients with SSc.<a class="elsevierStyleCrossRef" href="#bib0470">36</a> Emad et al.<a class="elsevierStyleCrossRef" href="#bib0475">37</a> described that out of 22 scleroderma patients who underwent CT angiography, 3 of them showed subclavian artery involvement, 5 brachial artery involvement and 4 radial artery involvement. Radiographic abnormalities appear to be of different types, including vascular attenuation patterns, intimal irregularities of the vessels or focal and proximal occlusions. No angiographic differences were found in this report in connection with limited or diffuse SSc. The only clinical manifestation of the disease that showed association with these vascular changes was pulmonary hypertension, however, this is not described when the origin of these changes is arteriosclerotic, inflammatory, vasculitic or otherwise. Park et al.,<a class="elsevierStyleCrossRef" href="#bib0480">38</a> retrospectively describe the findings observed in the ulnar artery by arteriography. The authors observed that the artery involvement by angiography was frequent and note that although they have no etiopathogenic explanation for these changes, patients with pathological angiograms did not differ in respect to cardiovascular risk factors compared to those without them.Both morphological and endothelial dysfunction ultrasound studies after an ischaemic stimulus also confirm the presence of macrovascular disease in SSc. In this regard, Rosato et al.,<a class="elsevierStyleCrossRef" href="#bib0485">39</a> describe ultrasound palmar artery pathological patterns in 36 patients with SSc compared with 20 controls. However, this involvement was not related to the presence of digital ulcers. Bartoli et al.,<a class="elsevierStyleCrossRef" href="#bib0490">40</a> described a greater brachial endothelial dysfunction after ischaemic stimulus and a larger carotid intima-media thickness in 35 SSc patients compared to controls. This difference remained statistically significant when adjusted for traditional cardiovascular risk factors.Also, using an ultrasound method that determines vascular elasticity coupled to a walk test in patients with SSc, significantly poorer carotid “biomechanical” properties have been described.<a class="elsevierStyleCrossRef" href="#bib0495">41</a> The evidence seems to be maintained when other indirect methods of macrovascular disease are used, such as the ankle-brachial index. Thus, Zeng et al.,<a class="elsevierStyleCrossRef" href="#bib0500">42</a> in a series of 48 patients with SSc, describe a higher prevalence of pathologic ankle-brachial index when compared with 46 controls without disease. Also Ho et al.,<a class="elsevierStyleCrossRef" href="#bib0505">43</a> show a higher prevalence of macrovascular disease using this indirect method in 54 patients with SSc and 43 controls. In the latter study, a carotid ultrasound was also performed to measure the intima-media thickness with a statistically significant relationship for increased subclinical carotid atherosclerosis in patients with SSc.On the other hand, it seems that patients with SSc have a higher prevalence of intermittent claudication. Thus, in a study using the WHO-Rose questionnaire to measure arterial disease of the lower limbs, its presence was observed in 53 patients with SSc compared to 43 controls,<a class="elsevierStyleCrossRef" href="#bib0510">44</a> recommending the screening of intermittent claudication in cases of SSc.We only found two studies in the literature that do not support the presence of atherosclerotic macrovascular disease in SSc. The first one<a class="elsevierStyleCrossRef" href="#bib0515">45</a> is a cross-sectional study in which carotid ultrasound was used to measure the intima-media thickness in 49 scleroderma patients and 32 controls; the second,<a class="elsevierStyleCrossRef" href="#bib0520">46</a> also a cross-sectional study in which the brachial dilation by ischaemic stimulus was determined for 36 patients with primary Raynaud's phenomenon, 42 scleroderma patients and 33 controls. In both studies, a higher prevalence of macrovascular disease was found even after performing a multivariate analysis adjusted for classic cardiovascular risk factors.VasculitisThe involvement of large vessels can also result from a systemic vasculitis. The differential diagnosis between vascular disease and vasculitis poses a diagnostic challenge if there is no histological study. Vasculitis in SSc is rare but not unlikely. In 58 autopsies performed to patients with SSc, vascular disease was observed in 24% versus 9% of vasculitis, but vascular disease coexisted with vasculitis in 5 out of 8 tissue biopsies corresponding to a digital amputation.<a class="elsevierStyleCrossRefs" href="#bib0525">47,48</a> Kao and Weyand<a class="elsevierStyleCrossRef" href="#bib0535">49</a> describe various types of vasculitis associated with SSc. The most common is the ANCA-positive vasculitis, particularly with perinuclear fluorescein pattern (p-ANCA). The following is a summary of the most important aspects.<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">(a)Temporal arteritis and Takayasu vasculitis.</li></ul>3 cases of temporal arteritis have been described in women with an average age of 60 and limited SSc. The clinical manifestations were the typical ones for this disease, except for a case that developed a lower extremity ulcer and normal erythrocyte sedimentation rate. A temporal artery biopsy was performed in all cases, confirming the diagnosis. Glucocorticoids were used as treatment and the outcome was favourable.<a class="elsevierStyleCrossRef" href="#bib0535">49</a>Takayasu vasculitis was described in 4 patients with diffuse and limited SSc. The presentation was similar to that of the general population with the exception of 2 cases, where age of presentation was over 40. There was no biopsy, so the question remains whether it was a Takayasu vasculitis or vascular involvement in SSc. The authors do not provide any data on the treatment used.<a class="elsevierStyleCrossRef" href="#bib0535">49</a><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010">(b)Vasculitis of medium and small vessel.</li></ul>Polyarteritis nodosa manifested in a patient with diffuse SSc in the form of nodular lesions in the lower limbs. The patient had no constitutional syndrome characteristic of polyarteritis nodosa nor involvement of other organs or multiple mononeuritis. Vasculitis was confirmed by histological study. Methotrexate treatment was used subcutaneously (dose of 20 mg/wk) and glucocorticoids. The progression was favourable. There are 4 other cases of polyarteritis nodosa in medical literature whose initial manifestation was multiple mononeuritis<a class="elsevierStyleCrossRefs" href="#bib0540">50–52</a> and one case also associated with Sjögren's syndrome.<a class="elsevierStyleCrossRef" href="#bib0550">52</a>There are also cases CNS vasculitis and mixed cryoglobulinemia.<a class="elsevierStyleCrossRefs" href="#bib0535">49,53,54</a>ANCA-positive vasculitis is the most common by far, p-ANCA vasculitis to be more precise. Of the 88 cases of vasculitis described in the article by Kao and Weyand,<a class="elsevierStyleCrossRef" href="#bib0535">49</a> 74 correspond to p-ANCA vasculitis, specific for the myeloperoxidase antigen. This vasculitis was observed in both the diffuse SSc as well as the limited, though it was more prevalent in the first. Renal involvement in the form of glomerulonephritis was the most common form of presentation. In recent years, cases of vasculitis of medium and small vessel associated with SSc have been reported,<a class="elsevierStyleCrossRefs" href="#bib0560">54–56</a> which stresses the importance of taking their diagnosis into account in the case of these patients.ConclusionsMacrovascular disease in the SSc may have a severe outcome unless it is diagnosed early. It is essential to conduct a thorough case history emphasizing the presence of cardiovascular risk factors and symptoms and/or signs suggestive of vasculopathy or vasculitis. On physical examination, all peripheral pulses should be palpated, performing the Allen, the Adson and the hyperabduction tests, which will help in assessing the patency of the radial and ulnar artery and the presence of vascular or neural compression. Doppler ultrasound and angiography will help in determining the degree of vascular involvement and, if possible, revascularization by angioplasty. Lab tests with screening for vasculitis are also necessary, and if in doubt, a tissue biopsy is a choice procedure to reach a definitive diagnosis. The diagnosis of one or the other is as complicated as essential, as the therapeutic approach is far from similar. Treatment depends on the degree of vascular involvement and the cause behind it.In the case of digital ulcers, non-pharmacological and pharmacological measures (antiplatelet and vasodilator agents) should be taken into account.<a class="elsevierStyleCrossRef" href="#bib0575">57</a> Non-digital ulcers are often refractory to conventional treatment and very painful, so the analgesic treatment should be adequate and revascularization should always be considered as first choice in these patients. Surgical sympathectomy could be an alternative when revascularization is not possible, although not always effective.<a class="elsevierStyleCrossRef" href="#bib0580">58</a> Antibiotic treatment of superinfected lesions to prevent osteomyelitis and sepsis is also paramount. If there is an underlying vasculitis, this should be treated urgently to prevent a fatal outcome.SSc is a rare disease among the connective tissue diseases and this complicates conducting clinical trials, and therefore, researching the pathogenesis of vascular involvement and developing new therapies. It is important to know each and every one of the different manifestations of macrovascular disease, as these may vary in each patient, hindering diagnosis and early treatment. However, with what has been published so far, there is enough data to enable us to approach the correct diagnosis.Conflict of interestsThe authors declare no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres632579" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec645273" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres632580" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec645272" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Pathogenesis of vascular involvement in systemic sclerosis" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Impairment of microcirculation" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Endothelial dysfunction and impaired pericytes" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Impaired angiogenesis and vasculogenesis" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Chronic platelet activation and impaired platelet aggregation" ] ] ] 6 => array:3 [ "identificador" => "sec0035" "titulo" => "Clinical manifestations of vasculopathy in systemic sclerosis" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Raynaud's phenomenon and digital ulcers" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Non digital ulcers" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Arteriosclerosis and systemic sclerosis" ] 3 => array:2 [ "identificador" => "sec0055" "titulo" => "Vasculitis" ] ] ] 7 => array:2 [ "identificador" => "sec0060" "titulo" => "Conclusions" ] 8 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflict of interests" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-09-30" "fechaAceptado" => "2014-12-11" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec645273" "palabras" => array:3 [ 0 => "Systemic sclerosis" 1 => "Vasculopathy" 2 => "Large vessels" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec645272" "palabras" => array:3 [ 0 => "Esclerosis sistémica" 1 => "Vasculopatía" 2 => "Gran vaso" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Vasculopathy in systemic sclerosis is a severe, in many cases irreversible, manifestation that can lead to amputation. While the classical clinical manifestations of the disease have to do with the involvement of microcirculation, proximal vessels of upper and lower limbs can also be affected. This involvement of large vessels may be related to systemic sclerosis, vasculitis or atherosclerotic, and the differential diagnosis is not easy. To conduct a proper and early diagnosis, it is essential to start prompt appropriate treatment. In this review, we examine the involvement of large vessels in scleroderma, an understudied manifestation with important prognostic and therapeutic implications." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La vasculopatía en la esclerosis sistémica es una manifestación grave, y en muchas ocasiones irreversible, que puede llevar a la amputación. Si bien las manifestaciones clínicas clásicas de la enfermedad tienen que ver con la afectación de la microcirculación, también los vasos proximales de extremidades superiores e inferiores pueden afectarse. Esta afectación de grandes vasos puede tener un origen relacionado con la esclerosis sistémica, vasculítico o arteriosclerótico por lo que llegar al diagnóstico no es fácil pero sí fundamental para empezar cuanto antes un tratamiento adecuado. En esta revisión repasamos la afectación de los grandes vasos en la esclerosis sistémica, manifestación poco estudiada y con importantes repercusiones pronósticas y terapéuticas." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Tejera Segura B, Ferraz-Amaro I. Vasculopatía de grandes vasos en la esclerosis sistémica. 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Large vessels vasculopathy in systemic sclerosis

Vasculopatía de grandes vasos en la esclerosis sistémica

Beatriz Tejera Segura

Corresponding author

btejerasegura@gmail.com

Corresponding author.

, Iván Ferraz-Amaro

Servicio de Reumatología, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Systemic sclerosis &#40;SSc&#41; is a connective tissue disease characterized by excessive collagen and other extracellular matrix components deposition on different organs&#46; In general&#44; 3 components are involved in the pathogenesis of SSc&#58; vascular&#44; in which the endothelium plays a major role&#59; fibrotic&#44; fibroblasts and myofibroblasts dependent&#59; and the immune system&#44; in which lymphocytes and their mediators play a main role&#46; Somehow&#44; these 3 components are interconnected and are responsible for the disease development&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Vascular involvement in SSc is a challenge for clinicians due to its high morbidity and mortality and the lack of effective treatment options when vasculopathy is present&#46; It is important to distinguish the concept of vascular disease and vasculitis&#58; vasculopathy encompasses any disease that affects a vessel&#44; while vasculitis is the inflammatory disease of a vessel due to an impaired immune system&#46; In this review we will focus primarily on two uncommon manifestations of scleroderma&#44; such as the involvement of large vessels and non-digital ulcers&#46; The rarity of large vessel involvement and the importance of a correct differential diagnosis justifies this review&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Pathogenesis of vascular involvement in systemic sclerosis</span><p id="par0015" class="elsevierStylePara elsevierViewall">Currently it is not known exactly what stimulus triggers vasculopathy in SSc&#46; It is thought that different infectious agents could be involved&#44; such as free radicals related to nitric oxide&#44; endothelial cells antibodies or cytotoxic T cells&#46; The point is that&#44; from a <span class="elsevierStyleItalic">precipitating factor</span> a series of processes that result in changes that start in microcirculation and eventually end up in fibrosis are activated&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">1&#8211;3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">This series of alterations can be summarized as follows&#58; microcirculation impairment&#44; endothelial dysfunction and pericyte involvement&#44; abnormal angiogenesis and vasculogenesis&#44; chronic activation of platelets and maintained vasoconstriction&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Impairment of microcirculation</span><p id="par0025" class="elsevierStylePara elsevierViewall">The earliest&#44; most frequent and severe SSc clinical manifestations&#44; with increased morbidity and mortality&#44; are the ones that result from changes in microcirculation&#46; Hair loss and altered capillary structure&#58; the basement membrane is thickened&#44; the endothelial cells of the capillary wall increase in size and there is a loss of intercellular junctions so gaps are formed&#44; vacuolization of the cytoplasm occurs and plasmalemma vesicles are lost&#46; Parallel to all this process&#44; intimal proliferation occurs by accumulation of proteoglycans in arteries and arterioles&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">3&#8211;7</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Endothelial dysfunction and impaired pericytes</span><p id="par0030" class="elsevierStylePara elsevierViewall">Endothelial damage occurs early in the SSc&#46; Endothelial dysfunction triggers such an imbalance of vasoactive molecules that vasoconstrictors increase and vasodilators decrease&#46; Increased von Willebrand factor in plasma as well as endothelin-1 point to endothelial dysfunction indicators&#46; The increase in both results in platelet aggregation and vasoconstriction&#44; which in turn produces continuous platelet adhesion and fibrin accumulation&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">2</span></a> This contributes to an intravascular thrombus formation&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">1&#44;8&#8211;10</span></a> On the other hand&#44; it is not clear that this process is associated to an apoptotic phenomenon affecting the endothelial cell&#44; resulting in phagocytosis by antigen presenting cells and cytotoxic T lymphocytes exposure&#46; Thus&#44; an alternative complement and coagulation pathway favouring thrombus formation would be activated&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">10&#8211;12</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Pericytes are contractile cells that wrap around the endothelial cells of capillaries and venules&#46; They regulate vascular maturation and stabilization during angiogenesis&#46; They express <span class="elsevierStyleItalic">cytokines</span> such as the &#946; receptor of the platelet-derived growth factor and the melanoma associated antigen of high molecular weight&#46; Elevated levels of these <span class="elsevierStyleItalic">cytokines</span> have been observed in patients with SSc&#44; Raynaud&#39;s phenomenon and vascular lesions&#46; In addition&#44; pericytes can be differentiated to smooth muscle cells&#44; fibroblasts and myofibroblasts&#44; contributing to increase the thickness of the capillary&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">13&#44;14</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Impaired angiogenesis and vasculogenesis</span><p id="par0040" class="elsevierStylePara elsevierViewall">Angiogenesis is the formation of new blood vessels from pre-existing vessels&#46; It depends on the activation&#44; proliferation and migration of endothelial cells&#46; It is caused by a stimulus that induces proteolytic enzymes that break the extracellular matrix&#46; The loss of capillaries and small vessels in scleroderma patients suggests a defect in the angiogenesis process&#44; due to the increase of proangiogenic and antiangiogenic agents&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">1&#44;15</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Vasculogenesis is the formation of a vessel from stem cells and its role in SSc is not so clear&#46; Stem cells migrate to where there has been endothelial damage&#44; but there is no optimal differentiation mechanism for these new endothelial cells to repair the damage&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">16&#8211;19</span></a> This fact shows that there may be a defect in these patients vasculogenesis&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Chronic platelet activation and impaired platelet aggregation</span><p id="par0050" class="elsevierStylePara elsevierViewall">A release of vasoactive agents that induce permanent vasoconstriction occurs&#46; This leads to a proliferation of intimal and smooth muscle cells and&#44; eventually&#44; fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">20</span></a> In summary&#44; obliterative vasculopathy combined with progressive fibrosis occurs in the SSc&#46; It can affect capillaries&#44; arterioles and&#44; less frequently&#44; medium and large calibre vessels&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Clinical manifestations of vasculopathy in systemic sclerosis</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Raynaud&#39;s phenomenon and digital ulcers</span><p id="par0055" class="elsevierStylePara elsevierViewall">The typical clinical manifestations of impaired microcirculation include Raynaud&#39;s phenomenon&#44; telangiectasia&#44; linear subungual bleeding or &#8220;splinter&#8221; haemorrhage and ulcer&#44; as the most severe manifestation&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Raynaud&#39;s phenomenon is a transient&#44; reversible vasospasm&#44; triggered by cold&#44; stress or spontaneous appearance&#46; It is characterized by three phases&#58; pallor&#44; cyanosis and hyperaemia&#46; It affects the acral areas and can be asymmetrical&#46; Its prevalence in the general population is less than 10&#37;&#44; however&#44; in patients with SSc&#44; the prevalence increases to 90&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">2</span></a> If Raynaud&#39;s phenomenon is maintained over time&#44; digital ulcer appears&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The digital ulcer in SSc is defined as an ischaemic-necrotic lesion with loss of dermoepidermal tissue substance located in the palmar surface of the fingers&#44; distal to the proximal interphalangeal joint&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">21&#44;22</span></a> These ulcers can be active &#40;less than 6 months&#41; or chronic &#40;more than 6 months&#41;&#46; It is essential to consider certain aspects such as edges&#44; size&#44; bed&#44; tissue exposure and the presence of subcutaneous calcinosis&#46; The most important risk factor for its development is a maintained and refractory to treatment Raynaud&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">2</span></a> In different studies with cohorts of SSc patients&#44; it has been observed that other risk factors for developing digital ulcers are&#58; male sex&#44; presence of pulmonary hypertension and&#47;or decreased diffusion&#44; diffuse type systemic scleroderma&#44; long term disease progression&#44; presence of scl-70 antibody and smoking&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">23&#44;24</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The association between anticardiolipin antibodies and digital ischaemia has been researched&#44; with conflicting data&#46; Herrick et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">25</span></a> found no difference in the prevalence of anticardiolipin antibodies in patients with SSc and ischaemic ulcers &#40;11&#47;31&#41; compared with those who did not present these conditions &#40;16&#47;31&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Nor did they find any differences among patients who required amputation &#40;5&#47;13&#41; and those that didn&#8217;t &#40;22&#47;55&#41;&#46; However&#44; in the Boin et al&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">26</span></a> study&#44; a positive correlation between anti-beta2-glycoprotein antibodies &#40;specifically IgA subtype&#41; and digital ischaemia was observed&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Almost 60&#37; of the patients with SSc develop an ulcer throughout their illness&#46; 30&#37; of cases correspond to ulcers with loss of soft tissue or bone and 11&#37; of cases have digital gangrene at 7 years of follow-up&#46; It is noteworthy that 25&#37; of patients with SSc have 2 or more digital ulcers in the first visit&#44; that is&#44; even before being diagnosed&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">2&#44;27&#8211;29</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Non digital ulcers</span><p id="par0085" class="elsevierStylePara elsevierViewall">Although the prevalence of digital ulcers is well documented&#44; this is not the case with non-digital ulcers&#46; However&#44; since the last century&#44; case series highlighting the impact of these on morbidity and mortality of patients with SSc have been published&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">30</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In the general population&#44; the most frequent causes are non-digital ulcers with venous involvement &#40;70&#37;&#41;&#44; followed by arterial &#40;15&#37;&#41; and mixed cause &#40;10&#37;&#41;&#44; for example by diabetes&#46; Instead&#44; the aetiology of non-digital ulcers in patients with SSc are mostly by arterial involvement and appear on extensor surfaces and bony prominences &#40;metacarpophalangeal joints&#44; proximal interphalangeal joints&#44; elbows&#44; ankles&#44; pretibial and forefoot regions&#41;&#46; Lower extremity ulcers are often extensive&#44; making it necessary to perform a differential diagnosis in those of vasculitic origin&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">2</span></a> Also&#44; areas where there is subcutaneous calcinosis are more likely to ulcerate&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">While vasospasm plays a fundamental role in the digital ulcers themselves&#44; in the case of non-digital ulcers&#44; repeated microtrauma is the main risk factor in areas of chronic contracture and atrophic skin&#46; Others are thinning of the skin&#44; loss of elasticity and peripheral neurological impairment that hinders tissue regeneration and repair&#44; which results in chronic ulcers&#44; making them more vulnerable to infection&#46; These ulcers respond less well to treatment with vasodilating agents compared to distal location ones&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">In a recent publication by Shanmugam et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">30</span></a> 249 cases of patients with limited and diffuse SSc were reviewed&#46; Non digital ulcer was defined as a lower extremity dermoepidermal lesion&#44; of more than 3 months&#8217; progression&#44; which has not improved despite standard treatment&#46; The prevalence of non-digital and lower limbs ulcers was 4&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41;&#46; Seven patients had bilateral ulcers and 3 unilateral&#46; Ulcer biopsy was performed in 50&#37; of cases and fibrosis stood out histologically&#46; None was compatible with vasculitis&#46; An autoimmune genetic study was requested and it was observed that patients with non-digital ulcer had heterozygous or homozygous mutation for gene <span class="elsevierStyleItalic">MTHFR-C677T</span> &#40;methylene tetrahydrofolate reductase gene&#44; enzyme involved in clotting&#41; and positive antiphospholipid antibodies &#40;without meeting the criteria for antiphospholipid syndrome&#41;&#46; However&#44; it is a study with only a few patients and would require a larger sample size to confirm this finding&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Furthermore&#44; Youssef et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">31</span></a> compared the prevalence of large vessel involvement &#40;diagnosed by the absence of peripheral pulses in the physical examination&#44; angiography or ultrasound Doppler&#41; of 31 patients with limited SSc relative to a control group adjusted for age&#44; sex and cardiovascular risk factors&#44; observing that the prevalence of macrovascular disease was higher in the group of patients with limited SSc &#40;58&#37; versus 9&#37;&#41;&#46; However&#44; no differences were found in the prevalence of coronary and cerebrovascular disease in any of the 2 groups&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In turn&#44; there are also cases of proximal vessel involvement in upper limbs&#44; mainly the ulnar artery&#46; Through arteriography&#44; Hasegawa et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">32</span></a> evaluated the prevalence of large vessel involvement in the upper and lower limbs in 8 patients with SSc and ulcers&#46; Macrovascular upper limb involvement was higher than the lower limbs &#40;7&#47;5&#41;&#46; The vessels affected in the upper limbs were the ulnar and radial arteries&#44; while in the lower they were the posterior tibial&#44; the arcuate and the pedia arteries&#46; The palmar and plantar arches were also affected&#46; In another study&#44;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">33</span></a> with a larger sample size &#40;20 patients with SSc&#41;&#44; a Doppler ultrasound was performed&#44; with the ulnar artery showing a narrower arterial lumen and an increased wall thickness compared to the control group&#44; although no significant differences were found with other vessels&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In short&#44; virtually all the vascular system of patients with SSc may be affected&#46; All the studies conducted advocate the use of angiography for the diagnosis and early revascularization&#44; if possible&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">34&#44;35</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Arteriosclerosis and systemic sclerosis</span><p id="par0120" class="elsevierStylePara elsevierViewall">In recent years&#44; in other autoimmune diseases&#44; such as rheumatoid arthritis and systemic lupus erythematosus&#44; an increase in ischaemic macrovascular diseases has been described&#44; probably related to accelerated atherosclerosis connected to the underlying inflammation&#46; It seems that this very fact may occur in patients with SSc&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">36</span></a> Emad et al&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">37</span></a> described that out of 22 scleroderma patients who underwent CT angiography&#44; 3 of them showed subclavian artery involvement&#44; 5 brachial artery involvement and 4 radial artery involvement&#46; Radiographic abnormalities appear to be of different types&#44; including vascular attenuation patterns&#44; intimal irregularities of the vessels or focal and proximal occlusions&#46; No angiographic differences were found in this report in connection with limited or diffuse SSc&#46; The only clinical manifestation of the disease that showed association with these vascular changes was pulmonary hypertension&#44; however&#44; this is not described when the origin of these changes is arteriosclerotic&#44; inflammatory&#44; vasculitic or otherwise&#46; Park et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">38</span></a> retrospectively describe the findings observed in the ulnar artery by arteriography&#46; The authors observed that the artery involvement by angiography was frequent and note that although they have no etiopathogenic explanation for these changes&#44; patients with pathological angiograms did not differ in respect to cardiovascular risk factors compared to those without them&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Both morphological and endothelial dysfunction ultrasound studies after an ischaemic stimulus also confirm the presence of macrovascular disease in SSc&#46; In this regard&#44; Rosato et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">39</span></a> describe ultrasound palmar artery pathological patterns in 36 patients with SSc compared with 20 controls&#46; However&#44; this involvement was not related to the presence of digital ulcers&#46; Bartoli et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">40</span></a> described a greater brachial endothelial dysfunction after ischaemic stimulus and a larger carotid intima-media thickness in 35 SSc patients compared to controls&#46; This difference remained statistically significant when adjusted for traditional cardiovascular risk factors&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Also&#44; using an ultrasound method that determines vascular elasticity coupled to a walk test in patients with SSc&#44; significantly poorer carotid &#8220;biomechanical&#8221; properties have been described&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">41</span></a> The evidence seems to be maintained when other indirect methods of macrovascular disease are used&#44; such as the ankle-brachial index&#46; Thus&#44; Zeng et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">42</span></a> in a series of 48 patients with SSc&#44; describe a higher prevalence of pathologic ankle-brachial index when compared with 46 controls without disease&#46; Also Ho et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">43</span></a> show a higher prevalence of macrovascular disease using this indirect method in 54 patients with SSc and 43 controls&#46; In the latter study&#44; a carotid ultrasound was also performed to measure the intima-media thickness with a statistically significant relationship for increased subclinical carotid atherosclerosis in patients with SSc&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">On the other hand&#44; it seems that patients with SSc have a higher prevalence of intermittent claudication&#46; Thus&#44; in a study using the WHO-Rose questionnaire to measure arterial disease of the lower limbs&#44; its presence was observed in 53 patients with SSc compared to 43 controls&#44;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">44</span></a> recommending the screening of intermittent claudication in cases of SSc&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">We only found two studies in the literature that do not support the presence of atherosclerotic macrovascular disease in SSc&#46; The first one<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">45</span></a> is a cross-sectional study in which carotid ultrasound was used to measure the intima-media thickness in 49 scleroderma patients and 32 controls&#59; the second&#44;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">46</span></a> also a cross-sectional study in which the brachial dilation by ischaemic stimulus was determined for 36 patients with primary Raynaud&#39;s phenomenon&#44; 42 scleroderma patients and 33 controls&#46; In both studies&#44; a higher prevalence of macrovascular disease was found even after performing a multivariate analysis adjusted for classic cardiovascular risk factors&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Vasculitis</span><p id="par0145" class="elsevierStylePara elsevierViewall">The involvement of large vessels can also result from a systemic vasculitis&#46; The differential diagnosis between vascular disease and vasculitis poses a diagnostic challenge if there is no histological study&#46; Vasculitis in SSc is rare but not unlikely&#46; In 58 autopsies performed to patients with SSc&#44; vascular disease was observed in 24&#37; versus 9&#37; of vasculitis&#44; but vascular disease coexisted with vasculitis in 5 out of 8 tissue biopsies corresponding to a digital amputation&#46;<a class="elsevierStyleCrossRefs" href="#bib0525"><span class="elsevierStyleSup">47&#44;48</span></a> Kao and Weyand<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">49</span></a> describe various types of vasculitis associated with SSc&#46; The most common is the ANCA-positive vasculitis&#44; particularly with perinuclear fluorescein pattern &#40;p-ANCA&#41;&#46; The following is a summary of the most important aspects&#46;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#40;a&#41;</span><p id="par0150" class="elsevierStylePara elsevierViewall">Temporal arteritis and Takayasu vasculitis&#46;</p></li></ul></p><p id="par0155" class="elsevierStylePara elsevierViewall">3 cases of temporal arteritis have been described in women with an average age of 60 and limited SSc&#46; The clinical manifestations were the typical ones for this disease&#44; except for a case that developed a lower extremity ulcer and normal erythrocyte sedimentation rate&#46; A temporal artery biopsy was performed in all cases&#44; confirming the diagnosis&#46; Glucocorticoids were used as treatment and the outcome was favourable&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">49</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Takayasu vasculitis was described in 4 patients with diffuse and limited SSc&#46; The presentation was similar to that of the general population with the exception of 2 cases&#44; where age of presentation was over 40&#46; There was no biopsy&#44; so the question remains whether it was a Takayasu vasculitis or vascular involvement in SSc&#46; The authors do not provide any data on the treatment used&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">49</span></a><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#40;b&#41;</span><p id="par0165" class="elsevierStylePara elsevierViewall">Vasculitis of medium and small vessel&#46;</p></li></ul></p><p id="par0170" class="elsevierStylePara elsevierViewall">Polyarteritis nodosa manifested in a patient with diffuse SSc in the form of nodular lesions in the lower limbs&#46; The patient had no constitutional syndrome characteristic of polyarteritis nodosa nor involvement of other organs or multiple mononeuritis&#46; Vasculitis was confirmed by histological study&#46; Methotrexate treatment was used subcutaneously &#40;dose of 20 <span class="elsevierStyleHsp" style=""></span>mg&#47;wk&#41; and glucocorticoids&#46; The progression was favourable&#46; There are 4 other cases of polyarteritis nodosa in medical literature whose initial manifestation was multiple mononeuritis<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">50&#8211;52</span></a> and one case also associated with Sj&#246;gren&#39;s syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">52</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">There are also cases CNS vasculitis and mixed cryoglobulinemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">49&#44;53&#44;54</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">ANCA-positive vasculitis is the most common by far&#44; p-ANCA vasculitis to be more precise&#46; Of the 88 cases of vasculitis described in the article by Kao and Weyand&#44;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">49</span></a> 74 correspond to p-ANCA vasculitis&#44; specific for the myeloperoxidase antigen&#46; This vasculitis was observed in both the diffuse SSc as well as the limited&#44; though it was more prevalent in the first&#46; Renal involvement in the form of glomerulonephritis was the most common form of presentation&#46; In recent years&#44; cases of vasculitis of medium and small vessel associated with SSc have been reported&#44;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">54&#8211;56</span></a> which stresses the importance of taking their diagnosis into account in the case of these patients&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conclusions</span><p id="par0185" class="elsevierStylePara elsevierViewall">Macrovascular disease in the SSc may have a severe outcome unless it is diagnosed early&#46; It is essential to conduct a thorough case history emphasizing the presence of cardiovascular risk factors and symptoms and&#47;or signs suggestive of vasculopathy or vasculitis&#46; On physical examination&#44; all peripheral pulses should be palpated&#44; performing the Allen&#44; the Adson and the hyperabduction tests&#44; which will help in assessing the patency of the radial and ulnar artery and the presence of vascular or neural compression&#46; Doppler ultrasound and angiography will help in determining the degree of vascular involvement and&#44; if possible&#44; revascularization by angioplasty&#46; Lab tests with screening for vasculitis are also necessary&#44; and if in doubt&#44; a tissue biopsy is a choice procedure to reach a definitive diagnosis&#46; The diagnosis of one or the other is as complicated as essential&#44; as the therapeutic approach is far from similar&#46; Treatment depends on the degree of vascular involvement and the cause behind it&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">In the case of digital ulcers&#44; non-pharmacological and pharmacological measures &#40;antiplatelet and vasodilator agents&#41; should be taken into account&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">57</span></a> Non-digital ulcers are often refractory to conventional treatment and very painful&#44; so the analgesic treatment should be adequate and revascularization should always be considered as first choice in these patients&#46; Surgical sympathectomy could be an alternative when revascularization is not possible&#44; although not always effective&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">58</span></a> Antibiotic treatment of superinfected lesions to prevent osteomyelitis and sepsis is also paramount&#46; If there is an underlying vasculitis&#44; this should be treated urgently to prevent a fatal outcome&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">SSc is a rare disease among the connective tissue diseases and this complicates conducting clinical trials&#44; and therefore&#44; researching the pathogenesis of vascular involvement and developing new therapies&#46; It is important to know each and every one of the different manifestations of macrovascular disease&#44; as these may vary in each patient&#44; hindering diagnosis and early treatment&#46; However&#44; with what has been published so far&#44; there is enough data to enable us to approach the correct diagnosis&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflict of interests</span><p id="par0200" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Introduction"
        ]
        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Pathogenesis of vascular involvement in systemic sclerosis"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Impairment of microcirculation"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Endothelial dysfunction and impaired pericytes"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Impaired angiogenesis and vasculogenesis"
            ]
            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Chronic platelet activation and impaired platelet aggregation"
            ]
          ]
        ]
        6 => array:3 [
          "identificador" => "sec0035"
          "titulo" => "Clinical manifestations of vasculopathy in systemic sclerosis"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Raynaud&#39;s phenomenon and digital ulcers"
            ]
            1 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Non digital ulcers"
            ]
            2 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Arteriosclerosis and systemic sclerosis"
            ]
            3 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Vasculitis"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0060"
          "titulo" => "Conclusions"
        ]
        8 => array:2 [
          "identificador" => "sec0065"
          "titulo" => "Conflict of interests"
        ]
        9 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2014-09-30"
    "fechaAceptado" => "2014-12-11"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec645273"
          "palabras" => array:3 [
            0 => "Systemic sclerosis"
            1 => "Vasculopathy"
            2 => "Large vessels"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec645272"
          "palabras" => array:3 [
            0 => "Esclerosis sist&#233;mica"
            1 => "Vasculopat&#237;a"
            2 => "Gran vaso"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Vasculopathy in systemic sclerosis is a severe&#44; in many cases irreversible&#44; manifestation that can lead to amputation&#46; While the classical clinical manifestations of the disease have to do with the involvement of microcirculation&#44; proximal vessels of upper and lower limbs can also be affected&#46; This involvement of large vessels may be related to systemic sclerosis&#44; vasculitis or atherosclerotic&#44; and the differential diagnosis is not easy&#46; To conduct a proper and early diagnosis&#44; it is essential to start prompt appropriate treatment&#46; In this review&#44; we examine the involvement of large vessels in scleroderma&#44; an understudied manifestation with important prognostic and therapeutic implications&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La vasculopat&#237;a en la esclerosis sist&#233;mica es una manifestaci&#243;n grave&#44; y en muchas ocasiones irreversible&#44; que puede llevar a la amputaci&#243;n&#46; Si bien las manifestaciones cl&#237;nicas cl&#225;sicas de la enfermedad tienen que ver con la afectaci&#243;n de la microcirculaci&#243;n&#44; tambi&#233;n los vasos proximales de extremidades superiores e inferiores pueden afectarse&#46; Esta afectaci&#243;n de grandes vasos puede tener un origen relacionado con la esclerosis sist&#233;mica&#44; vascul&#237;tico o arterioscler&#243;tico por lo que llegar al diagn&#243;stico no es f&#225;cil pero s&#237; fundamental para empezar cuanto antes un tratamiento adecuado&#46; En esta revisi&#243;n repasamos la afectaci&#243;n de los grandes vasos en la esclerosis sist&#233;mica&#44; manifestaci&#243;n poco estudiada y con importantes repercusiones pron&#243;sticas y terap&#233;uticas&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Tejera Segura B&#44; Ferraz-Amaro I&#46; Vasculopat&#237;a de grandes vasos en la esclerosis sist&#233;mica&#46; Med Clin &#40;Barc&#41;&#46; 2015&#59;145&#58;488&#8211;492&#46;</p>"
      ]
    ]
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