Clase fenómeno de raynaud iavm 2013

Fenómeno de
Raynaud
Patogenia
y
Diagnóstico Diferencial
Ignacio AlfredoValerio Morales
Médico Residente en Reumatología
martes, 10 de septiembre de 13

Fenómeno de Raynaud
Historia
http://www.historiadelamedicina.org/raynaud.html
Maurice Auguste Gabriel
Raynaud (1834 - 1881)
1862
Anatomía patológica Francesa
1862 Tesis doctoral
1866 Profesor de Curso Sainte-Périne,
Saint Antoine (ejército)
Varios artículos
1876 Medalla de oro del Cólera
Estudios en Gangrenas
1929 Thomas Lewis
Nació el 5 de julio de 1834 en París. Su padre era Jacques Auguste, profesor en el Colegio real Bourbon. Su madre era Félicité Marie Vernois.
Estudió medicina en París con la ayuda de su tío, el conocido profesor Ange-Gabriel-Maxime Ver- nois (1809-1877).
Se doctoró en 862 con la tesis De l’asphyxie locale et de la gangrène symétrique des extrémités. Ese mismo año se doctoró también en letras con la tesis Les Médecins au temps de Molière,
thèse pour le doctorat, présentée à la Faculté des lettres
En 1865 fue médico del bureau central e impartió el curso de clínica médica en el Hôtel-Dieu, en sustitución de Piorry (865-66).
En 1866 fue encargado de curso complementario sobre enfermedades mentales y nerviosas.
Al año siguiente fue profesor suplente de patología interna sustituyendo a Monneret.
En 1868 fue médico de los Hospitales: Sainte-Périne, Saint-Antoine (872), Lariboisière (872) y Charité (880).
En 1870 impartió un curso sobre las enfermedades de la armada.
Tras una revisión escrupulosa y puesta al día de las gangrenas, Raynaud señala más adelante:
“...Je me propose de démontrer quíl existe une variété de gangrène sèche, affectant les ex- trémités, qu’il est impossible d’expliquer par une oblitération vasculaire ; variété caracté-
risée surtout par une remarquable tendance à la symétrie, en sorte qu’elle affecte toujours des parties similaires, les deux membres supé- rieurs ou inférieurs, ou les quatre à la fois ; plus dans
certains cas, le nez et les oreilles ; et je chercherai à prouver que cette espèce de grangène a sa cause dans un vice d’inervation des vaisseaux capillaires, qu’il me restera à préciser... “
En el texto se exponen como ejemplo diferentes historias clínicas o casos detallados cuando predo- mina el elemento nervioso, en su forma benigna, en su forma grave, cuando hay
lesiones del aparato circulatorio demostradas en la autopsia, etc. En el capítulo tercero se refiere Raynaud a la sintomatología, diagnóstico, pronóstico, causas, naturaleza de la
enfermedad y tratamiento. Acompañan al texto una serie de grabados.
Murió joven a consecuencia de sus padecimientos cardíacos el 29 de junio de 1888 en París.

Historia
Maurice Auguste Gabriel
Raynaud (1834 - 1881)
1862
1929 Thomas Lewis
1930 Fenómeno de Raynaud vs Enfermedad de
Raynaud
1950 Puede tener Enfermedad Subyacente asociada.
<<Allen&Brown>>
http://www.historiadelamedicina.org/raynaud.html
Thomas Lewis proposed in 1929 that RP was due to “local fault,” rather than a defect in the central nervous system
in the 1930s by Allen and Brown2~ who divided RS into Raynaud's phenomenon and Raynaud's disease on the basis of the absence or presence of an associated disease.
However, as early as the 1950s, it was recognized that Raynaud's phenomenon may precede an underlying disease by many years.

Introducción
“Trastorno isquémico episódico en los dedos de las manos y los
pies, manifestado por palidez, cianosis y rubor de la piel, en
respuesta a estímulos como el frío o el estrés emocional”
J. Am. Acad. Dermatol. 59 (2008) 633–653
Episodic color changes of the hands and feet in response to cold or stress, known as Raynaud Phenomenon (RP), are a frequent complaint among patients presenting to pediatric
rheumatology clinics.
The ﬁrst description of vasomotor instability triggered by cold exposure, or “local asphyxia of the extremities,” is ascribed to A.G. Maurice Raynaud, a French medical student, whose name
has become synonymous with this disorder.1
Despite 150 years of clinical observation and basic research, only recently have signiﬁcant inroads been established to explain the biological basis for this condition and to establish
evidence-based therapeutic interventions
Thomas Lewis proposed in 1929 that RP was due to “local fault,” rather than a defect in the central nervous system.

Epidemiología
Distribución mundial
Afecta 3-5% de la población
Incidencia 2.2% Fem / 1.5% Masc.
Zonas de clima frío*
Prevalencia: Fem 1,8-30% / Hombre
4-14%
Gemelos Homocigotos 38%
Gemelos Heterocigotos 18%
Prevalencia: 80-90% de Niños y Adultos
con Esclerosis sistémica o EMTC
...y en 10 a 45% de LES...
,,,33% Sjögren...
...20% Dermato o polimiositis
...12.3 - 20% Artritis Reumatoide.
Reumatol Clin. 2006;2 Supl 3:S10-5
Reumatol Clin. 2008;4(2):59-66 / Lancet 2001; 357: 2042–48
New onset RP should, therefore, prompt consideration and examination for signs and symptoms of systemic disease and, potentially, further rheumatological evaluation.

Epidemiología Factores de Riesgo
Historia Familiar en 25%
Sexo Femenino
Clima Frío
Ocupacion:Vibración
Edad en hombres
ETOH y Estado Marital en Mujeres
Betabloqueadores,TRH
Hipertensión arterial
Consumo de Tabaco
Edad Promedio de presentación 14
años
27% Despúes de los 40 años
Inicio - 2 años - 12.6% tendrá
enfermedad de tejido conectivo
SSc en 15 a 20% si hay
Anormalidades capilares de uña +
AutoAc al presentarse el FdR
Reumatol Clin. 2008;4(2):59-66

Clasiﬁcación
Clasiﬁcación

Clasiﬁcación
F.#Raynaud#
Primario#
Secundario#
Lancet2001;357:2042–48
Raynaud’s phenomenon is classified as primary (formerly Raynaud’s disease) if there is no known underlying illness and secondary (formerly Raynaud’s syndrome) if there is an associated
disorder detected upon assessment; the distinction is important, because prognosis, severity, and treatment can all be affected.
Many non-inflammatory processes and most systemic rheumatic diseases can be associated with Raynaud’s phenomenon.
However, the most frequent association is with systemic sclerosis (scleroderma).
Actual prevalence data are incomplete, although Raynaud’s phenomenon is thought to occur in more than 90% of patients with scleroderma, 10–45% with systemic lupus, a third of patients
with primary Sjögren’s syndrome, 20% with dermatomyositis or polymyositis, and 10–20% with rheumatoid arthritis.18

Clasiﬁcación
F.#Raynaud#
Primario#
Secundario#
Riesgo de progresión a
Enf.Tejido Conectivo
2%
a 10 años + > 6.3%
Landry et al. JVasc Surg 1996; 23: 76–78.
Seropositividad
Lancet2001;357:2042–48
Raynaud’s phenomenon is classified as primary (formerly Raynaud’s disease) if there is no known underlying illness and secondary (formerly Raynaud’s syndrome) if there is an associated
disorder detected upon assessment; the distinction is important, because prognosis, severity, and treatment can all be affected.
Many non-inflammatory processes and most systemic rheumatic diseases can be associated with Raynaud’s phenomenon.
However, the most frequent association is with systemic sclerosis (scleroderma).
Actual prevalence data are incomplete, although Raynaud’s phenomenon is thought to occur in more than 90% of patients with scleroderma, 10–45% with systemic lupus, a third of patients
with primary Sjögren’s syndrome, 20% with dermatomyositis or polymyositis, and 10–20% with rheumatoid arthritis.18

Clasificación Primario vs Secundario
Vascular dysfunction in primary RP is, by definition, fully reversible, whereas secondary RP may combine defective function and structural abnormalities.
SSc-associated RP fundamentally differs from primary RP because of its associated vasculopathy, involving fibrous intimal proliferation with associated intravascular thrombi.

DisfunciónVascular primaria totalmente reversible = Primario

DisfunciónVascular primaria totalmente reversible = Primario
Vasculopatía - Fibrosis - -Proliferación - Trombosis = Secundario (SS)

Fisiopatogenia
Patogenia

Patogenia
Fisiopatogenia
&
Fenómeno de Raynaud Primario

Patogenia GENÉTICA
ARTHRITIS & RHEUMATISM , 43,(7),2000, pp 1641–1646
The most significant evidence of linkage was seen for D6S261, which satisfies the Lander and Kruglyak criteria for suggestive linkage
Only one potential candidate gene, the Beta subunit of the muscle acetylcholine receptor, was found to map to within the 5 areas of possible linkage.
Outside these areas were 2 further candidate genes, the serotonin 1B and 1E receptors linkage at D6S261.
The fact that 5 areas of possible linkage have been found indicates that primary RP may be an oligogenic condition, although the findings in some of the areas may be false positive
Using the likelihood ratio test to compare the 2 models, HoLOD and HeLOD were found to significantly differ at D9S156 (P < 0.0003), D17S1791 (P < 0.007), and D7S664 (P < 0.04), indicating evidence of genetic
heterogeneity at these loci. This finding indicates that the genetic basis to primary RP may vary between individuals.
Objective. To identify chromosomal regions containing genes involved in the susceptibility to primary Raynaud’s phenomenon (RP).
Methods. Six extended families with multiple individuals affected with primary RP (n = 37) were examined for linkage in a 2-stage, whole-genome screen, using a total of 298 microsatellite markers.
Results. Multipoint, nonparametric linkage analysis identified 5 areas of possible linkage, with a nominal level of significance of P < 0.05. Analysis of a finer map of markers in these regions defined the regions of
linkage as 21.4 cM on 6q13–6q23.3 (D6S261; P < 0.0004), 10.2 cM on 7p22–7p15 (D7S664; P < 0.014), 1.6 cM on 9p23–9p22 (D9S156; P < 0.0075), 5.1 cM on 17p13.1–17p12 (D17S1791; P < 0.036), and 11.8 cM on
Xp11.4–Xp11.23 (DXS8054; P < 0.006).
Three potential candidate genes map to these regions: the B subunit of the muscle acetylcholine receptor and the serotonin 1B and 1E receptors.
Conclusion. These results provide evidence of the presence and location of genes that are involved in the genetic susceptibility to primary RP.

Mecanismos Patogénicos
Intravascular+
Neural+
Vascular+
Patogenia
VasoconstricciónVasodilatación
Rheumatology (Oxford) 45 (2006) iii33–35.
N. Engl. J. Med. 347 (2002) 1001–1008./ Rheum. Dis. Clin. North. Am. 29 (2003) 275–291
In broad terms, blood flow volume is regulated by an interactive system involving neural signals, cellular mediators, circulating hormones, and soluble vasoactive compounds.
The inherent tone, or contractile activity, of vascular smooth muscle varies substantially between different arterial structures, ranging from relatively high basal tone in the coronary circulation to low or
absent in the pulmonary circulation, and it can increase or decrease dramatically
Numerous mechanisms participate in the regulation of vascular tone, including both intrinsic functions of vascular smooth muscle and endothelial cells, and extrinsic effects of nerves, adjacent tissues,
circulating cells, and soluble factors

Mecanismos Patogénicos
Intravascular+
Neural+
Vascular+
Patogenia
VasoconstricciónVasodilatación
Respuesta vasomotora local
excesiva:
frío, calor y estrés emocional
Rheumatology (Oxford) 45 (2006) iii33–35.
N. Engl. J. Med. 347 (2002) 1001–1008./ Rheum. Dis. Clin. North. Am. 29 (2003) 275–291
In broad terms, blood flow volume is regulated by an interactive system involving neural signals, cellular mediators, circulating hormones, and soluble vasoactive compounds.
The inherent tone, or contractile activity, of vascular smooth muscle varies substantially between different arterial structures, ranging from relatively high basal tone in the coronary circulation to low or
absent in the pulmonary circulation, and it can increase or decrease dramatically
Numerous mechanisms participate in the regulation of vascular tone, including both intrinsic functions of vascular smooth muscle and endothelial cells, and extrinsic effects of nerves, adjacent tissues,
circulating cells, and soluble factors

Patogenia
Nat. Rev Rheumatol. 8, 469–479 (2012)
Valerio-Morales IA 2013
VASCULAR
INTRAVASCULARNEURAL
OTROS

Patogenia
VASCULAR
INTRAVASCULARNEURAL
OTROS
Endotelio
Prostaciclina
NO
Endotelina-1*
Angiotensinogeno*
*.-Profibrótico
sobreexpresado en SSc
Proliferación
Contracción-relajación
Agregación plaquetaria
Baja Adhesión Leucos
Músculo Liso

Vía autonómica
Vía Sensorial
Receptores alfa-
adrenérgicos*
Regulan(Vasos(
1-Simpático: (Norepi)
2- Parasimpático (Sustancia
P,VIP, CGRP, NKA)
3- Sensitivas
4 - SNC
Patogenia
VASCULAR
INTRAVASCULARNEURAL
OTROS
Endotelio
Prostaciclina
NO
Endotelina-1*
Angiotensinogeno*
*.-Profibrótico
Proliferación
Músculo Liso

Vía autonómica
Vía Sensorial
Receptores alfa-
adrenérgicos*
Regulan(Vasos(
P,VIP, CGRP, NKA)
3- Sensitivas
4 - SNC
Patogenia
VASCULAR
INTRAVASCULARNEURAL
OTROS
Endotelio
Prostaciclina
NO
Endotelina-1*
Angiotensinogeno*
*.-Profibrótico
Proliferación
Músculo Liso
+ Adhesión plaquetaria/
activación
Fibrinólisis
Defectuosa!
+Trombina
+Viscosidad sanguínea
Vasoconstrictores
Serotonina
TGF-B
PDGF
Profibrosis

Vía autonómica
Vía Sensorial
Receptores alfa-
adrenérgicos*
Regulan(Vasos(
P,VIP, CGRP, NKA)
3- Sensitivas
4 - SNC
Patogenia
VASCULAR
INTRAVASCULARNEURAL
OTROS
Endotelio
Prostaciclina
NO
Endotelina-1*
Angiotensinogeno*
*.-Profibrótico
Proliferación
Músculo Liso
+ Adhesión plaquetaria/
activación
Fibrinólisis
Defectuosa!
+Trombina
+Viscosidad sanguínea
Vasoconstrictores
Serotonina
TGF-B
PDGF
Profibrosis
Endocrino: Estrógenos – R-Alfa adrenérgicos
Hematológico:Viscosidad +, Deformabilidad -

Patogenia
Dedos/Piel*
Distal*
+(Alfa1R)*
Serotonina/
TXA*
Isquemia/
Frío!ROS*
Rho/Rho1K* Vía Rho-Kinasa
-  Amplifica Respuesta del
Músculo Liso al Frío
-  Induce expresión de R-
Alfa Adrenérgicos 2c
-  Sensibiliza fibras
contrátiles al Ca+

Patogenia
Factores Involucrados
en la patogenia del
Primario

Patogenia
DisfunciónVascular
&
Espectro
Esclerosis Sistémica
Systemic sclerosis (ssc) is a connective tissue and autoimmune disease of unknown etiology that affects various organ systems, including the lungs, heart, gastrointestinal tract and kidneys.1
the three major features of ssc are systemic vascular dysfunction, the presence of mononuclear cell infiltrates and connective tissue fibrosis

Patogenia & SSc
Fibroblasto*
Endotelio*
miRNA*
S.*Inmunológico*
Estrés*
Oxida=vo*
Trojanowska, M. Nat. Rev. Rheumatol. 6, 453–460 (2010)
Cellular and molecular pathways underlying fibrosis in systemic sclerosis. Injury caused by viruses, autoantibodies, ischemia‐reperfusion or toxins triggers vascular damage and inflammation.
Activated inflammatory cells secrete cytokines and growth factors.
Endothelial injury results in generation of ROS, intravascular coagulation and platelet activation with release of serotonin, vasoactive mediators, thrombin and platelet‐derived growth factor, and sets
in motion progressive vascular remodeling leading to luminal occlusion, reduced blood flow and tissue hypoxia. Secreted mediators, such as TGF‐β and Wnt10b, cause fibroblast activation and
differentiation into myofibroblasts, which produce excess amounts of collagen, contract and remodel the connective tissue, and resist elimination by apoptosis.
The stiff and hypoxic ECM of the fibrotic tissue further activates myofibroblasts.
Injury also directly induces transdifferentiation of pericytes, epithelial cells and endothelial cells into myofibroblasts, expanding the tissue pool of matrix‐synthesizing, activated myofibroblasts.
Abbreviations: CXCL12, CXC‐chemokine ligand 12; CXCR4, CXC‐chemokine receptor 4; ECM, extracellular matrix; IFN, interferon; ROS, reactive oxygen species; TGF‐β, transforming growth factor β;
TH2 cell, type 2 helper T cell; TLR, Toll‐like receptor.

Patogenia & SSc
Cellular and molecular pathways underlying fibrosis in systemic sclerosis. Injury caused by viruses, autoantibodies, ischemia‐reperfusion or toxins triggers vascular damage and inflammation.
Activated inflammatory cells secrete cytokines and growth factors.
Endothelial injury results in generation of ROS, intravascular coagulation and platelet activation with release of serotonin, vasoactive mediators, thrombin and platelet‐derived growth factor, and sets
in motion progressive vascular remodeling leading to luminal occlusion, reduced blood flow and tissue hypoxia. Secreted mediators, such as TGF‐β and Wnt10b, cause fibroblast activation and
differentiation into myofibroblasts, which produce excess amounts of collagen, contract and remodel the connective tissue, and resist elimination by apoptosis.
The stiff and hypoxic ECM of the fibrotic tissue further activates myofibroblasts.
Injury also directly induces transdifferentiation of pericytes, epithelial cells and endothelial cells into myofibroblasts, expanding the tissue pool of matrix‐synthesizing, activated myofibroblasts.
Abbreviations: CXCL12, CXC‐chemokine ligand 12; CXCR4, CXC‐chemokine receptor 4; ECM, extracellular matrix; IFN, interferon; ROS, reactive oxygen species; TGF‐β, transforming growth factor β;
TH2 cell, type 2 helper T cell; TLR, Toll‐like receptor.

Patogenia & SSc

Patogenia & SSc
Gabrielli A et al. N Engl J Med 2009;360:1989-2003.
Figure 4. Lesions in Different Stages of Scleroderma.
As shown in Panel A, microvascular injury is one of the early events in the pathogenesis of scleroderma and is characterized by endothelial-cell damage, the proliferation of basal-lamina layers,
occasional entrapment of peripheral-blood mononuclear cells in the vessel wall, and initial perivascular mononuclear-cell infiltrates.
Endothelial cells show signs of increased programmed cell death.
One or more reactive oxygen species (ROS)–generating triggering agents could be responsible for this stage.
ROS may be generated inside the vascular lumen by peripheral-blood cells or within the vessel wall by macrophages, endothelial cells, vascular smooth-muscle cells, or adventitial fibroblasts in
response to one or more noxious agents.
Although low levels of ROS are necessary for normal vascular function, excessive production is responsible for functional and structural damage.
As shown in Panel B, uncontrolled production of ROS activates local mesenchymal cells, inducing chemotaxis, proliferation, extracellular-matrix production, and the release of cytokines and growth
factors that amplify the inflammatory focus. An autocrine circuitry (Ha-Ras–extracellular-signal–regulated kinases 1 and 2 [ERK1/2]/ROS) maintains ROS at levels that are high because of the reduced
turnover of cytokine receptors. Structural and functional abnormalities of vessel walls and intravascular changes occur, leading to overt clinical symptoms.
As shown in Panel C, the next stage is dominated by fibrosis, derangement of visceral-organ architecture, rarefaction of blood vessels, and consequently, hypoxia, which contributes to the
maintenance of fibrosis.
As shown in Panel D, once the single or multiple mechanisms responsible for mesenchymal-cell activation subside or recede or mesenchymal cells themselves undergo senescence or apoptosis, 81 the
disease burns out. The clinical picture is dominated by internal-organ derangement. Triggering, amplifying, and maintenance factors are not necessarily confined to a single stage. Environmental,
local, and genetic factors can influence the disease progression.
In the inset, coupling of the NADPH oxidase to the glutathione (GSH) cycle is shown. Glucose metabolism, in particular G6PD, generates NADPH/H+, which is rapidly oxidized by NADPH oxidase enzymes
to NADP+ H+-e-. H+ enters the GSH cycle: oxidized GSH (GSSG) is reduced by GSH reductase (GRH) to GSH, which is oxidized back to GSSG by GSH peroxidase. This enzyme uses as a preferred substrate
H2O2 (2GSH+H2O2→GS–SG+2H2O), produced by SOD and superoxide generated by the NADPH oxidase cycle. GSH is synthesized from amino acids by the enzyme γ-glutamyl-cysteine synthetase, a
rate-limiting reaction, which is tightly dependent on ATP. ATP depletion reduces GSH synthesis, increases peroxides, and unleashes the NADPH oxidase cycle, which generates a large excess of ROS,
unbuffered by GSH.

Patogenia & SSc
Indian Journal of Dermatology 2013; 58(4)
Si bien esta diapositiva explica de manera general la fisiopatogenia de la esclerosis sistémica, vamos a entrar en detalle en aquellos fenómenos descritos en la génesis y perpetuación del
daño vascular y desrregulacion en Esclerosis sistémica, lo que nos llevará a abordar estos cuatro aspectos fundamentales involucrados en la vasculopatía de SSc.:
Angiogénesis defectuosa
Misma que debemos acoplar al ulterior desarrollo de fibrosis
y la participación de las celulas mesenquimatosas, fibroblastos, matriz extracelular agregadas a los demás mecanismos esquematizados en la imagen.

Patogenia & SSc
Angiogenesis defectuosa
Vasculopatía-Fibrosis
Cel. Mesenquimatosas
Matriz Extracelular
Indian Journal of Dermatology 2013; 58(4)
Si bien esta diapositiva explica de manera general la fisiopatogenia de la esclerosis sistémica, vamos a entrar en detalle en aquellos fenómenos descritos en la génesis y perpetuación del
daño vascular y desrregulacion en Esclerosis sistémica, lo que nos llevará a abordar estos cuatro aspectos fundamentales involucrados en la vasculopatía de SSc.:
Angiogénesis defectuosa
Misma que debemos acoplar al ulterior desarrollo de fibrosis
y la participación de las celulas mesenquimatosas, fibroblastos, matriz extracelular agregadas a los demás mecanismos esquematizados en la imagen.

ENDOTELIO
CAPA MUSCULAR (MEDIA)
ADVENTICIA
Pericitos
Stem
Cell
Mioﬁbroblasto PLT
T
Fibroblasto
B
CP
Patogenia & SSc
Como ya se comentó la SSc es unica dentro del espectro de las enfermedades reumáticas debido al depósito acelerado de colageno y fibrosis tisular. En esta diapositiva abordo los
aspectos mas representativos en cuanto a la afectación vascular por SSc se refiere.

Patogenia & SSc
ADVENTICIA
Clinic Rev Allerg Immunol (2009) 36:150–175
Endothelial cells: The endothelium is a metabolically active tissue that, under normal circumstances, regulates regional blood flow, transportation of nutrients, regulating coagulation and fibrinolysis,
and migration of blood cells while maintaining an antithrombotic lining in the vasculature. These important biologic functions are achieved through production of a complex array of molecules
including vasodilators (e.g., nitric oxide and prostacyclin), vasoconstrictors (e.g., endothelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron
microscopy studies from skin biopsy specimens of patients demonstrate capillaries with thickening of the basement lamina and endothelial cells with a round or oval nucleus, cytoplasm filled with
intermediate filaments, swelling of the mitochondria, smooth vesicles, and remnants of endoplasmic reticulum suggestive of damaged endothelial cells.
The lumen of vessels was narrowed by endothelial cells, granular material, and platelets [77]. While light microscopy showed normal endothelial cells, other studies reported an increase in the number
of cytoplasmic intermediate filaments, reduced numbers of micropincytic vesicles, and luminal surface blebs [79, 80]. These findings are reminiscent of cells undergoing apoptosis. Perivascular
edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascular disease was seen in early skin lesions
before tissue fibrosis. [3H]Thymidine labeling of dermal tissue demon- strates increased labeling of endothelial cells consistent with perturbation of this cell layer [81, 82]. Basement membrane of
capillaries is thickened and displays evidence for increased fibronectin, collagen type IV, and laminin [78]. The main alterations seen by electron microscopy from studies of capillaries can be
summarized as (1) gaps, vacuolization, and eventual destruction of endothelial cells, (2) reduplication of the basal lamina, (3) perivascular cellular infiltrates consisting of lymphocytes, plasma cells,
macrophages, or monocytes, and (4) fibroblasts and pericytes with enlarged, rough endoplasmic reticulum accompanied by perivascular fibrosis [83]. These studies suggested that the endothelial
cells are being injured in scleroderma, and there is a perivascular cellular reaction underway involving immune cells and fibroblasts, a vascular–cellular interaction that precedes the later stage of
tissue fibrosis.
Skin biopsies were studied to define the biological phenotype of scleroderma endothelial cells and the potential associated cause of the loss of capillaries. The molecules defining the scleroderma
phenotype was the loss of vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation, and overexpression of antiangiogenic interferon alpha and
overexpression of RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis

Patogenia & SSc
ENDOTELIO
ADVENTICIA
tissue fibrosis.

Patogenia & SSc
ADVENTICIA
ENDOTELIO: PDGF, Endoteilna-1, Selectinas, Integrinas, NO, Prostaciclina
tissue fibrosis.

Patogenia & SSc
ADVENTICIA
Microscopía electrónica:
1) Huecos
2)Vacuolización/apoptosis
3) Inﬁltrado perivascular
inﬂamatorio
4) Fibroblastos y pericitos con
prominentes RER
5) Fibrosis perivascular
tissue fibrosis.

Patogenia & SSc
ADVENTICIA
Microscopía electrónica:
1) Huecos
2)Vacuolización/apoptosis
3) Infiltrado perivascular
inflamatorio
4) Fibroblastos y pericitos con
prominentes RER
5) Fibrosis perivascular
Fenotipo que Define
Vasculopatía en
esclerodermia:
- Pérdida de Caderina endotelial
- Sobreexpresión de RGS5
tissue fibrosis.

Patogenia & SSc
ENDOTELIO
ADVENTICIA
Antiangiogenicos Proangiogenicos
VEGF
Procoagulates/
Fibrinolísis
Vasodilatadores
Vasoconstrictores
The downstream effects of blood vessel perturbation produce “biomarkers” of vascular damage. Endothelial cell injury results in an increased production of cytokines like endothelin-1 or impaired
release of vasoactive molecules like nitric oxide (NO) and prostacyclin. This creates an imbalance of factors that regulate local blood flow and thus contributes to vascular instability seen in
scleroderma.
Activation of endothelial cells may also tip the balance of intravascular coagulation/fibrinolysis in favor of coagulation, alter release of vasoactive molecules, and trigger the release of growth,
profibrotic, and angiogenic factors. The disturbance in the vascular tissue has been detected by measuring circulating markers of vascular disease [85].
Studies of the peripheral blood involving series of scleroderma patients demonstrate abnormalities in factors and other markers of vascular perturbation including: von Willebrand factor; circulating
endothelin-1, soluble adhesion molecules, thrombospondin, thrombomodulin (TM), circulating endothelial cells, N-terminal pro-brain natriuretic peptide, antiendothelial cell antibodies, serum vascular
endothelial growth factor (VEGF), endostatin, plasminogen activator, prostacyclin and thromboxane metabolites. Evidence for endothelial cell dysfunction using skin biopsy material is also reported.
For example, studies of patient skin samples demonstrated platelet adhesion, decreased storage of factor VII-related antigen, and altered vessel morphology

Patogenia & SSc
ENDOTELIO
ADVENTICIA
Procoagulates/
Fibrinolísis
Von Willebrand factor
An increased Von Willebrand factor activity and factor VIII/von Willebrand factor (fVIII/vWf) antigen concentra- tions are reported in patients with scleroderma [86–89]. Higher circulating
levels of both activities are thought to reﬂect in vivo endothelial injury [86]. Skin biopsies from patients were studied using immunohistochemistry demon- strating that vWf is leaked to the
perivascular space/matrix and thus available for release into the systemic circulation [90]. Indicators of endothelial injury were further implied when patients with scleroderma were found to
have abnormal levels of vWf, circulating levels of immune complexes, and oxidized lipoproteins

Patogenia & SSc
ENDOTELIO
ADVENTICIA
Procoagulates/
Fibrinolísis
VwF$
VwF$
VwF$
VwF$
VwF$
VwF$
VwF$
VwF$
VwF$
VwF$
VwF$
VwF$
VwF$
VwF$
VwF$
Von Willebrand factor
An increased Von Willebrand factor activity and factor VIII/von Willebrand factor (fVIII/vWf) antigen concentra- tions are reported in patients with scleroderma [86–89]. Higher circulating
levels of both activities are thought to reﬂect in vivo endothelial injury [86]. Skin biopsies from patients were studied using immunohistochemistry demon- strating that vWf is leaked to the
perivascular space/matrix and thus available for release into the systemic circulation [90]. Indicators of endothelial injury were further implied when patients with scleroderma were found to
have abnormal levels of vWf, circulating levels of immune complexes, and oxidized lipoproteins

Patogenia & SSc
ENDOTELIO
ADVENTICIA
Procoagulates/
Fibrinolísis
Secundaria a Activación endotelial
Liberan PDGF y TGF-Beta
Beta-tromboglobulina, Tromboxano
Quimioatracción leucocitaria
Complejos plaqueta-Leucocito
PLT
Platelet activation
It is apparent that in vivo platelet activation in scleroderma is secondary to endothelial activation [103]. Activated platelets release a host of vasoactive and proﬁbrotic factors that mediate
vasoconstriction, platelet aggregation, leukocyte chemoattraction, activation of interstitial ﬁbroblasts, and proliferation of myointimal cells. Among these platelet products, platelet-derived
growth factor (PDGF) and TGF-β, in particular, are thought to play an important role in the biology of scleroderma by promoting increased production and deposition of extracellular matrix.
Several studies give evidence for activation of platelets in scleroderma including elevated levels of circulating platelet aggregates, increased plasma levels of β-thromboglobulin, enhanced
adhesion of scleroderma derived platelets, increased circulating microparticles containing platelet fragments, increased circulating platelet–leukocyte complexes, and increased urinary levels of
thromboxane likely derive from activated platelets

Patogenia & SSc
ENDOTELIO
ADVENTICIA
Procoagulates/
Fibrinolísis
VwF$
VwF$
VwF$
Activación
Plaquetaria
Secundaria a Activación endotelial
Liberan PDGF y TGF-Beta
Beta-tromboglobulina, Tromboxano
Quimioatracción leucocitaria
Complejos plaqueta-Leucocito
PLT
Platelet activation
It is apparent that in vivo platelet activation in scleroderma is secondary to endothelial activation [103]. Activated platelets release a host of vasoactive and proﬁbrotic factors that mediate
vasoconstriction, platelet aggregation, leukocyte chemoattraction, activation of interstitial ﬁbroblasts, and proliferation of myointimal cells. Among these platelet products, platelet-derived
growth factor (PDGF) and TGF-β, in particular, are thought to play an important role in the biology of scleroderma by promoting increased production and deposition of extracellular matrix.
Several studies give evidence for activation of platelets in scleroderma including elevated levels of circulating platelet aggregates, increased plasma levels of β-thromboglobulin, enhanced
adhesion of scleroderma derived platelets, increased circulating microparticles containing platelet fragments, increased circulating platelet–leukocyte complexes, and increased urinary levels of
thromboxane likely derive from activated platelets

Patogenia & SSc
ENDOTELIO
ADVENTICIA
Procoagulates/
Fibrinolísis
Interacciones:
Cel-Cel
Cel-Matriz
E- Selectina / P-Selectina
Mol. de Adhesión Celular 1
Integrinas: B-1 y B-4
ELAM-1/ sELAM-1
ICAM-1/ sICAM-1
VCAM-1 / sICAM-1
Adhesion molecules
Another marker of vascular disease is the presence of adhesion proteins involved in cell–cell interaction and cell– matrix interactions that are found elevated in scleroderma skin, especially in
perivascular infiltrates. Isolated microvascular endothelial cells express adhesion molecules E-selectin, intercellular adhesion molecule-1, and beta-1 and beta-4 integrin receptors in cell culture [113].
The endothelial leukocyte adhesion molecule 1 (ELAM-1) and intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule (VCAM-1), E-selectin, and P- selectin are found in endothelial
cells in skin from patients with rapidly progressive scleroderma but not in normal skin.
The soluble form of endothelial leukocyte adhesion molecule-1 (sELAM) is also reported elevated in scleroderma .
Soluble intercellular adhesion molecule-1 and soluble interleukin-2 receptors were significantly increased in both plasma and suction blister fluid from systemic sclerosis patients compared with healthy
volun- teers, providing evidence for activation of endothelial cells and CD3-positive cells, T cells in scleroderma patients.
Several other reports confirm that increased circulating sICAM-1, sVCAM-1, P-selectin, and E-selectin occur in scleroderma compared to controls
To evaluate the relationship between systemic manifestations and immunological markers of endothelial cell activation, sVCAM-1, soluble E-selectin, VEGF, and ET-1 were determined to be elevated in
scleroderma patients who had significant organ involvement.
Interestingly, a study of subtypes of scleroderma suggests that injury to the pulmonary and renal vascular may have distinct mechanisms.
In patients with scleroderma renal crisis, the level of E-selectin, sVCAM-1, and sICAM-1 were elevated, but they were not consistently elevated in patients with pulmonary hypertension

Patogenia & SSc
ENDOTELIO
ADVENTICIA
Procoagulates/
Fibrinolísis
Moléculas de
Adhesión
Interacciones:
Cel-Cel
Cel-Matriz
E- Selectina / P-Selectina
Mol. de Adhesión Celular 1
Integrinas: B-1 y B-4
ELAM-1/ sELAM-1
ICAM-1/ sICAM-1
VCAM-1 / sICAM-1
Adhesion molecules
Another marker of vascular disease is the presence of adhesion proteins involved in cell–cell interaction and cell– matrix interactions that are found elevated in scleroderma skin, especially in
perivascular infiltrates. Isolated microvascular endothelial cells express adhesion molecules E-selectin, intercellular adhesion molecule-1, and beta-1 and beta-4 integrin receptors in cell culture [113].
The endothelial leukocyte adhesion molecule 1 (ELAM-1) and intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule (VCAM-1), E-selectin, and P- selectin are found in endothelial
cells in skin from patients with rapidly progressive scleroderma but not in normal skin.
The soluble form of endothelial leukocyte adhesion molecule-1 (sELAM) is also reported elevated in scleroderma .
Soluble intercellular adhesion molecule-1 and soluble interleukin-2 receptors were significantly increased in both plasma and suction blister fluid from systemic sclerosis patients compared with healthy
volun- teers, providing evidence for activation of endothelial cells and CD3-positive cells, T cells in scleroderma patients.
Several other reports confirm that increased circulating sICAM-1, sVCAM-1, P-selectin, and E-selectin occur in scleroderma compared to controls
To evaluate the relationship between systemic manifestations and immunological markers of endothelial cell activation, sVCAM-1, soluble E-selectin, VEGF, and ET-1 were determined to be elevated in
scleroderma patients who had significant organ involvement.
Interestingly, a study of subtypes of scleroderma suggests that injury to the pulmonary and renal vascular may have distinct mechanisms.
In patients with scleroderma renal crisis, the level of E-selectin, sVCAM-1, and sICAM-1 were elevated, but they were not consistently elevated in patients with pulmonary hypertension

Patogenia & SSc
ENDOTELIO
ADVENTICIA
Vasoconstrictores
ET-1
ET-1
ET-1
Endothelin-1
Endothelin-1 is a 21-amino-acid peptide with potent vasoconstrictive and proliferative effects that could mediate vascular injury and tissue fibrosis in scleroderma [92, 93]. Endothelin-1
released from the endothelial cells can act on vascular smooth muscle cells potentially inducing the expression of vascular myofibroblast. It can also act in an autocrine manner on the vascular
endothelium itself. There are multiple sources of ET-1 in addition to endothelial cells including macrophages, epithelial cells, and mesenchymal cells. Enothelin-1 is elevated in the plasma of
patients compared to controls, and it increases during cold exposure in selected scleroderma patients [94]. Endothelin-1 is found in association with high levels of soluble intercellular adhesion
molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and thrombomodulin in the blood of scleroderma patients [95–100]. The localiza- tion of ET-1 on specimens
obtained by skin biopsies find that ET-1 deposits in the endothelial cells and dermal fibroblasts and has a positive correlation with the serum levels of ET-1 [101]. Another study found a
significant increase of ET-1, tissue-type plasminogen, plasminogen activator inhibitor, transforming growth factor-beta, and β- thromboglobulin in patients with scleroderma suggesting both
involvement of endothelial cells and associated platelet activation [102]. Elevated ET-1 is not only a biomarker of vascular disease, but may itself be causing abnormal vascular reactivity and
mediating tissue fibrosis by its pro-fibrotic properties via activating TGF-β. Therefore, inhibiting ET-1 activity is considered an attractive target in treating scleroderma vascular disease

Patogenia & SSc
ENDOTELIO
ADVENTICIA
VasoconstrictoresENDOTELINA-1
ET-1
ET-1
ET-1
Fuentes de endotelina:
- Cel. Endotelial
- Macrofago
- Cel. Epiteliales
- Cel. Mesenquimales
Endothelin-1

Patogenia & SSc
ENDOTELIO
ADVENTICIA
VasoconstrictoresENDOTELINA-1
ET-1
ET-1
ET-1
Acciones de ET-1 en SSc:
- Vasocontricción
- Induce proliferación
- Activación plaquetaria
- Expresa sICAM-1 sVCAM
- Induce TGF-Beta
VCAM
/ICAM'
VCAM
/ICAM'
VCAM
/ICAM'
VCAM
/ICAM'
Endothelin-1

Patogenia & SSc
ENDOTELIO
ADVENTICIA
Baja expresión de β3
integrina
PTX3
ENDOSTATINA
Angiostatina
μPA/μPA receptor +
MMP-12
Kalistatina
VEGF A la alza
VEGFR-1
FGF2
TGF-β
Activadores del
plasminógeno
Kininas/Kalikreina
9,11,12 a la baja
Plasma&
Tóxico&
There is both clinical and in vitro evidence for defective angiogenesis in scleroderma .
For example, the finding of decreased capillary density in the skin and a low tissue expression of the β3 integrin complex, molecules important in facilitating the action of vascular endothelial
growth factor, is consistent with disordered angiogenesis. Serum from scleroderma patients is toxic for endothelial cells and in vitro studies demonstrate inhibition of cell migration and
vascular tube formation. Mononuclear cell support of angiogenesis is also abnormal in scleroderma. There are also several studies suggesting an imbalance of the production of proangiogenic
and antiangiogenic factors, thus favoring a decreased ability to form new vessels. Giusti et al. identified genes involved in impaired angiogenesis by compared transcriptosomes of
microvascular endothelial cells from normal subjects and patients with scleroderma. Scleroderma endothelial cells over-expressed proangiogenic transcripts but also up-regulated a variety of
genes that have a negative effect on angiogenesis.
These authors speculate from their data (including in vitro studies of endothelial cell invasion and migration) that stabilization of a proangiogenic pattern dictated by angiogenesis factors (e.g.,
VEGF) is blocked or altered by up-regulation of angiogenesis inhibitors such as the pent(r)axin-3 (PTX3), known to inhibit the proangiogenic effect of fibroblast growth factor-2 (FGF2).
Paradoxically, despite clinical and laboratory evidence of defect angiogensis in scleroderma, there is an increase in VEGF, a key mediator of angiogensis and endothelial cell survival.
Transforming growth factor β1 released from immune cells and tissue matrix can activate fibroblast and also promote angiogenesis.
In fact, an in vitro study using skin biopsies cultured with chick embryo chorioallantoic membrane demonstrated that scleroderma samples increased vascular counts and promoted a dense
mononuclear cell infiltrate when compared to normal skin, a finding consistent with increased proangiogenic factors in the scleroderma skin.
High levels of VEGF were found in early in disease and in cases without digital ulcers suggesting that the VEGF was present to enhance vascular repair. VEGF exerts its function by binding to
the tyrosine kinase receptors VEGFR1 (flt-1) and VEGFR2 (flk-1). Skin biopsies from the forearm of patients with scleroderma investigated the expression of VEGF, VEGFR- 2, and GLUT-1,
the hypoxia-associated glucose transporter molecule.
Increased GLUT-1 provides evidence for tissue hypoxia, and increased unbound VEGF suggest a source for increased blood levels of VEGF .

Patogenia & SSc
ENDOTELIO
ADVENTICIA
Angiogénesis
integrina
PTX3
ENDOSTATINA
Angiostatina
MMP-12
Kalistatina
VEGF A la alza
VEGFR-1
FGF2
TGF-β
Activadores del
plasminógeno
Kininas/Kalikreina
9,11,12 a la baja
Plasma&
Tóxico&

Patogenia & SSc
ENDOTELIO
ADVENTICIA
AngiogénesisAntiangiogénicos Proangiogénicos
integrina
PTX3
ENDOSTATINA
Angiostatina
MMP-12
Kalistatina
VEGF A la alza
VEGFR-1
FGF2
TGF-β
Activadores del
plasminógeno
Kininas/Kalikreina
9,11,12 a la baja
Plasma&
Tóxico&

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