Fenómeno de Raynaud

Patogenia y

Diagnóstico Diferencial

Ignacio Alfredo Valerio MoralesMédico Residente en Reumatología

martes, 10 de septiembre de 13

Fenómeno de RaynaudHistoria

http://www.historiadelamedicina.org/raynaud.html

Maurice Auguste Gabriel Raynaud (1834 - 1881)

1862

Anatomía patológica Francesa1862 Tesis doctoral1866 Profesor de Curso Sainte-Périne,

Saint Antoine (ejército)Varios artículos1876 Medalla de oro del Cólera Estudios en Gangrenas

1929 Thomas Lewis

martes, 10 de septiembre de 13Nació 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.

Fenómeno de RaynaudHistoria

http://www.historiadelamedicina.org/raynaud.html

Maurice Auguste Gabriel Raynaud (1834 - 1881)

1862

Anatomía patológica Francesa1862 Tesis doctoral1866 Profesor de Curso Sainte-Périne,

Saint Antoine (ejército)Varios artículos1876 Medalla de oro del Cólera Estudios en Gangrenas

1929 Thomas Lewis

martes, 10 de septiembre de 13Nació 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.

Fenómeno de RaynaudHistoria

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

martes, 10 de septiembre de 13Thomas 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.

Fenómeno de RaynaudHistoria

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

martes, 10 de septiembre de 13Thomas 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.

Fenómeno de RaynaudIntroducción

“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) 633–653martes, 10 de septiembre de 13Episodic 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.

Fenómeno de RaynaudIntroducción

“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) 633–653martes, 10 de septiembre de 13Episodic 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.

Fenómeno de RaynaudEpidemiología

Distribución mundialAfecta 3-5% de la poblaciónIncidencia 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:S10-5Reumatol Clin. 2008;4(2):59-66 / Lancet 2001; 357: 2042–48

martes, 10 de septiembre de 13New onset RP should, therefore, prompt consideration and examination for signs and symptoms of systemic disease and, potentially, further rheumatological evaluation.

Fenómeno de RaynaudEpidemiología

Distribución mundialAfecta 3-5% de la poblaciónIncidencia 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:S10-5Reumatol Clin. 2008;4(2):59-66 / Lancet 2001; 357: 2042–48

martes, 10 de septiembre de 13New onset RP should, therefore, prompt consideration and examination for signs and symptoms of systemic disease and, potentially, further rheumatological evaluation.

Fenómeno de RaynaudEpidemiología Factores de Riesgo

Historia Familiar en 25%Sexo FemeninoClima FríoOcupacion: VibraciónEdad en hombresETOH y Estado Marital en MujeresBetabloqueadores, TRHHipertensión arterial Consumo de TabacoEdad Promedio de presentación 14

años27% Despúes de los 40 añosInicio - 2 años - 12.6% tendrá

enfermedad de tejido conectivoSSc en 15 a 20% si hay

Anormalidades capilares de uña + AutoAc al presentarse el FdR

Reumatol Clin. 2006;2 Supl 3:S10-5Reumatol Clin. 2008;4(2):59-66

martes, 10 de septiembre de 13

Fenómeno de RaynaudEpidemiología Factores de Riesgo

Historia Familiar en 25%Sexo FemeninoClima FríoOcupacion: VibraciónEdad en hombresETOH y Estado Marital en MujeresBetabloqueadores, TRHHipertensión arterial Consumo de TabacoEdad Promedio de presentación 14

años27% Despúes de los 40 añosInicio - 2 años - 12.6% tendrá

enfermedad de tejido conectivoSSc en 15 a 20% si hay

Anormalidades capilares de uña + AutoAc al presentarse el FdR

Reumatol Clin. 2006;2 Supl 3:S10-5Reumatol Clin. 2008;4(2):59-66

martes, 10 de septiembre de 13

Clasificación

Fenómeno de RaynaudClasificación

martes, 10 de septiembre de 13

Fenómeno de RaynaudClasificación

F.#Raynaud

#

Primario#

Secundario#

Lanc

et 2

001;

357

: 204

2–48

martes, 10 de septiembre de 13Raynaud’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

Fenómeno de RaynaudClasificación

F.#Raynaud

#

Primario#

Secundario#

Lanc

et 2

001;

357

: 204

2–48

martes, 10 de septiembre de 13Raynaud’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

Fenómeno de RaynaudClasificación

F.#Raynaud

#

Primario#

Secundario#

Lanc

et 2

001;

357

: 204

2–48

martes, 10 de septiembre de 13Raynaud’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

Fenómeno de RaynaudClasificación

F.#Raynaud

#

Primario#

Secundario#

Riesgo de progresión a Enf. Tejido Conectivo

2%a 10 años + > 6.3%

Landry et al. J Vasc Surg 1996; 23: 76–78.

Seropositividad

Lanc

et 2

001;

357

: 204

2–48

martes, 10 de septiembre de 13Raynaud’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

Fenómeno de RaynaudClasificación Primario vs Secundario

Reumatol Clin. 2006;2 Supl 3:S10-5Reumatol Clin. 2008;4(2):59-66 / Lancet 2001; 357: 2042–48

martes, 10 de septiembre de 13Vascular 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.

Fenómeno de RaynaudClasificación Primario vs Secundario

Disfunción Vascular primaria totalmente reversible = Primario

Reumatol Clin. 2006;2 Supl 3:S10-5Reumatol Clin. 2008;4(2):59-66 / Lancet 2001; 357: 2042–48

martes, 10 de septiembre de 13Vascular 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.

Fenómeno de RaynaudClasificación Primario vs Secundario

Disfunción Vascular primaria totalmente reversible = Primario

Vasculopatía - Fibrosis - -Proliferación - Trombosis = Secundario (SS)Reumatol Clin. 2006;2 Supl 3:S10-5

Reumatol Clin. 2008;4(2):59-66 / Lancet 2001; 357: 2042–48

martes, 10 de septiembre de 13Vascular 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.

Fisiopatogenia

Fenómeno de RaynaudPatogenia

martes, 10 de septiembre de 13

Fenómeno de RaynaudPatogenia

Fisiopatogenia &

Fenómeno de Raynaud Primario

martes, 10 de septiembre de 13

Fenómeno de RaynaudPatogenia GENÉTICA

ARTHRITIS & RHEUMATISM , 43,(7),2000, pp 1641–1646martes, 10 de septiembre de 13The 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 con- taining 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.

Fenómeno de RaynaudPatogenia GENÉTICA

ARTHRITIS & RHEUMATISM , 43,(7),2000, pp 1641–1646martes, 10 de septiembre de 13The 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 con- taining 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.

Fenómeno de RaynaudPatogenia GENÉTICA

ARTHRITIS & RHEUMATISM , 43,(7),2000, pp 1641–1646martes, 10 de septiembre de 13The 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 con- taining 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+

Fenómeno de RaynaudPatogenia

VasoconstricciónVasodilataciónRheumatology (Oxford) 45 (2006) iii33–35.

N. Engl. J. Med. 347 (2002) 1001–1008./ Rheum. Dis. Clin. North. Am. 29 (2003) 275–291 martes, 10 de septiembre de 13In 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+

Fenómeno de RaynaudPatogenia

VasoconstricciónVasodilataciónRheumatology (Oxford) 45 (2006) iii33–35.

N. Engl. J. Med. 347 (2002) 1001–1008./ Rheum. Dis. Clin. North. Am. 29 (2003) 275–291 martes, 10 de septiembre de 13In 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+

Fenómeno de RaynaudPatogenia

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

martes, 10 de septiembre de 13In 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

Fenómeno de RaynaudPatogenia

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

VASCULAR

INTRAVASCULAR NEURAL

OTROS

martes, 10 de septiembre de 13

Fenómeno de RaynaudPatogenia

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

VASCULAR

INTRAVASCULAR NEURAL

OTROS

Endotelio Prostaciclina

NO Endotelina-1*

Angiotensinogeno* *.-Profibrótico

sobreexpresado en SSc

Proliferación Contracción-relajación Agregación plaquetaria Baja Adhesión Leucos

Músculo Liso

martes, 10 de septiembre de 13

Vía autonómica Vía Sensorial

Receptores alfa-adrenérgicos*

Regulan(Va

sos(

1-Simpático: (Norepi) 2- Parasimpático (Sustancia

P, VIP, CGRP, NKA) 3- Sensitivas

4 - SNC

Fenómeno de RaynaudPatogenia

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

VASCULAR

INTRAVASCULAR NEURAL

OTROS

Endotelio Prostaciclina

NO Endotelina-1*

Angiotensinogeno* *.-Profibrótico

sobreexpresado en SSc

Proliferación Contracción-relajación Agregación plaquetaria Baja Adhesión Leucos

Músculo Liso

martes, 10 de septiembre de 13

Vía autonómica Vía Sensorial

Receptores alfa-adrenérgicos*

Regulan(Va

sos(

1-Simpático: (Norepi) 2- Parasimpático (Sustancia

P, VIP, CGRP, NKA) 3- Sensitivas

4 - SNC

Fenómeno de RaynaudPatogenia

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

VASCULAR

INTRAVASCULAR NEURAL

OTROS

Endotelio Prostaciclina

NO Endotelina-1*

Angiotensinogeno* *.-Profibrótico

sobreexpresado en SSc

Proliferación Contracción-relajación Agregación plaquetaria Baja Adhesión Leucos

Músculo Liso

+ Adhesión plaquetaria/activación Fibrinólisis

Defectuosa! +Trombina

+ Viscosidad sanguínea

Vasoconstrictores Serotonina

TGF-B PDGF

Profibrosis

martes, 10 de septiembre de 13

Vía autonómica Vía Sensorial

Receptores alfa-adrenérgicos*

Regulan(Va

sos(

1-Simpático: (Norepi) 2- Parasimpático (Sustancia

P, VIP, CGRP, NKA) 3- Sensitivas

4 - SNC

Fenómeno de RaynaudPatogenia

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

VASCULAR

INTRAVASCULAR NEURAL

OTROS

Endotelio Prostaciclina

NO Endotelina-1*

Angiotensinogeno* *.-Profibrótico

sobreexpresado en SSc

Proliferación Contracción-relajación Agregación plaquetaria Baja Adhesión Leucos

Músculo Liso

+ Adhesión plaquetaria/activación Fibrinólisis

Defectuosa! +Trombina

+ Viscosidad sanguínea

Vasoconstrictores Serotonina

TGF-B PDGF

Profibrosis

Endocrino: Estrógenos – R-Alfa adrenérgicos Hematológico: Viscosidad +, Deformabilidad -

martes, 10 de septiembre de 13

Fenómeno de RaynaudPatogenia

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

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+

martes, 10 de septiembre de 13

Fenómeno de RaynaudPatogenia

Factores Involucrados

en la patogenia del

Fenómeno de Raynaud

Primario

Reumatol Clin. 2006;2 Supl 3:S10-5

martes, 10 de septiembre de 13

Fenómeno de RaynaudPatogenia

Factores Involucrados

en la patogenia del

Fenómeno de Raynaud

Primario

Reumatol Clin. 2006;2 Supl 3:S10-5

martes, 10 de septiembre de 13

Fenómeno de RaynaudPatogenia

Factores Involucrados

en la patogenia del

Fenómeno de Raynaud

Primario

Reumatol Clin. 2006;2 Supl 3:S10-5

martes, 10 de septiembre de 13

Fenómeno de RaynaudPatogenia

Factores Involucrados

en la patogenia del

Fenómeno de Raynaud

Primario

Reumatol Clin. 2006;2 Supl 3:S10-5

martes, 10 de septiembre de 13

Fenómeno de RaynaudPatogenia

Factores Involucrados

en la patogenia del

Fenómeno de Raynaud

Primario

Reumatol Clin. 2006;2 Supl 3:S10-5

martes, 10 de septiembre de 13

Fenómeno de RaynaudPatogenia

Factores Involucrados

en la patogenia del

Fenómeno de Raynaud

Primario

Reumatol Clin. 2006;2 Supl 3:S10-5

martes, 10 de septiembre de 13

Fenómeno de RaynaudPatogenia

Disfunción Vascular&

EspectroEsclerosis Sistémica

martes, 10 de septiembre de 13Systemic 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

Fenómeno de RaynaudPatogenia & SSc

Fibroblasto*

Endotelio*

miRNA*

S.*Inmunológico*

Estrés*Oxida=vo*

Trojanowska, M. Nat. Rev. Rheumatol. 6, 453–460 (2010)

martes, 10 de septiembre de 13Cellular 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.

Fenómeno de RaynaudPatogenia & SSc

Trojanowska, M. Nat. Rev. Rheumatol. 6, 453–460 (2010)

martes, 10 de septiembre de 13Cellular 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.

Fenómeno de RaynaudPatogenia & SSc

Trojanowska, M. Nat. Rev. Rheumatol. 6, 453–460 (2010)

martes, 10 de septiembre de 13

Fenómeno de RaynaudPatogenia & SSc

Gabrielli A et al. N Engl J Med 2009;360:1989-2003.

martes, 10 de septiembre de 13Figure 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.

Fenómeno de RaynaudPatogenia & SSc

Indian Journal of Dermatology 2013; 58(4)martes, 10 de septiembre de 13Si 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 defectuosaMisma que debemos acoplar al ulterior desarrollo de fibrosisy la participación de las celulas mesenquimatosas, fibroblastos, matriz extracelular agregadas a los demás mecanismos esquematizados en la imagen.

Fenómeno de RaynaudPatogenia & SSc

Angiogenesis defectuosaVasculopatía-FibrosisCel. Mesenquimatosas

Matriz ExtracelularIndian Journal of Dermatology 2013; 58(4)

martes, 10 de septiembre de 13Si 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 defectuosaMisma que debemos acoplar al ulterior desarrollo de fibrosisy la participación de las celulas mesenquimatosas, fibroblastos, matriz extracelular agregadas a los demás mecanismos esquematizados en la imagen.

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Pericitos

Stem Cell

Miofibroblasto PLT

T

Fibroblasto

BCP

Fenómeno de RaynaudPatogenia & SSc

martes, 10 de septiembre de 13Como 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.

Fenómeno de RaynaudPatogenia & SSc

CAPA MUSCULAR (MEDIA)

ADVENTICIA

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Endothelial 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., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy 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 apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar 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

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Endothelial 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., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy 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 apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar 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

Fenómeno de RaynaudPatogenia & SSc

CAPA MUSCULAR (MEDIA)

ADVENTICIA

ENDOTELIO: PDGF, Endoteilna-1, Selectinas, Integrinas, NO, Prostaciclina

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Endothelial 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., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy 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 apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar 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

Fenómeno de RaynaudPatogenia & SSc

CAPA MUSCULAR (MEDIA)

ADVENTICIA

ENDOTELIO: PDGF, Endoteilna-1, Selectinas, Integrinas, NO, Prostaciclina

Microscopía electrónica:1) Huecos

2)Vacuolización/apoptosis3) Infiltrado perivascular

inflamatorio4) Fibroblastos y pericitos con

prominentes RER5) Fibrosis perivascular

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Endothelial 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., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy 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 apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar 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

Fenómeno de RaynaudPatogenia & SSc

CAPA MUSCULAR (MEDIA)

ADVENTICIA

ENDOTELIO: PDGF, Endoteilna-1, Selectinas, Integrinas, NO, Prostaciclina

Microscopía electrónica:1) Huecos

2)Vacuolización/apoptosis3) Infiltrado perivascular

inflamatorio4) Fibroblastos y pericitos con

prominentes RER5) Fibrosis perivascular

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Endothelial 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., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy 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 apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar 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

Fenómeno de RaynaudPatogenia & SSc

CAPA MUSCULAR (MEDIA)

ADVENTICIA

ENDOTELIO: PDGF, Endoteilna-1, Selectinas, Integrinas, NO, Prostaciclina

Microscopía electrónica:1) Huecos

2)Vacuolización/apoptosis3) Infiltrado perivascular

inflamatorio4) Fibroblastos y pericitos con

prominentes RER5) Fibrosis perivascular

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Endothelial 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., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy 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 apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar 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

Fenómeno de RaynaudPatogenia & SSc

CAPA MUSCULAR (MEDIA)

ADVENTICIA

ENDOTELIO: PDGF, Endoteilna-1, Selectinas, Integrinas, NO, Prostaciclina

Microscopía electrónica:1) Huecos

2)Vacuolización/apoptosis3) Infiltrado perivascular

inflamatorio4) Fibroblastos y pericitos con

prominentes RER5) Fibrosis perivascular

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Endothelial 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., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy 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 apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar 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

Fenómeno de RaynaudPatogenia & SSc

CAPA MUSCULAR (MEDIA)

ADVENTICIA

ENDOTELIO: PDGF, Endoteilna-1, Selectinas, Integrinas, NO, Prostaciclina

Microscopía electrónica:1) Huecos

2)Vacuolización/apoptosis3) Infiltrado perivascular

inflamatorio4) Fibroblastos y pericitos con

prominentes RER5) Fibrosis perivascular

Fenotipo que Define Vasculopatía en esclerodermia:

- Pérdida de Caderina endotelial- Sobreexpresión de RGS5

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Endothelial 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., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy 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 apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar 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

Fenómeno de RaynaudPatogenia & SSc

CAPA MUSCULAR (MEDIA)

ADVENTICIA

ENDOTELIO: PDGF, Endoteilna-1, Selectinas, Integrinas, NO, Prostaciclina

Microscopía electrónica:1) Huecos

2)Vacuolización/apoptosis3) Infiltrado perivascular

inflamatorio4) Fibroblastos y pericitos con

prominentes RER5) Fibrosis perivascular

Fenotipo que Define Vasculopatía en esclerodermia:

- Pérdida de Caderina endotelial- Sobreexpresión de RGS5

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Endothelial 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., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy 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 apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar 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

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Antiangiogenicos Proangiogenicos

VEGF

Procoagulates/Fibrinolísis

Vasodilatadores

Vasoconstrictores

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13The 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 coagula- tion, 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 adhe- sion 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

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Antiangiogenicos Proangiogenicos

VEGF

Procoagulates/Fibrinolísis

Vasodilatadores

Vasoconstrictores

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13The 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 coagula- tion, 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 adhe- sion 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

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Procoagulates/Fibrinolísis

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Von 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

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Procoagulates/Fibrinolísis

VwF$

VwF$

VwF$VwF$

VwF$

VwF$VwF$

VwF$

VwF$

VwF$

VwF$

VwF$

VwF$

VwF$

VwF$

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Von 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

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Procoagulates/Fibrinolísis

Secundaria a Activación endotelialLiberan PDGF y TGF-Beta

Beta-tromboglobulina, TromboxanoQuimioatracción leucocitaria

Complejos plaqueta-Leucocito

PLT

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Platelet activation

It is apparent that in vivo platelet activation in sclero- derma 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 includ- ing 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

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Procoagulates/Fibrinolísis

VwF$

VwF$

VwF$

Activación Plaquetaria

Secundaria a Activación endotelialLiberan PDGF y TGF-Beta

Beta-tromboglobulina, TromboxanoQuimioatracción leucocitaria

Complejos plaqueta-Leucocito

PLT

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Platelet activation

It is apparent that in vivo platelet activation in sclero- derma 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 includ- ing 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

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Procoagulates/Fibrinolísis

Interacciones:Cel-Cel

Cel-Matriz

E- Selectina / P-SelectinaMol. de Adhesión Celular 1Integrinas: B-1 y B-4ELAM-1/ sELAM-1ICAM-1/ sICAM-1VCAM-1 / sICAM-1

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Adhesion 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

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Procoagulates/Fibrinolísis

Moléculas de Adhesión

Interacciones:Cel-Cel

Cel-Matriz

E- Selectina / P-SelectinaMol. de Adhesión Celular 1Integrinas: B-1 y B-4ELAM-1/ sELAM-1ICAM-1/ sICAM-1VCAM-1 / sICAM-1

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Adhesion 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

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Vasoconstrictores

ET-1

ET-1

ET-1

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Endothelin-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

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

VasoconstrictoresENDOTELINA-1

ET-1

ET-1

ET-1

Fuentes de endotelina:- Cel. Endotelial- Macrofago- Cel. Epiteliales- Cel. Mesenquimales

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Endothelin-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

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

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'

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Endothelin-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

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Baja expresión de β3 integrina

PTX3ENDOSTATINA

AngiostatinaμPA/μPA receptor +

MMP-12Kalistatina

VEGF A la alzaVEGFR-1

FGF2TGF-β

Activadores del plasminógeno

Kininas/Kalikreina9,11,12 a la baja

Plasma&Tóxico&

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13There 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 endo- thelial 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 .

Up- regulation of VEGF and its receptors VEGFR-1 and VEGFR-2, found in skin specimens of scleroderma patients, suggest a chronic increase in VEGF may actually mediate aberrant microvessels. This may occur if other necessary growth factors are defective, and the high levels of VEGFR actually blocks VEGF action and inhibits angiogenesis. Interestingly, an increased blood level of flt- 1 (VEGFR-1) is associated with placental vascular disease and preeclampsia in systemic lupus erythematosus.

Endostatin, a angiogenesis inhibitor derived from type XVIII collagen, is also elevated compared to controls, and this increase associates with the presence of more severe clinical involvement. A recent study noted that scleroderma patients have an increase in intact plasminogen, normal plasmin, and increased amounts of the cleavage fragment of plasminogen and angiostatin, another potent inhibitor of angiogenesis. These investigators postulated that proteases released by activated immune cells cleave plasminogen via granzyme B, increase angiostatin, and thus inhibit new vessel formation. They provide convincing in vitro data using scleroderma plasma to support this concept.

Microvascular endothelial cells must lyse extracellular matrix to enter surrounding tissue and form new vessels. Plasminogen activators are important in angiogenesis by altering the adhesion of endothelial cells to tissue matrix. Endothelial cells isolated from the dermis of patients with diffuse scleroderma and the cell-associated urokinase-type plasminogen activator (μPA)/μPA receptor (μPAR) system was therefore investigated .

Overproduction of matrix metalloproteinase 12 (MMP-12) by scleroderma endothelial cells accounted for cleavage of μPAR and an impairment of angiogenesis in vitro, suggesting that this pathway inhibits activation of plasminogen and thus may contribute to reduced angiogenesis.

Kallikreins are also proteolytic enzymes that hydrolyze kininogens to kinins, thus leading to cleavage of plasmin. Kinins are thought to promote angiogenesis, since they play a role that leads to endothelial cell migration, proliferation, and differentiation. Tissue kallikrein is increased in the serum of scleroderma patients, particularly in those with signs of early vascular disease. Kallistatin, the natural inhibitor of tissue kallikrein, is localized in skin samples from scleroderma patients in the endothelial cells of the microvessels and in the perivascualr infiltrate, while blood levels are not increased . These data suggest that the release of kinins as part of the early inflammatory phase of scleroderma may be a compensatory attempt to promote angiogenesis. However, a decreased expression of kallikreins 9, 11, and 12 in scleroderma cells compared to normal was also reported.

Thus, evidence suggests that, during the acute inflammatory phase of scleroderma, proangiogenic factors like VEGF and kinins are released perhaps to promote new vessels. However, a variety of proteolytic enzymes are active including granzymes that cleave plasminogen to produce angiostatin and MMP-12 to cleave μPAR, while abnormally low levels of specific kallikreins diminish generation of kinins. These laboratory data coupled with the clinical features of scleroderma vascular disease strongly support the concept that, despite increased levels of proangiogenic factors, there is a number of antiangiogenic pathways that create defective angiogenesis prevent- ing new vessel formation. There is also evidence of impaired vascular repair or vasculogenesis.

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Angiogénesis

Baja expresión de β3 integrina

PTX3ENDOSTATINA

AngiostatinaμPA/μPA receptor +

MMP-12Kalistatina

VEGF A la alzaVEGFR-1

FGF2TGF-β

Activadores del plasminógeno

Kininas/Kalikreina9,11,12 a la baja

Plasma&Tóxico&

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13There 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 endo- thelial 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 .

Up- regulation of VEGF and its receptors VEGFR-1 and VEGFR-2, found in skin specimens of scleroderma patients, suggest a chronic increase in VEGF may actually mediate aberrant microvessels. This may occur if other necessary growth factors are defective, and the high levels of VEGFR actually blocks VEGF action and inhibits angiogenesis. Interestingly, an increased blood level of flt- 1 (VEGFR-1) is associated with placental vascular disease and preeclampsia in systemic lupus erythematosus.

Endostatin, a angiogenesis inhibitor derived from type XVIII collagen, is also elevated compared to controls, and this increase associates with the presence of more severe clinical involvement. A recent study noted that scleroderma patients have an increase in intact plasminogen, normal plasmin, and increased amounts of the cleavage fragment of plasminogen and angiostatin, another potent inhibitor of angiogenesis. These investigators postulated that proteases released by activated immune cells cleave plasminogen via granzyme B, increase angiostatin, and thus inhibit new vessel formation. They provide convincing in vitro data using scleroderma plasma to support this concept.

Microvascular endothelial cells must lyse extracellular matrix to enter surrounding tissue and form new vessels. Plasminogen activators are important in angiogenesis by altering the adhesion of endothelial cells to tissue matrix. Endothelial cells isolated from the dermis of patients with diffuse scleroderma and the cell-associated urokinase-type plasminogen activator (μPA)/μPA receptor (μPAR) system was therefore investigated .

Overproduction of matrix metalloproteinase 12 (MMP-12) by scleroderma endothelial cells accounted for cleavage of μPAR and an impairment of angiogenesis in vitro, suggesting that this pathway inhibits activation of plasminogen and thus may contribute to reduced angiogenesis.

Kallikreins are also proteolytic enzymes that hydrolyze kininogens to kinins, thus leading to cleavage of plasmin. Kinins are thought to promote angiogenesis, since they play a role that leads to endothelial cell migration, proliferation, and differentiation. Tissue kallikrein is increased in the serum of scleroderma patients, particularly in those with signs of early vascular disease. Kallistatin, the natural inhibitor of tissue kallikrein, is localized in skin samples from scleroderma patients in the endothelial cells of the microvessels and in the perivascualr infiltrate, while blood levels are not increased . These data suggest that the release of kinins as part of the early inflammatory phase of scleroderma may be a compensatory attempt to promote angiogenesis. However, a decreased expression of kallikreins 9, 11, and 12 in scleroderma cells compared to normal was also reported.

Thus, evidence suggests that, during the acute inflammatory phase of scleroderma, proangiogenic factors like VEGF and kinins are released perhaps to promote new vessels. However, a variety of proteolytic enzymes are active including granzymes that cleave plasminogen to produce angiostatin and MMP-12 to cleave μPAR, while abnormally low levels of specific kallikreins diminish generation of kinins. These laboratory data coupled with the clinical features of scleroderma vascular disease strongly support the concept that, despite increased levels of proangiogenic factors, there is a number of antiangiogenic pathways that create defective angiogenesis prevent- ing new vessel formation. There is also evidence of impaired vascular repair or vasculogenesis.

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

AngiogénesisAntiangiogénicos Proangiogénicos

Baja expresión de β3 integrina

PTX3ENDOSTATINA

AngiostatinaμPA/μPA receptor +

MMP-12Kalistatina

VEGF A la alzaVEGFR-1

FGF2TGF-β

Activadores del plasminógeno

Kininas/Kalikreina9,11,12 a la baja

Plasma&Tóxico&

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13There 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 endo- thelial 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 .

Up- regulation of VEGF and its receptors VEGFR-1 and VEGFR-2, found in skin specimens of scleroderma patients, suggest a chronic increase in VEGF may actually mediate aberrant microvessels. This may occur if other necessary growth factors are defective, and the high levels of VEGFR actually blocks VEGF action and inhibits angiogenesis. Interestingly, an increased blood level of flt- 1 (VEGFR-1) is associated with placental vascular disease and preeclampsia in systemic lupus erythematosus.

Endostatin, a angiogenesis inhibitor derived from type XVIII collagen, is also elevated compared to controls, and this increase associates with the presence of more severe clinical involvement. A recent study noted that scleroderma patients have an increase in intact plasminogen, normal plasmin, and increased amounts of the cleavage fragment of plasminogen and angiostatin, another potent inhibitor of angiogenesis. These investigators postulated that proteases released by activated immune cells cleave plasminogen via granzyme B, increase angiostatin, and thus inhibit new vessel formation. They provide convincing in vitro data using scleroderma plasma to support this concept.

Microvascular endothelial cells must lyse extracellular matrix to enter surrounding tissue and form new vessels. Plasminogen activators are important in angiogenesis by altering the adhesion of endothelial cells to tissue matrix. Endothelial cells isolated from the dermis of patients with diffuse scleroderma and the cell-associated urokinase-type plasminogen activator (μPA)/μPA receptor (μPAR) system was therefore investigated .

Overproduction of matrix metalloproteinase 12 (MMP-12) by scleroderma endothelial cells accounted for cleavage of μPAR and an impairment of angiogenesis in vitro, suggesting that this pathway inhibits activation of plasminogen and thus may contribute to reduced angiogenesis.

Kallikreins are also proteolytic enzymes that hydrolyze kininogens to kinins, thus leading to cleavage of plasmin. Kinins are thought to promote angiogenesis, since they play a role that leads to endothelial cell migration, proliferation, and differentiation. Tissue kallikrein is increased in the serum of scleroderma patients, particularly in those with signs of early vascular disease. Kallistatin, the natural inhibitor of tissue kallikrein, is localized in skin samples from scleroderma patients in the endothelial cells of the microvessels and in the perivascualr infiltrate, while blood levels are not increased . These data suggest that the release of kinins as part of the early inflammatory phase of scleroderma may be a compensatory attempt to promote angiogenesis. However, a decreased expression of kallikreins 9, 11, and 12 in scleroderma cells compared to normal was also reported.

Thus, evidence suggests that, during the acute inflammatory phase of scleroderma, proangiogenic factors like VEGF and kinins are released perhaps to promote new vessels. However, a variety of proteolytic enzymes are active including granzymes that cleave plasminogen to produce angiostatin and MMP-12 to cleave μPAR, while abnormally low levels of specific kallikreins diminish generation of kinins. These laboratory data coupled with the clinical features of scleroderma vascular disease strongly support the concept that, despite increased levels of proangiogenic factors, there is a number of antiangiogenic pathways that create defective angiogenesis prevent- ing new vessel formation. There is also evidence of impaired vascular repair or vasculogenesis.

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Vasodilatadores

Respuestas Endotelio-Dependientes deficientesProducción NO, no dependiente de endoletio

alteradaPeroxinitrito y nitrotirosina ElevadosExcresión urinaria alta de F2-isoprostanos

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Nitric oxide

Nitric oxide (NO) is now known to be what was previously called the endothelium-derived relaxing factor. It relaxes vascular smooth muscle by increasing cellular cyclic guanosine monophosphate (cGMP). NO is made by many cells by either constitutive NO synthetase (noted as eNOS for endothelial cells) or inducible NO synthetase (iNOS). NO has diverse biological functions in addition to its vasodilating properties including inhibiting platelet aggre- gation, acting as a mediator of cytotoxicity, reducing of cytokine endothelial cell activation, regulating vascular cell trafficking, and providing neurotransmission. Defective NO production by scleroderma digital vessels is postulated to be responsible for enhanced vasoconstriction following stress or cold exposure. Circumstantial evidence for a defect in vascular NO production comes from laboratory studies that demonstrate a decrease response to endothelium- dependent responses but not to endothelium-independent pathways. In addition, intra-arterial infusion of nitroprusside or L-arginine, the physiologic substrate for NO, decreased cold-induced vasospasm in scleroderma. However, there is also evidence for abnormal overproduction of NO. Increased total serum NO (total nitrate and nitrite) was reported in one study [164]. Anderson et al. suggested that the production of endothelial-derived NO is disturbed in scleroderma when they found that plasma nitrate and 24-h urinary excretion of cGMP were significantly elevated in patients compared with controls. The levels of plasma nitrate in the patients correlated significantly with levels of sVCAM-1 and E-selectin and approached a significant correlation with sICAM-1, suggesting that acti- vated endothelial cells may produce plasma nitrate. Dermal microvascular endothelial cells isolated from scleroderma patients were used to investigate the eNOS. This study found evidence for an intrinsic defect in the mechanism of NO production in endothelial cells isolated from scleroderma patients. Exhaled NO is reported to be decreased and increased in scleroderma, perhaps, the discrepancy is in part due to differences in the subgroups of patients studied. For example, exhaled NO is decreased in patients with PAH compared to normal subjects and scleroderma patients without PAH but increased exhaled NO in patients with interstitial lung disease.

NO production is increased following induction of iNOS, and a switch in endothelial cell expression from eNOS to iNOS occurs in the microcirculation.

This enhanced contribution of NO production by increased activity of iNOS may lead to increase tissue damage. Under circumstances of ischemia/hypoxia-reperfusion (i.e., Raynaud’s phenomenon associated with scleroderma), NO can mediate free radical tissue injury by interacting with superoxide anion to produce peroxynitrate, a powerful oxidizing agent. Increased circulatory levels of nitrotyrosine, a marker for peroxynitrite production, are reported in scleroderma . Increased levels of urinary F2-isoprostanes, a measure of in vivo lipid peroxidation, is also noted in patients with scleroderma compared to healthy controls. This, coupled with the other evidence of an increased oxidative stress (see below) and a reduced antioxidant capacity , sets the scene for enhanced tissue injury and fibrosis

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Oxido Nítrico

Respuestas Endotelio-Dependientes deficientesProducción NO, no dependiente de endoletio

alteradaPeroxinitrito y nitrotirosina ElevadosExcresión urinaria alta de F2-isoprostanos

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Nitric oxide

Nitric oxide (NO) is now known to be what was previously called the endothelium-derived relaxing factor. It relaxes vascular smooth muscle by increasing cellular cyclic guanosine monophosphate (cGMP). NO is made by many cells by either constitutive NO synthetase (noted as eNOS for endothelial cells) or inducible NO synthetase (iNOS). NO has diverse biological functions in addition to its vasodilating properties including inhibiting platelet aggre- gation, acting as a mediator of cytotoxicity, reducing of cytokine endothelial cell activation, regulating vascular cell trafficking, and providing neurotransmission. Defective NO production by scleroderma digital vessels is postulated to be responsible for enhanced vasoconstriction following stress or cold exposure. Circumstantial evidence for a defect in vascular NO production comes from laboratory studies that demonstrate a decrease response to endothelium- dependent responses but not to endothelium-independent pathways. In addition, intra-arterial infusion of nitroprusside or L-arginine, the physiologic substrate for NO, decreased cold-induced vasospasm in scleroderma. However, there is also evidence for abnormal overproduction of NO. Increased total serum NO (total nitrate and nitrite) was reported in one study [164]. Anderson et al. suggested that the production of endothelial-derived NO is disturbed in scleroderma when they found that plasma nitrate and 24-h urinary excretion of cGMP were significantly elevated in patients compared with controls. The levels of plasma nitrate in the patients correlated significantly with levels of sVCAM-1 and E-selectin and approached a significant correlation with sICAM-1, suggesting that acti- vated endothelial cells may produce plasma nitrate. Dermal microvascular endothelial cells isolated from scleroderma patients were used to investigate the eNOS. This study found evidence for an intrinsic defect in the mechanism of NO production in endothelial cells isolated from scleroderma patients. Exhaled NO is reported to be decreased and increased in scleroderma, perhaps, the discrepancy is in part due to differences in the subgroups of patients studied. For example, exhaled NO is decreased in patients with PAH compared to normal subjects and scleroderma patients without PAH but increased exhaled NO in patients with interstitial lung disease.

NO production is increased following induction of iNOS, and a switch in endothelial cell expression from eNOS to iNOS occurs in the microcirculation.

This enhanced contribution of NO production by increased activity of iNOS may lead to increase tissue damage. Under circumstances of ischemia/hypoxia-reperfusion (i.e., Raynaud’s phenomenon associated with scleroderma), NO can mediate free radical tissue injury by interacting with superoxide anion to produce peroxynitrate, a powerful oxidizing agent. Increased circulatory levels of nitrotyrosine, a marker for peroxynitrite production, are reported in scleroderma . Increased levels of urinary F2-isoprostanes, a measure of in vivo lipid peroxidation, is also noted in patients with scleroderma compared to healthy controls. This, coupled with the other evidence of an increased oxidative stress (see below) and a reduced antioxidant capacity , sets the scene for enhanced tissue injury and fibrosis

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Oxido Nítrico

Baja producción

Respuestas Endotelio-Dependientes deficientesProducción NO, no dependiente de endoletio

alteradaPeroxinitrito y nitrotirosina ElevadosExcresión urinaria alta de F2-isoprostanos

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Nitric oxide

Nitric oxide (NO) is now known to be what was previously called the endothelium-derived relaxing factor. It relaxes vascular smooth muscle by increasing cellular cyclic guanosine monophosphate (cGMP). NO is made by many cells by either constitutive NO synthetase (noted as eNOS for endothelial cells) or inducible NO synthetase (iNOS). NO has diverse biological functions in addition to its vasodilating properties including inhibiting platelet aggre- gation, acting as a mediator of cytotoxicity, reducing of cytokine endothelial cell activation, regulating vascular cell trafficking, and providing neurotransmission. Defective NO production by scleroderma digital vessels is postulated to be responsible for enhanced vasoconstriction following stress or cold exposure. Circumstantial evidence for a defect in vascular NO production comes from laboratory studies that demonstrate a decrease response to endothelium- dependent responses but not to endothelium-independent pathways. In addition, intra-arterial infusion of nitroprusside or L-arginine, the physiologic substrate for NO, decreased cold-induced vasospasm in scleroderma. However, there is also evidence for abnormal overproduction of NO. Increased total serum NO (total nitrate and nitrite) was reported in one study [164]. Anderson et al. suggested that the production of endothelial-derived NO is disturbed in scleroderma when they found that plasma nitrate and 24-h urinary excretion of cGMP were significantly elevated in patients compared with controls. The levels of plasma nitrate in the patients correlated significantly with levels of sVCAM-1 and E-selectin and approached a significant correlation with sICAM-1, suggesting that acti- vated endothelial cells may produce plasma nitrate. Dermal microvascular endothelial cells isolated from scleroderma patients were used to investigate the eNOS. This study found evidence for an intrinsic defect in the mechanism of NO production in endothelial cells isolated from scleroderma patients. Exhaled NO is reported to be decreased and increased in scleroderma, perhaps, the discrepancy is in part due to differences in the subgroups of patients studied. For example, exhaled NO is decreased in patients with PAH compared to normal subjects and scleroderma patients without PAH but increased exhaled NO in patients with interstitial lung disease.

NO production is increased following induction of iNOS, and a switch in endothelial cell expression from eNOS to iNOS occurs in the microcirculation.

This enhanced contribution of NO production by increased activity of iNOS may lead to increase tissue damage. Under circumstances of ischemia/hypoxia-reperfusion (i.e., Raynaud’s phenomenon associated with scleroderma), NO can mediate free radical tissue injury by interacting with superoxide anion to produce peroxynitrate, a powerful oxidizing agent. Increased circulatory levels of nitrotyrosine, a marker for peroxynitrite production, are reported in scleroderma . Increased levels of urinary F2-isoprostanes, a measure of in vivo lipid peroxidation, is also noted in patients with scleroderma compared to healthy controls. This, coupled with the other evidence of an increased oxidative stress (see below) and a reduced antioxidant capacity , sets the scene for enhanced tissue injury and fibrosis

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Regulador de Crecimiento celular, inflamación, fibrosis vascular

ANG II alta, baja capacidad p/metabolizarlaRegula TGF-β, CTGF (a la alza)

Vasoconstrictores

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Angiotensin II (ANG II), a potent vasoconstrictor, also regulates cell growth, inflammation, and vascular fibrosis. ANG II regulates TGF-β by increasing is its activation. Inhibition of the angiotensin type 1 (AT1) receptor diminishes the tissue expression of TGF-β and thus reduces extracellular and vascular fibrosis [173]. Blockade of the AT1 receptor is known to reduce TGF-β induced myopathy and arterial fibrosis in Marfan’s syndrome [174, 175]. ANG II can also increase connective tissue growth factor (CTGF), another potent profibrotic factor implicated in vascular and tissue fibrosis [176]. Thus, it is possible that an increase in the level of ANG II might mediate vascular and/or tissue fibrosis in scleroderma via induction of TGF-β and CTGF. Studies find a depressed capacity to metabolize an angiotensin-converting enzyme synthetic substrate in scleroderma patients, thus potentially increasing ANG II levels [177, 178]. Studies of ACE and eNOS polymorphisms suggested that specific alleles of ACE and eNOS were associated with scleroderma [179]. Increased plasma levels of ANG II and low levels of the vasodilator angiotensin [1–7] were found in scleroderma patients compared to controls, again suggesting a dysfunction of the angiotensin-derived cascade that may alter vascular tone and biology

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Regulador de Crecimiento celular, inflamación, fibrosis vascular

ANG II alta, baja capacidad p/metabolizarlaRegula TGF-β, CTGF (a la alza)

VasoconstrictoresAngiotensina

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Angiotensin II (ANG II), a potent vasoconstrictor, also regulates cell growth, inflammation, and vascular fibrosis. ANG II regulates TGF-β by increasing is its activation. Inhibition of the angiotensin type 1 (AT1) receptor diminishes the tissue expression of TGF-β and thus reduces extracellular and vascular fibrosis [173]. Blockade of the AT1 receptor is known to reduce TGF-β induced myopathy and arterial fibrosis in Marfan’s syndrome [174, 175]. ANG II can also increase connective tissue growth factor (CTGF), another potent profibrotic factor implicated in vascular and tissue fibrosis [176]. Thus, it is possible that an increase in the level of ANG II might mediate vascular and/or tissue fibrosis in scleroderma via induction of TGF-β and CTGF. Studies find a depressed capacity to metabolize an angiotensin-converting enzyme synthetic substrate in scleroderma patients, thus potentially increasing ANG II levels [177, 178]. Studies of ACE and eNOS polymorphisms suggested that specific alleles of ACE and eNOS were associated with scleroderma [179]. Increased plasma levels of ANG II and low levels of the vasodilator angiotensin [1–7] were found in scleroderma patients compared to controls, again suggesting a dysfunction of the angiotensin-derived cascade that may alter vascular tone and biology

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Respuesta Dependiente de Endotelio. **Respuesta No dependiente de Endotelio. Ok en SScα2-AR y Vía Rho-KinasaNeuropéptidos Vasodilatadores a la Baja: Sustacia P,

CGRPVasos responden a CGRP en SScNiveles elevador s deTMEndoglina & Adrenomodulina a la Alza

Vasoconstrictores

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Widespread abnormal vascular function is another manifestation of vascular disease in scleroderma . For example, abnormal microvascular responses are localized to both small and large vessels of the digits . Functional capacity of the microcirculation is impaired in scleroderma when measuring reactivity following arterial occlusion and local heat exposure.

Endothelium-dependent and -independent vasodilatation is found impaired in patients with Raynaud’s phenomenon secondary to scleroderma.

However, most evidence suggests that a major defect causing the disturbed reactivity is secondary to endothelial cell dysfunction. Studies find a reduction in skin digital vasodilatory reserve in response to applied acetylcholine, an endothelium-dependent vasodilator. Intra-arterial delivery of methacholine, bradykinin, or substance P (endothelium-dependent vasodilators) and sodium nitroprusside (endothelium-independent vasodilator) showed a decreased response to endothelium-dependent responses but not to endothelium-independent pathways. Fursspan et al. presented in vitro evidence using cutaneous arterioles that increased tyrosine phosphorylation was responsible for cold-induced vasoconstriction in Raynaud’s patients.

In a recent review, Flavahan states that cold-induced vasoconstriction is a normal cutaneous response to protect the normal host from heat loss . The major mediator of regulation of the cutaneous thermoregulatory vessels is via the sympathetic nerve activity through the neurotransmitter norepinephrine (NE). Vasoconstriction occurs when NE engages the α1 and α2-adrenoceptors (α2-AR) on vascular smooth muscle. Flavahan’s laboratory has discovered that the subtype α2c-AR is thermosensitive and is upregulated on smooth muscle during cold exposure. Increased expres- sion of α2c-AR occurs following vascular stress including oxidative stress via the Rho-kinase pathway [190]. Abnor- mal reactivity of vessels in scleroderma via this pathway is suggested by the finding of increased sensitivity of vascular smooth muscle α2-AR expression in scleroderma skin vessels [191] (see “Treatment of scleroderma vascular disease”).

Neuropeptides released by cutaneous sensory nerves can also mediate vascular responses via an endothelial- dependent pathway or they can stimulate smooth muscle directly. Abnormality of the vasodilatory neuropeptides substance P and calcitonin gene-related peptide (CGRP) has been postulated to occur in Raynaud’s phenomenon and in scleroderma [192, 193]. Substance P is also release from endothelial cells [194]. Bunker et al. found a reduced number of CGRP immunoreactive neurons in the skin, while Brain et al. reported that normal cutaneous responses followed subcutaneous injection of CGRP in patients with Raynaud’s or scleroderma [195, 196]. Intravenous CGRP improved hand and digital blood flow and skin temperature in patients with severe Raynaud’s phenomenon [197]. These data support the concept that there is a deficiency of CGRP release but that vessels have a normal capacity to respond.

The role of estrogen in regulation of vascular flow has also been investigated in Raynaud’s phenomenon and in scleroderma [193, 198]. Short-term therapy with estrogen (measures done 15 min following 25 mg intravenous con- jugated estrogen) and long-term therapy improved flow- mediated dilatation of vessels in the forearm, a measure considered reflecting endothelium-dependent vasodilatation [185, 198]. However, there is evidence that estrogen use may increase the risk for Raynaud’s phenomenon [199], and the exact effect of estrogen in patients with scleroderma needs more study

Other factors

Membrane thrombomodulin (TM) is a natural antithrombin glycoprotein with anticoagulant properties that, when it is detected in the circulation, is considered a marker of endothelial injury. Plasma levels of TM are reported elevated in some scleroderma patients and patients with Raynaud’s phenomenon [201, 202].

Soluble endoglin may potentially be a biomarker for scleroderma vascular disease in that high levels of in the circulation were reported to associate with a vascular pheno- type of cutaneous ulcerations and evidence of pulmonary vascular disease with low diffusing capacity [55].

Plasma adrenomedullin, a vasodilating peptide, was measured in 62 scleroderma patients and compared to 21 healthy controls [164]. The adrenomedullin level was significantly elevated in the subgroup of scleroderma patients with both severe Raynaud’s and elevated pulmo- nary artery pressure.

Fenómeno de RaynaudPatogenia & SSc

ENDOTELIOCAPA MUSCULAR (MEDIA)

ADVENTICIA

Respuesta Dependiente de Endotelio. **Respuesta No dependiente de Endotelio. Ok en SScα2-AR y Vía Rho-KinasaNeuropéptidos Vasodilatadores a la Baja: Sustacia P,

CGRPVasos responden a CGRP en SScNiveles elevador s deTMEndoglina & Adrenomodulina a la Alza

VasoconstrictoresReactividad Vascular

Clinic Rev Allerg Immunol (2009) 36:150–175

martes, 10 de septiembre de 13Widespread abnormal vascular function is another manifestation of vascular disease in scleroderma . For example, abnormal microvascular responses are localized to both small and large vessels of the digits . Functional capacity of the microcirculation is impaired in scleroderma when measuring reactivity following arterial occlusion and local heat exposure.

Endothelium-dependent and -independent vasodilatation is found impaired in patients with Raynaud’s phenomenon secondary to scleroderma.

However, most evidence suggests that a major defect causing the disturbed reactivity is secondary to endothelial cell dysfunction. Studies find a reduction in skin digital vasodilatory reserve in response to applied acetylcholine, an endothelium-dependent vasodilator. Intra-arterial delivery of methacholine, bradykinin, or substance P (endothelium-dependent vasodilators) and sodium nitroprusside (endothelium-independent vasodilator) showed a decreased response to endothelium-dependent responses but not to endothelium-independent pathways. Fursspan et al. presented in vitro evidence using cutaneous arterioles that increased tyrosine phosphorylation was responsible for cold-induced vasoconstriction in Raynaud’s patients.

In a recent review, Flavahan states that cold-induced vasoconstriction is a normal cutaneous response to protect the normal host from heat loss . The major mediator of regulation of the cutaneous thermoregulatory vessels is via the sympathetic nerve activity through the neurotransmitter norepinephrine (NE). Vasoconstriction occurs when NE engages the α1 and α2-adrenoceptors (α2-AR) on vascular smooth muscle. Flavahan’s laboratory has discovered that the subtype α2c-AR is thermosensitive and is upregulated on smooth muscle during cold exposure. Increased expres- sion of α2c-AR occurs following vascular stress including oxidative stress via the Rho-kinase pathway [190]. Abnor- mal reactivity of vessels in scleroderma via this pathway is suggested by the finding of increased sensitivity of vascular smooth muscle α2-AR expression in scleroderma skin vessels [191] (see “Treatment of scleroderma vascular disease”).

Neuropeptides released by cutaneous sensory nerves can also mediate vascular responses via an endothelial- dependent pathway or they can stimulate smooth muscle directly. Abnormality of the vasodilatory neuropeptides substance P and calcitonin gene-related peptide (CGRP) has been postulated to occur in Raynaud’s phenomenon and in scleroderma [192, 193]. Substance P is also release from endothelial cells [194]. Bunker et al. found a reduced number of CGRP immunoreactive neurons in the skin, while Brain et al. reported that normal cutaneous responses followed subcutaneous injection of CGRP in patients with Raynaud’s or scleroderma [195, 196]. Intravenous CGRP improved hand and digital blood flow and skin temperature in patients with severe Raynaud’s phenomenon [197]. These data support the concept that there is a deficiency of CGRP release but that vessels have a normal capacity to respond.

The role of estrogen in regulation of vascular flow has also been investigated in Raynaud’s phenomenon and in scleroderma [193, 198]. Short-term therapy with estrogen (measures done 15 min following 25 mg intravenous con- jugated estrogen) and long-term therapy improved flow- mediated dilatation of vessels in the forearm, a measure considered reflecting endothelium-dependent vasodilatation [185, 198]. However, there is evidence that estrogen use may increase the risk for Raynaud’s phenomenon [199], and the exact effect of estrogen in patients with scleroderma needs more study

Other factors

Membrane thrombomodulin (TM) is a natural antithrombin glycoprotein with anticoagulant properties that, when it is detected in the circulation, is considered a marker of endothelial injury. Plasma levels of TM are reported elevated in some scleroderma patients and patients with Raynaud’s phenomenon [201, 202].

Soluble endoglin may potentially be a biomarker for scleroderma vascular disease in that high levels of in the circulation were reported to associate with a vascular pheno- type of cutaneous ulcerations and evidence of pulmonary vascular disease with low diffusing capacity [55].

Plasma adrenomedullin, a vasodilating peptide, was measured in 62 scleroderma patients and compared to 21 healthy controls [164]. The adrenomedullin level was significantly elevated in the subgroup of scleroderma patients with both severe Raynaud’s and elevated pulmo- nary artery pressure.

Fenómeno de RaynaudPatogenia & SSc

Denton, C. P. & Ong, V. H. Nat. Rev. Rheumatol. 9, 451–464 (2013)

martes, 10 de septiembre de 13Possible links between vasculopathy and fibrosis in SSc. Vascular injury due to an unknown trigger and the influx of the immune cells are the early events in SSc. High levels of VEGF and other proangiogenic mediators derived from the activated immune cells facilitate proliferation of endothelial cells and pericytes in an attempt to restore injured vessels. For reasons that are still not clearly understood, but which may involve imbalance of proangiogenic and antiangiogenic mediators, intrinsic properties of endothelial cells, and the fibroblast-secreted antiangiogenic factors (for example, MMP12) this process fails, leading to vessel regression. In the presence of TGF-β or other immune mediators (such as cytokines and chemokines), or both, endothelial cells could acquire a migratory phenotype through endothelial–mesenchymal transition and enter the surrounding tissue, where they further differentiate into collagen-producing cells. Likewise, pericytes could transdifferentiate into fibroblasts or myofibroblasts and produce collagen. In SSc, intrinsic abnormal properties of endothelial cells and pericytes might render vascular cells particularly susceptible to undergoing these transitions. Activated resident fibroblasts and fibrocytes that enter the injured tissue from the circulation are likely to represent additional source of collagen producing cells that contribute to fibrosis in SSc lesion. Abbreviations: EPCs, endothelial progenitor cells; VEGF, vascular endothelial growth factor; MMP12, matrix metalloproteinase 12; SSc, systemic sclerosis; TGF-β, transforming

Fenómeno de RaynaudDiagnóstico

Diagnóstico

martes, 10 de septiembre de 13Diagnosis of Raynaud phenomenon is based on the history of colour change in the fingers. Understanding why the patient has the condition is a big diagnostic challenge and any underlying cause must be identified and treated (Box 1).

Fenómeno de RaynaudDiagnóstico

ARTHRITIS & RHEUMATISM , 43,(7),2000, pp 1641–1646

Presentación Clínica

Anticuerpos

Capilaroscopía

Otros

martes, 10 de septiembre de 13Recent advances in the diagnosis of Raynaud phenomenon have been the recognition that in patients with Raynaud phenomenon, abnormalities in nailfold capillary pattern and SSc­specific autoantibodies are independent risk factors for SSc,62 and in line with these findings, the increased application of capillaroscopy in both clinical practice and research. One study in 586 patients with Raynaud phenomenon who were followed for 3,197 patients years reported development of SSc in 1.8% of patients with normal capillary patterns who did not have an SSc­specific autoantibody, in 25.8% of patients with an abnormal capillary pattern, in 35.4% of patients with a specific autoantibody, and in 79.5% of those with both an abnormal capillary pattern and an SSc­specific autoantibody.62 Patients with both predictors were 60 times more likely to develop SSc than those with neither predictor. One study63 reported that 14.6% of 129 patients with primary Raynaud phenomenon developed abnormal capillary patterns over a mean period of 29.4 months, allowing early identification of patients who were most likely to develop a SSc­spectrum disorder.

Fenómeno de Raynaud

Clinic Rev Allerg Immunol (2009) 36:150–17

Diagnóstico

martes, 10 de septiembre de 13Raynaud’s phenomenon is the clinical manifestation of disease of the thermoregulatory vessels in the skin and disease of medium and small vessels in the peripheral arterial system of the limbs and acral parts of the body. Triphasic color changes (pallor, cyanosis, and hyperemia) occur as an exaggeration or perturbation of normal responses to the environmental temperature and activity (i.e., vasospasm). It occurs primarily in the fingers with relative sparing of the thumbs. It can also occur in the toes, tongue, ears, and nose.

Typically Raynaud’s attacks are symmetrical, involving both hands with patients noting that there is a dominant more sensitive finger(s), usually the index and middle fingers. A typical attack will continue with signs and symptoms of ischemia until rewarming (removal of the cold or stress trigger).

In a warm environment, the attack will usually resolve in about 15– 20 min. Unlike patients with primary Raynaud’s phenom- enon who have mild episodes that rarely interfere with daily activities and generally improve with aging [4, 5], patients with scleroderma experience intense and frequent ischemic.

events associated with recurrent digital ulcers in 25–39% of cases [6–9].

A survey of patients at one center reported that younger patients with high Rodnan skin score were at higher risk for developing ulcers, and they usually occurred within 5 years of non-Raynaud’s symptoms [10].

Digital amputation secondary to occlusion of digital arteries occur in a subset of (11%) patients, usually with limited skin disease with the presence of anticentromere antibody [11–13].

Macrovascular disease is recognized in conjunction with the more distal small-vessel pathology [14–16]. Certainly, there is frequent and severe involvement of digital arteries [17].

Interestingly, evidence suggests a predilection for significant occlusive disease in the ulnar artery in patients with limited scleroderma that is associated with critical ischemic events [18–20].

One study has reported that measured increased arterial stiffness in scleroderma pre- dicted more severe organ disease [21]. Although macrovascular disease occurs, it is in the peripheral circulation; generalized premature atherosclerosis in typical locations is not uniformly detected in scleroderma, as is thought to occur in other rheumatic diseases [22].

However, there are reports of early atherosclerosis in scleroderma. For example, Sherer et al. report evidence for more atherosclerosis in the carotid arteries in scleroderma compared to normal subjects [23].

In one study, macrovascular disease was found to be more prevalent in cases that have a specific angiotensin-converting enzyme (ACE) polymorphism (D allele), a polymorphism that normally associates with an increase risk for atherosclerosis [24].

The measurement of brachial artery flow-mediated vasodilation can be used to evaluate both endothelium-dependent and endothelium- independent responses. Two studies demonstrated an impaired response of the brachial artery flow in scleroderma; in one, it associated with increased carotid intima media thickness [25], but it did not associate with carotid disease in the second study [26]. Both studies did report an increase in carotid thickening.

Evidence for an increase risk for coronary artery disease is controversial. Pathological studies find little involvement [27–29], and a survey of coronary angiograms was unremarkable for significant coronary disease [30].

Cerebrovascular disease is not considered to be increased in scleroderma. More studies are needed, but the data suggest that significant peripheral macrovascular disease is not secondary to premature atherosclerosis and is independent of traditional risk factors for atherosclerosis. Usual sites of atherosclerosis are likely to be no more common than expected in a similar nonscleroderma population.

Telangiectases

Clinically visible telangiectases on the skin and mucous membranes is another manifestation of microvascular disease in scleroderma. These lesions are composed of vasodilated postcapillary venules without evidence of inflammation or neovascularization [46, 47]. Telangiec- tases are seen primarily on the fingers, hands, face, and mucous membranes but can occur on limbs and trunk in the late stages of the disease. They are more likely to occur in patients with limited scleroderma than early diffuse scleroderma but become prominent in longstand- ing scleroderma of any subtype. The pathological mech- anism causing the formation of telangiectases in scleroderma is not defined, but they are likely the manifestation of a failed or aberrant effort of angiogenesis. Increased endothelial proliferation was demonstrated from autoradiographic studies of cutaneous telangiectases from the skin of patients with scleroderma, It is caused by mutations in elements of the transforming growth factor-beta (TGF-β) receptor com- plex: endoglin, a coreceptor, responsible for HHT1, or ALK1 (activin receptor-like kinase 1), a type I receptor leading to HHT2.

Telangiectasia were found more frequently in scleroderma patients with elevated soluble endoglin (sENG), and an association between an ENG gene polymorphism and pulmonary arterial hypertension (PAH) was suggested by a study with a relatively small sample size, High levels of circulating sENG were reported in scleroderma with a vascular phenotype of cutaneous ulcerations and evidence of pulmonary vascular disease with low diffusing capacity

Another study found increased endoglin expression on dermal endothelial cells in scleroderma but no increased serum levels

Fenómeno de Raynaud

Clinic Rev Allerg Immunol (2009) 36:150–17

Diagnóstico

martes, 10 de septiembre de 13Raynaud’s phenomenon is the clinical manifestation of disease of the thermoregulatory vessels in the skin and disease of medium and small vessels in the peripheral arterial system of the limbs and acral parts of the body. Triphasic color changes (pallor, cyanosis, and hyperemia) occur as an exaggeration or perturbation of normal responses to the environmental temperature and activity (i.e., vasospasm). It occurs primarily in the fingers with relative sparing of the thumbs. It can also occur in the toes, tongue, ears, and nose.

Typically Raynaud’s attacks are symmetrical, involving both hands with patients noting that there is a dominant more sensitive finger(s), usually the index and middle fingers. A typical attack will continue with signs and symptoms of ischemia until rewarming (removal of the cold or stress trigger).

In a warm environment, the attack will usually resolve in about 15– 20 min. Unlike patients with primary Raynaud’s phenom- enon who have mild episodes that rarely interfere with daily activities and generally improve with aging [4, 5], patients with scleroderma experience intense and frequent ischemic.

events associated with recurrent digital ulcers in 25–39% of cases [6–9].

A survey of patients at one center reported that younger patients with high Rodnan skin score were at higher risk for developing ulcers, and they usually occurred within 5 years of non-Raynaud’s symptoms [10].

Digital amputation secondary to occlusion of digital arteries occur in a subset of (11%) patients, usually with limited skin disease with the presence of anticentromere antibody [11–13].

Macrovascular disease is recognized in conjunction with the more distal small-vessel pathology [14–16]. Certainly, there is frequent and severe involvement of digital arteries [17].

Interestingly, evidence suggests a predilection for significant occlusive disease in the ulnar artery in patients with limited scleroderma that is associated with critical ischemic events [18–20].

One study has reported that measured increased arterial stiffness in scleroderma pre- dicted more severe organ disease [21]. Although macrovascular disease occurs, it is in the peripheral circulation; generalized premature atherosclerosis in typical locations is not uniformly detected in scleroderma, as is thought to occur in other rheumatic diseases [22].

However, there are reports of early atherosclerosis in scleroderma. For example, Sherer et al. report evidence for more atherosclerosis in the carotid arteries in scleroderma compared to normal subjects [23].

In one study, macrovascular disease was found to be more prevalent in cases that have a specific angiotensin-converting enzyme (ACE) polymorphism (D allele), a polymorphism that normally associates with an increase risk for atherosclerosis [24].

The measurement of brachial artery flow-mediated vasodilation can be used to evaluate both endothelium-dependent and endothelium- independent responses. Two studies demonstrated an impaired response of the brachial artery flow in scleroderma; in one, it associated with increased carotid intima media thickness [25], but it did not associate with carotid disease in the second study [26]. Both studies did report an increase in carotid thickening.

Evidence for an increase risk for coronary artery disease is controversial. Pathological studies find little involvement [27–29], and a survey of coronary angiograms was unremarkable for significant coronary disease [30].

Cerebrovascular disease is not considered to be increased in scleroderma. More studies are needed, but the data suggest that significant peripheral macrovascular disease is not secondary to premature atherosclerosis and is independent of traditional risk factors for atherosclerosis. Usual sites of atherosclerosis are likely to be no more common than expected in a similar nonscleroderma population.

Telangiectases

Clinically visible telangiectases on the skin and mucous membranes is another manifestation of microvascular disease in scleroderma. These lesions are composed of vasodilated postcapillary venules without evidence of inflammation or neovascularization [46, 47]. Telangiec- tases are seen primarily on the fingers, hands, face, and mucous membranes but can occur on limbs and trunk in the late stages of the disease. They are more likely to occur in patients with limited scleroderma than early diffuse scleroderma but become prominent in longstand- ing scleroderma of any subtype. The pathological mech- anism causing the formation of telangiectases in scleroderma is not defined, but they are likely the manifestation of a failed or aberrant effort of angiogenesis. Increased endothelial proliferation was demonstrated from autoradiographic studies of cutaneous telangiectases from the skin of patients with scleroderma, It is caused by mutations in elements of the transforming growth factor-beta (TGF-β) receptor com- plex: endoglin, a coreceptor, responsible for HHT1, or ALK1 (activin receptor-like kinase 1), a type I receptor leading to HHT2.

Telangiectasia were found more frequently in scleroderma patients with elevated soluble endoglin (sENG), and an association between an ENG gene polymorphism and pulmonary arterial hypertension (PAH) was suggested by a study with a relatively small sample size, High levels of circulating sENG were reported in scleroderma with a vascular phenotype of cutaneous ulcerations and evidence of pulmonary vascular disease with low diffusing capacity

Another study found increased endoglin expression on dermal endothelial cells in scleroderma but no increased serum levels

Fenómeno de Raynaud

Clinic Rev Allerg Immunol (2009) 36:150–17

Diagnóstico

martes, 10 de septiembre de 13Raynaud’s phenomenon is the clinical manifestation of disease of the thermoregulatory vessels in the skin and disease of medium and small vessels in the peripheral arterial system of the limbs and acral parts of the body. Triphasic color changes (pallor, cyanosis, and hyperemia) occur as an exaggeration or perturbation of normal responses to the environmental temperature and activity (i.e., vasospasm). It occurs primarily in the fingers with relative sparing of the thumbs. It can also occur in the toes, tongue, ears, and nose.

Typically Raynaud’s attacks are symmetrical, involving both hands with patients noting that there is a dominant more sensitive finger(s), usually the index and middle fingers. A typical attack will continue with signs and symptoms of ischemia until rewarming (removal of the cold or stress trigger).

In a warm environment, the attack will usually resolve in about 15– 20 min. Unlike patients with primary Raynaud’s phenom- enon who have mild episodes that rarely interfere with daily activities and generally improve with aging [4, 5], patients with scleroderma experience intense and frequent ischemic.

events associated with recurrent digital ulcers in 25–39% of cases [6–9].

A survey of patients at one center reported that younger patients with high Rodnan skin score were at higher risk for developing ulcers, and they usually occurred within 5 years of non-Raynaud’s symptoms [10].

Digital amputation secondary to occlusion of digital arteries occur in a subset of (11%) patients, usually with limited skin disease with the presence of anticentromere antibody [11–13].

Macrovascular disease is recognized in conjunction with the more distal small-vessel pathology [14–16]. Certainly, there is frequent and severe involvement of digital arteries [17].

Interestingly, evidence suggests a predilection for significant occlusive disease in the ulnar artery in patients with limited scleroderma that is associated with critical ischemic events [18–20].

One study has reported that measured increased arterial stiffness in scleroderma pre- dicted more severe organ disease [21]. Although macrovascular disease occurs, it is in the peripheral circulation; generalized premature atherosclerosis in typical locations is not uniformly detected in scleroderma, as is thought to occur in other rheumatic diseases [22].

However, there are reports of early atherosclerosis in scleroderma. For example, Sherer et al. report evidence for more atherosclerosis in the carotid arteries in scleroderma compared to normal subjects [23].

In one study, macrovascular disease was found to be more prevalent in cases that have a specific angiotensin-converting enzyme (ACE) polymorphism (D allele), a polymorphism that normally associates with an increase risk for atherosclerosis [24].

The measurement of brachial artery flow-mediated vasodilation can be used to evaluate both endothelium-dependent and endothelium- independent responses. Two studies demonstrated an impaired response of the brachial artery flow in scleroderma; in one, it associated with increased carotid intima media thickness [25], but it did not associate with carotid disease in the second study [26]. Both studies did report an increase in carotid thickening.

Evidence for an increase risk for coronary artery disease is controversial. Pathological studies find little involvement [27–29], and a survey of coronary angiograms was unremarkable for significant coronary disease [30].

Cerebrovascular disease is not considered to be increased in scleroderma. More studies are needed, but the data suggest that significant peripheral macrovascular disease is not secondary to premature atherosclerosis and is independent of traditional risk factors for atherosclerosis. Usual sites of atherosclerosis are likely to be no more common than expected in a similar nonscleroderma population.

Telangiectases

Clinically visible telangiectases on the skin and mucous membranes is another manifestation of microvascular disease in scleroderma. These lesions are composed of vasodilated postcapillary venules without evidence of inflammation or neovascularization [46, 47]. Telangiec- tases are seen primarily on the fingers, hands, face, and mucous membranes but can occur on limbs and trunk in the late stages of the disease. They are more likely to occur in patients with limited scleroderma than early diffuse scleroderma but become prominent in longstand- ing scleroderma of any subtype. The pathological mech- anism causing the formation of telangiectases in scleroderma is not defined, but they are likely the manifestation of a failed or aberrant effort of angiogenesis. Increased endothelial proliferation was demonstrated from autoradiographic studies of cutaneous telangiectases from the skin of patients with scleroderma, It is caused by mutations in elements of the transforming growth factor-beta (TGF-β) receptor com- plex: endoglin, a coreceptor, responsible for HHT1, or ALK1 (activin receptor-like kinase 1), a type I receptor leading to HHT2.

Telangiectasia were found more frequently in scleroderma patients with elevated soluble endoglin (sENG), and an association between an ENG gene polymorphism and pulmonary arterial hypertension (PAH) was suggested by a study with a relatively small sample size, High levels of circulating sENG were reported in scleroderma with a vascular phenotype of cutaneous ulcerations and evidence of pulmonary vascular disease with low diffusing capacity

Another study found increased endoglin expression on dermal endothelial cells in scleroderma but no increased serum levels

Fenómeno de Raynaud

Clinic Rev Allerg Immunol (2009) 36:150–17

Diagnóstico

martes, 10 de septiembre de 13Raynaud’s phenomenon is the clinical manifestation of disease of the thermoregulatory vessels in the skin and disease of medium and small vessels in the peripheral arterial system of the limbs and acral parts of the body. Triphasic color changes (pallor, cyanosis, and hyperemia) occur as an exaggeration or perturbation of normal responses to the environmental temperature and activity (i.e., vasospasm). It occurs primarily in the fingers with relative sparing of the thumbs. It can also occur in the toes, tongue, ears, and nose.

Typically Raynaud’s attacks are symmetrical, involving both hands with patients noting that there is a dominant more sensitive finger(s), usually the index and middle fingers. A typical attack will continue with signs and symptoms of ischemia until rewarming (removal of the cold or stress trigger).

In a warm environment, the attack will usually resolve in about 15– 20 min. Unlike patients with primary Raynaud’s phenom- enon who have mild episodes that rarely interfere with daily activities and generally improve with aging [4, 5], patients with scleroderma experience intense and frequent ischemic.

events associated with recurrent digital ulcers in 25–39% of cases [6–9].

A survey of patients at one center reported that younger patients with high Rodnan skin score were at higher risk for developing ulcers, and they usually occurred within 5 years of non-Raynaud’s symptoms [10].

Digital amputation secondary to occlusion of digital arteries occur in a subset of (11%) patients, usually with limited skin disease with the presence of anticentromere antibody [11–13].

Macrovascular disease is recognized in conjunction with the more distal small-vessel pathology [14–16]. Certainly, there is frequent and severe involvement of digital arteries [17].

Interestingly, evidence suggests a predilection for significant occlusive disease in the ulnar artery in patients with limited scleroderma that is associated with critical ischemic events [18–20].

One study has reported that measured increased arterial stiffness in scleroderma pre- dicted more severe organ disease [21]. Although macrovascular disease occurs, it is in the peripheral circulation; generalized premature atherosclerosis in typical locations is not uniformly detected in scleroderma, as is thought to occur in other rheumatic diseases [22].

However, there are reports of early atherosclerosis in scleroderma. For example, Sherer et al. report evidence for more atherosclerosis in the carotid arteries in scleroderma compared to normal subjects [23].

In one study, macrovascular disease was found to be more prevalent in cases that have a specific angiotensin-converting enzyme (ACE) polymorphism (D allele), a polymorphism that normally associates with an increase risk for atherosclerosis [24].

The measurement of brachial artery flow-mediated vasodilation can be used to evaluate both endothelium-dependent and endothelium- independent responses. Two studies demonstrated an impaired response of the brachial artery flow in scleroderma; in one, it associated with increased carotid intima media thickness [25], but it did not associate with carotid disease in the second study [26]. Both studies did report an increase in carotid thickening.

Evidence for an increase risk for coronary artery disease is controversial. Pathological studies find little involvement [27–29], and a survey of coronary angiograms was unremarkable for significant coronary disease [30].

Cerebrovascular disease is not considered to be increased in scleroderma. More studies are needed, but the data suggest that significant peripheral macrovascular disease is not secondary to premature atherosclerosis and is independent of traditional risk factors for atherosclerosis. Usual sites of atherosclerosis are likely to be no more common than expected in a similar nonscleroderma population.

Telangiectases

Clinically visible telangiectases on the skin and mucous membranes is another manifestation of microvascular disease in scleroderma. These lesions are composed of vasodilated postcapillary venules without evidence of inflammation or neovascularization [46, 47]. Telangiec- tases are seen primarily on the fingers, hands, face, and mucous membranes but can occur on limbs and trunk in the late stages of the disease. They are more likely to occur in patients with limited scleroderma than early diffuse scleroderma but become prominent in longstand- ing scleroderma of any subtype. The pathological mech- anism causing the formation of telangiectases in scleroderma is not defined, but they are likely the manifestation of a failed or aberrant effort of angiogenesis. Increased endothelial proliferation was demonstrated from autoradiographic studies of cutaneous telangiectases from the skin of patients with scleroderma, It is caused by mutations in elements of the transforming growth factor-beta (TGF-β) receptor com- plex: endoglin, a coreceptor, responsible for HHT1, or ALK1 (activin receptor-like kinase 1), a type I receptor leading to HHT2.

Telangiectasia were found more frequently in scleroderma patients with elevated soluble endoglin (sENG), and an association between an ENG gene polymorphism and pulmonary arterial hypertension (PAH) was suggested by a study with a relatively small sample size, High levels of circulating sENG were reported in scleroderma with a vascular phenotype of cutaneous ulcerations and evidence of pulmonary vascular disease with low diffusing capacity

Another study found increased endoglin expression on dermal endothelial cells in scleroderma but no increased serum levels

Fenómeno de Raynaud

Clinic Rev Allerg Immunol (2009) 36:150–17

Diagnóstico

martes, 10 de septiembre de 13Raynaud’s phenomenon is the clinical manifestation of disease of the thermoregulatory vessels in the skin and disease of medium and small vessels in the peripheral arterial system of the limbs and acral parts of the body. Triphasic color changes (pallor, cyanosis, and hyperemia) occur as an exaggeration or perturbation of normal responses to the environmental temperature and activity (i.e., vasospasm). It occurs primarily in the fingers with relative sparing of the thumbs. It can also occur in the toes, tongue, ears, and nose.

Typically Raynaud’s attacks are symmetrical, involving both hands with patients noting that there is a dominant more sensitive finger(s), usually the index and middle fingers. A typical attack will continue with signs and symptoms of ischemia until rewarming (removal of the cold or stress trigger).

In a warm environment, the attack will usually resolve in about 15– 20 min. Unlike patients with primary Raynaud’s phenom- enon who have mild episodes that rarely interfere with daily activities and generally improve with aging [4, 5], patients with scleroderma experience intense and frequent ischemic.

events associated with recurrent digital ulcers in 25–39% of cases [6–9].

A survey of patients at one center reported that younger patients with high Rodnan skin score were at higher risk for developing ulcers, and they usually occurred within 5 years of non-Raynaud’s symptoms [10].

Digital amputation secondary to occlusion of digital arteries occur in a subset of (11%) patients, usually with limited skin disease with the presence of anticentromere antibody [11–13].

Macrovascular disease is recognized in conjunction with the more distal small-vessel pathology [14–16]. Certainly, there is frequent and severe involvement of digital arteries [17].

Interestingly, evidence suggests a predilection for significant occlusive disease in the ulnar artery in patients with limited scleroderma that is associated with critical ischemic events [18–20].

One study has reported that measured increased arterial stiffness in scleroderma pre- dicted more severe organ disease [21]. Although macrovascular disease occurs, it is in the peripheral circulation; generalized premature atherosclerosis in typical locations is not uniformly detected in scleroderma, as is thought to occur in other rheumatic diseases [22].

However, there are reports of early atherosclerosis in scleroderma. For example, Sherer et al. report evidence for more atherosclerosis in the carotid arteries in scleroderma compared to normal subjects [23].

In one study, macrovascular disease was found to be more prevalent in cases that have a specific angiotensin-converting enzyme (ACE) polymorphism (D allele), a polymorphism that normally associates with an increase risk for atherosclerosis [24].

The measurement of brachial artery flow-mediated vasodilation can be used to evaluate both endothelium-dependent and endothelium- independent responses. Two studies demonstrated an impaired response of the brachial artery flow in scleroderma; in one, it associated with increased carotid intima media thickness [25], but it did not associate with carotid disease in the second study [26]. Both studies did report an increase in carotid thickening.

Evidence for an increase risk for coronary artery disease is controversial. Pathological studies find little involvement [27–29], and a survey of coronary angiograms was unremarkable for significant coronary disease [30].

Cerebrovascular disease is not considered to be increased in scleroderma. More studies are needed, but the data suggest that significant peripheral macrovascular disease is not secondary to premature atherosclerosis and is independent of traditional risk factors for atherosclerosis. Usual sites of atherosclerosis are likely to be no more common than expected in a similar nonscleroderma population.

Telangiectases

Clinically visible telangiectases on the skin and mucous membranes is another manifestation of microvascular disease in scleroderma. These lesions are composed of vasodilated postcapillary venules without evidence of inflammation or neovascularization [46, 47]. Telangiec- tases are seen primarily on the fingers, hands, face, and mucous membranes but can occur on limbs and trunk in the late stages of the disease. They are more likely to occur in patients with limited scleroderma than early diffuse scleroderma but become prominent in longstand- ing scleroderma of any subtype. The pathological mech- anism causing the formation of telangiectases in scleroderma is not defined, but they are likely the manifestation of a failed or aberrant effort of angiogenesis. Increased endothelial proliferation was demonstrated from autoradiographic studies of cutaneous telangiectases from the skin of patients with scleroderma, It is caused by mutations in elements of the transforming growth factor-beta (TGF-β) receptor com- plex: endoglin, a coreceptor, responsible for HHT1, or ALK1 (activin receptor-like kinase 1), a type I receptor leading to HHT2.

Telangiectasia were found more frequently in scleroderma patients with elevated soluble endoglin (sENG), and an association between an ENG gene polymorphism and pulmonary arterial hypertension (PAH) was suggested by a study with a relatively small sample size, High levels of circulating sENG were reported in scleroderma with a vascular phenotype of cutaneous ulcerations and evidence of pulmonary vascular disease with low diffusing capacity

Another study found increased endoglin expression on dermal endothelial cells in scleroderma but no increased serum levels

Fenómeno de Raynaud

Clinic Rev Allerg Immunol (2009) 36:150–17

Diagnóstico

martes, 10 de septiembre de 13Raynaud’s phenomenon is the clinical manifestation of disease of the thermoregulatory vessels in the skin and disease of medium and small vessels in the peripheral arterial system of the limbs and acral parts of the body. Triphasic color changes (pallor, cyanosis, and hyperemia) occur as an exaggeration or perturbation of normal responses to the environmental temperature and activity (i.e., vasospasm). It occurs primarily in the fingers with relative sparing of the thumbs. It can also occur in the toes, tongue, ears, and nose.

Typically Raynaud’s attacks are symmetrical, involving both hands with patients noting that there is a dominant more sensitive finger(s), usually the index and middle fingers. A typical attack will continue with signs and symptoms of ischemia until rewarming (removal of the cold or stress trigger).

In a warm environment, the attack will usually resolve in about 15– 20 min. Unlike patients with primary Raynaud’s phenom- enon who have mild episodes that rarely interfere with daily activities and generally improve with aging [4, 5], patients with scleroderma experience intense and frequent ischemic.

events associated with recurrent digital ulcers in 25–39% of cases [6–9].

A survey of patients at one center reported that younger patients with high Rodnan skin score were at higher risk for developing ulcers, and they usually occurred within 5 years of non-Raynaud’s symptoms [10].

Digital amputation secondary to occlusion of digital arteries occur in a subset of (11%) patients, usually with limited skin disease with the presence of anticentromere antibody [11–13].

Macrovascular disease is recognized in conjunction with the more distal small-vessel pathology [14–16]. Certainly, there is frequent and severe involvement of digital arteries [17].

Interestingly, evidence suggests a predilection for significant occlusive disease in the ulnar artery in patients with limited scleroderma that is associated with critical ischemic events [18–20].

One study has reported that measured increased arterial stiffness in scleroderma pre- dicted more severe organ disease [21]. Although macrovascular disease occurs, it is in the peripheral circulation; generalized premature atherosclerosis in typical locations is not uniformly detected in scleroderma, as is thought to occur in other rheumatic diseases [22].

However, there are reports of early atherosclerosis in scleroderma. For example, Sherer et al. report evidence for more atherosclerosis in the carotid arteries in scleroderma compared to normal subjects [23].

In one study, macrovascular disease was found to be more prevalent in cases that have a specific angiotensin-converting enzyme (ACE) polymorphism (D allele), a polymorphism that normally associates with an increase risk for atherosclerosis [24].

The measurement of brachial artery flow-mediated vasodilation can be used to evaluate both endothelium-dependent and endothelium- independent responses. Two studies demonstrated an impaired response of the brachial artery flow in scleroderma; in one, it associated with increased carotid intima media thickness [25], but it did not associate with carotid disease in the second study [26]. Both studies did report an increase in carotid thickening.

Evidence for an increase risk for coronary artery disease is controversial. Pathological studies find little involvement [27–29], and a survey of coronary angiograms was unremarkable for significant coronary disease [30].

Cerebrovascular disease is not considered to be increased in scleroderma. More studies are needed, but the data suggest that significant peripheral macrovascular disease is not secondary to premature atherosclerosis and is independent of traditional risk factors for atherosclerosis. Usual sites of atherosclerosis are likely to be no more common than expected in a similar nonscleroderma population.

Telangiectases

Clinically visible telangiectases on the skin and mucous membranes is another manifestation of microvascular disease in scleroderma. These lesions are composed of vasodilated postcapillary venules without evidence of inflammation or neovascularization [46, 47]. Telangiec- tases are seen primarily on the fingers, hands, face, and mucous membranes but can occur on limbs and trunk in the late stages of the disease. They are more likely to occur in patients with limited scleroderma than early diffuse scleroderma but become prominent in longstand- ing scleroderma of any subtype. The pathological mech- anism causing the formation of telangiectases in scleroderma is not defined, but they are likely the manifestation of a failed or aberrant effort of angiogenesis. Increased endothelial proliferation was demonstrated from autoradiographic studies of cutaneous telangiectases from the skin of patients with scleroderma, It is caused by mutations in elements of the transforming growth factor-beta (TGF-β) receptor com- plex: endoglin, a coreceptor, responsible for HHT1, or ALK1 (activin receptor-like kinase 1), a type I receptor leading to HHT2.

Telangiectasia were found more frequently in scleroderma patients with elevated soluble endoglin (sENG), and an association between an ENG gene polymorphism and pulmonary arterial hypertension (PAH) was suggested by a study with a relatively small sample size, High levels of circulating sENG were reported in scleroderma with a vascular phenotype of cutaneous ulcerations and evidence of pulmonary vascular disease with low diffusing capacity

Another study found increased endoglin expression on dermal endothelial cells in scleroderma but no increased serum levels

Fenómeno de Raynaud

Clinic Rev Allerg Immunol (2009) 36:150–17

Diagnóstico

martes, 10 de septiembre de 13Raynaud’s phenomenon is the clinical manifestation of disease of the thermoregulatory vessels in the skin and disease of medium and small vessels in the peripheral arterial system of the limbs and acral parts of the body. Triphasic color changes (pallor, cyanosis, and hyperemia) occur as an exaggeration or perturbation of normal responses to the environmental temperature and activity (i.e., vasospasm). It occurs primarily in the fingers with relative sparing of the thumbs. It can also occur in the toes, tongue, ears, and nose.

Typically Raynaud’s attacks are symmetrical, involving both hands with patients noting that there is a dominant more sensitive finger(s), usually the index and middle fingers. A typical attack will continue with signs and symptoms of ischemia until rewarming (removal of the cold or stress trigger).

In a warm environment, the attack will usually resolve in about 15– 20 min. Unlike patients with primary Raynaud’s phenom- enon who have mild episodes that rarely interfere with daily activities and generally improve with aging [4, 5], patients with scleroderma experience intense and frequent ischemic.

events associated with recurrent digital ulcers in 25–39% of cases [6–9].

A survey of patients at one center reported that younger patients with high Rodnan skin score were at higher risk for developing ulcers, and they usually occurred within 5 years of non-Raynaud’s symptoms [10].

Digital amputation secondary to occlusion of digital arteries occur in a subset of (11%) patients, usually with limited skin disease with the presence of anticentromere antibody [11–13].

Macrovascular disease is recognized in conjunction with the more distal small-vessel pathology [14–16]. Certainly, there is frequent and severe involvement of digital arteries [17].

Interestingly, evidence suggests a predilection for significant occlusive disease in the ulnar artery in patients with limited scleroderma that is associated with critical ischemic events [18–20].

One study has reported that measured increased arterial stiffness in scleroderma pre- dicted more severe organ disease [21]. Although macrovascular disease occurs, it is in the peripheral circulation; generalized premature atherosclerosis in typical locations is not uniformly detected in scleroderma, as is thought to occur in other rheumatic diseases [22].

However, there are reports of early atherosclerosis in scleroderma. For example, Sherer et al. report evidence for more atherosclerosis in the carotid arteries in scleroderma compared to normal subjects [23].

In one study, macrovascular disease was found to be more prevalent in cases that have a specific angiotensin-converting enzyme (ACE) polymorphism (D allele), a polymorphism that normally associates with an increase risk for atherosclerosis [24].

The measurement of brachial artery flow-mediated vasodilation can be used to evaluate both endothelium-dependent and endothelium- independent responses. Two studies demonstrated an impaired response of the brachial artery flow in scleroderma; in one, it associated with increased carotid intima media thickness [25], but it did not associate with carotid disease in the second study [26]. Both studies did report an increase in carotid thickening.

Evidence for an increase risk for coronary artery disease is controversial. Pathological studies find little involvement [27–29], and a survey of coronary angiograms was unremarkable for significant coronary disease [30].

Cerebrovascular disease is not considered to be increased in scleroderma. More studies are needed, but the data suggest that significant peripheral macrovascular disease is not secondary to premature atherosclerosis and is independent of traditional risk factors for atherosclerosis. Usual sites of atherosclerosis are likely to be no more common than expected in a similar nonscleroderma population.

Telangiectases

Clinically visible telangiectases on the skin and mucous membranes is another manifestation of microvascular disease in scleroderma. These lesions are composed of vasodilated postcapillary venules without evidence of inflammation or neovascularization [46, 47]. Telangiec- tases are seen primarily on the fingers, hands, face, and mucous membranes but can occur on limbs and trunk in the late stages of the disease. They are more likely to occur in patients with limited scleroderma than early diffuse scleroderma but become prominent in longstand- ing scleroderma of any subtype. The pathological mech- anism causing the formation of telangiectases in scleroderma is not defined, but they are likely the manifestation of a failed or aberrant effort of angiogenesis. Increased endothelial proliferation was demonstrated from autoradiographic studies of cutaneous telangiectases from the skin of patients with scleroderma, It is caused by mutations in elements of the transforming growth factor-beta (TGF-β) receptor com- plex: endoglin, a coreceptor, responsible for HHT1, or ALK1 (activin receptor-like kinase 1), a type I receptor leading to HHT2.

Telangiectasia were found more frequently in scleroderma patients with elevated soluble endoglin (sENG), and an association between an ENG gene polymorphism and pulmonary arterial hypertension (PAH) was suggested by a study with a relatively small sample size, High levels of circulating sENG were reported in scleroderma with a vascular phenotype of cutaneous ulcerations and evidence of pulmonary vascular disease with low diffusing capacity

Another study found increased endoglin expression on dermal endothelial cells in scleroderma but no increased serum levels

Fenómeno de RaynaudDiagnóstico

BHCVSGANAPFTTórax Óseo, Tele de TóraxAnticentrómero, Anti-Topoisomerasa, Anti-RNP

IIIImagen Vascular: Doppler -->AngioTAC o

AngioIRMCapilaroscopíaEcocardiogramaPFRVHC, Crioglobulinas

Denton, C. P. & Ong, V. H. Nat. Rev. Rheumatol. 9, 451–464 (2013)

martes, 10 de septiembre de 13

Fenómeno de RaynaudCapilaroscopía

Descrita por Maricq y cols.Altamente específica en espectro de SScDermatoscopio 10x / Oftalmoscopio 20-40dpVideocapilaroscopía 200-600xSensible al cambio. Incrementó Sensibilidad al Dx 67 a 99%

Capilaroscop

ía+

Temprana+

Ac1va+

Tardía+

Asas capilaresHemorragiasAreas avascularesMIcrohemorragiasCapilares arborizados

M. Cutolo et al. Best Practice & Research Clinical Rheumatology Vol. 22, No. 6, pp. 1093–1108, 2008

martes, 10 de septiembre de 13Nailfold capillaroscopy

Normal nailfold capillaries are reassuring, whereas a ‘scleroderma­pattern’ showing capillary dilatation and areas of avascularity, first described by Maricq et al.70 is highly specific for an underlying SSc­spectrum disorder. High magnification videocapillaroscopy (200–600×) has revitalised the interest in capillaroscopy in recent years.71 However, clinicians without access to standard widefield microscopy or videocapillaroscopy, can visual­ ise capillaries using a dermatoscope (magnification in order of 10×) or opthalmoscope,72 which detects more obvious abnormalities.

A method for scoring the scleroderma­pattern, as ‘early’, ‘active’ and ‘late’, has been described.7

Key features of the early pattern, which are highly relevant to early diagnosis of a SSc­spectrum disorder in patients with Raynaud phenomenon, are presence of a small number of giant capillaries and of microhaemorrhages, without obvious capillary loss.

There is considerable interest in expanding clinical applications of capillaroscopy; for example, in improving the prediction of SSc through quantifying the abnormalities, and in predicting the risk of digital ulcera­ tion.

The recent increased emphasis on capillaroscopy is demonstrated in the proposed European criteria for early SSc: a scleroderma­pattern on capillaroscopy is one of the criteria.

(A) Normal nailfold pattern on nailfold capil- laroscopy (magnification ×200). (B) In the early stages of scleroderma, capillaroscopy shows well-preserved capillary architecture and density, as well as dilated and giant capil- laries. (C) In active scleroderma, it shows numerous giant capillaries and hemorrhages, a moderate loss of capillaries, and disorganized capillary architecture. (D) In late sclero- derma, the capillary architecture is severely disorganized, with “dropouts,” arborized capillaries, and the absence of giant capillaries.

Fenómeno de RaynaudCapilaroscopía

Descrita por Maricq y cols.Altamente específica en espectro de SScDermatoscopio 10x / Oftalmoscopio 20-40dpVideocapilaroscopía 200-600xSensible al cambio. Incrementó Sensibilidad al Dx 67 a 99%

Capilaroscop

ía+

Temprana+

Ac1va+

Tardía+

Asas capilaresHemorragiasAreas avascularesMIcrohemorragiasCapilares arborizados

M. Cutolo et al. Best Practice & Research Clinical Rheumatology Vol. 22, No. 6, pp. 1093–1108, 2008

martes, 10 de septiembre de 13Nailfold capillaroscopy

Normal nailfold capillaries are reassuring, whereas a ‘scleroderma­pattern’ showing capillary dilatation and areas of avascularity, first described by Maricq et al.70 is highly specific for an underlying SSc­spectrum disorder. High magnification videocapillaroscopy (200–600×) has revitalised the interest in capillaroscopy in recent years.71 However, clinicians without access to standard widefield microscopy or videocapillaroscopy, can visual­ ise capillaries using a dermatoscope (magnification in order of 10×) or opthalmoscope,72 which detects more obvious abnormalities.

A method for scoring the scleroderma­pattern, as ‘early’, ‘active’ and ‘late’, has been described.7

Key features of the early pattern, which are highly relevant to early diagnosis of a SSc­spectrum disorder in patients with Raynaud phenomenon, are presence of a small number of giant capillaries and of microhaemorrhages, without obvious capillary loss.

There is considerable interest in expanding clinical applications of capillaroscopy; for example, in improving the prediction of SSc through quantifying the abnormalities, and in predicting the risk of digital ulcera­ tion.

The recent increased emphasis on capillaroscopy is demonstrated in the proposed European criteria for early SSc: a scleroderma­pattern on capillaroscopy is one of the criteria.

(A) Normal nailfold pattern on nailfold capil- laroscopy (magnification ×200). (B) In the early stages of scleroderma, capillaroscopy shows well-preserved capillary architecture and density, as well as dilated and giant capil- laries. (C) In active scleroderma, it shows numerous giant capillaries and hemorrhages, a moderate loss of capillaries, and disorganized capillary architecture. (D) In late sclero- derma, the capillary architecture is severely disorganized, with “dropouts,” arborized capillaries, and the absence of giant capillaries.

Fenómeno de RaynaudCapilaroscopía

Descrita por Maricq y cols.Altamente específica en espectro de SScDermatoscopio 10x / Oftalmoscopio 20-40dpVideocapilaroscopía 200-600xSensible al cambio. Incrementó Sensibilidad al Dx 67 a 99%

Capilaroscop

ía+

Temprana+

Ac1va+

Tardía+

Asas capilaresHemorragiasAreas avascularesMIcrohemorragiasCapilares arborizados

M. Cutolo et al. Best Practice & Research Clinical Rheumatology Vol. 22, No. 6, pp. 1093–1108, 2008

martes, 10 de septiembre de 13Nailfold capillaroscopy

Normal nailfold capillaries are reassuring, whereas a ‘scleroderma­pattern’ showing capillary dilatation and areas of avascularity, first described by Maricq et al.70 is highly specific for an underlying SSc­spectrum disorder. High magnification videocapillaroscopy (200–600×) has revitalised the interest in capillaroscopy in recent years.71 However, clinicians without access to standard widefield microscopy or videocapillaroscopy, can visual­ ise capillaries using a dermatoscope (magnification in order of 10×) or opthalmoscope,72 which detects more obvious abnormalities.

A method for scoring the scleroderma­pattern, as ‘early’, ‘active’ and ‘late’, has been described.7

Key features of the early pattern, which are highly relevant to early diagnosis of a SSc­spectrum disorder in patients with Raynaud phenomenon, are presence of a small number of giant capillaries and of microhaemorrhages, without obvious capillary loss.

There is considerable interest in expanding clinical applications of capillaroscopy; for example, in improving the prediction of SSc through quantifying the abnormalities, and in predicting the risk of digital ulcera­ tion.

The recent increased emphasis on capillaroscopy is demonstrated in the proposed European criteria for early SSc: a scleroderma­pattern on capillaroscopy is one of the criteria.

(A) Normal nailfold pattern on nailfold capil- laroscopy (magnification ×200). (B) In the early stages of scleroderma, capillaroscopy shows well-preserved capillary architecture and density, as well as dilated and giant capil- laries. (C) In active scleroderma, it shows numerous giant capillaries and hemorrhages, a moderate loss of capillaries, and disorganized capillary architecture. (D) In late sclero- derma, the capillary architecture is severely disorganized, with “dropouts,” arborized capillaries, and the absence of giant capillaries.

Fenómeno de RaynaudCapilaroscopía

Descrita por Maricq y cols.Altamente específica en espectro de SScDermatoscopio 10x / Oftalmoscopio 20-40dpVideocapilaroscopía 200-600xSensible al cambio. Incrementó Sensibilidad al Dx 67 a 99%

Capilaroscop

ía+

Temprana+

Ac1va+

Tardía+

Asas capilaresHemorragiasAreas avascularesMIcrohemorragiasCapilares arborizados

M. Cutolo et al. Best Practice & Research Clinical Rheumatology Vol. 22, No. 6, pp. 1093–1108, 2008

martes, 10 de septiembre de 13Nailfold capillaroscopy

Normal nailfold capillaries are reassuring, whereas a ‘scleroderma­pattern’ showing capillary dilatation and areas of avascularity, first described by Maricq et al.70 is highly specific for an underlying SSc­spectrum disorder. High magnification videocapillaroscopy (200–600×) has revitalised the interest in capillaroscopy in recent years.71 However, clinicians without access to standard widefield microscopy or videocapillaroscopy, can visual­ ise capillaries using a dermatoscope (magnification in order of 10×) or opthalmoscope,72 which detects more obvious abnormalities.

A method for scoring the scleroderma­pattern, as ‘early’, ‘active’ and ‘late’, has been described.7

Key features of the early pattern, which are highly relevant to early diagnosis of a SSc­spectrum disorder in patients with Raynaud phenomenon, are presence of a small number of giant capillaries and of microhaemorrhages, without obvious capillary loss.

There is considerable interest in expanding clinical applications of capillaroscopy; for example, in improving the prediction of SSc through quantifying the abnormalities, and in predicting the risk of digital ulcera­ tion.

The recent increased emphasis on capillaroscopy is demonstrated in the proposed European criteria for early SSc: a scleroderma­pattern on capillaroscopy is one of the criteria.

(A) Normal nailfold pattern on nailfold capil- laroscopy (magnification ×200). (B) In the early stages of scleroderma, capillaroscopy shows well-preserved capillary architecture and density, as well as dilated and giant capil- laries. (C) In active scleroderma, it shows numerous giant capillaries and hemorrhages, a moderate loss of capillaries, and disorganized capillary architecture. (D) In late sclero- derma, the capillary architecture is severely disorganized, with “dropouts,” arborized capillaries, and the absence of giant capillaries.

Fenómeno de RaynaudCapilaroscopía

Descrita por Maricq y cols.Altamente específica en espectro de SScDermatoscopio 10x / Oftalmoscopio 20-40dpVideocapilaroscopía 200-600xSensible al cambio. Incrementó Sensibilidad al Dx 67 a 99%

Capilaroscop

ía+

Temprana+

Ac1va+

Tardía+

Asas capilaresHemorragiasAreas avascularesMIcrohemorragiasCapilares arborizados

M. Cutolo et al. Best Practice & Research Clinical Rheumatology Vol. 22, No. 6, pp. 1093–1108, 2008

martes, 10 de septiembre de 13Nailfold capillaroscopy

Normal nailfold capillaries are reassuring, whereas a ‘scleroderma­pattern’ showing capillary dilatation and areas of avascularity, first described by Maricq et al.70 is highly specific for an underlying SSc­spectrum disorder. High magnification videocapillaroscopy (200–600×) has revitalised the interest in capillaroscopy in recent years.71 However, clinicians without access to standard widefield microscopy or videocapillaroscopy, can visual­ ise capillaries using a dermatoscope (magnification in order of 10×) or opthalmoscope,72 which detects more obvious abnormalities.

A method for scoring the scleroderma­pattern, as ‘early’, ‘active’ and ‘late’, has been described.7

Key features of the early pattern, which are highly relevant to early diagnosis of a SSc­spectrum disorder in patients with Raynaud phenomenon, are presence of a small number of giant capillaries and of microhaemorrhages, without obvious capillary loss.

There is considerable interest in expanding clinical applications of capillaroscopy; for example, in improving the prediction of SSc through quantifying the abnormalities, and in predicting the risk of digital ulcera­ tion.

The recent increased emphasis on capillaroscopy is demonstrated in the proposed European criteria for early SSc: a scleroderma­pattern on capillaroscopy is one of the criteria.

(A) Normal nailfold pattern on nailfold capil- laroscopy (magnification ×200). (B) In the early stages of scleroderma, capillaroscopy shows well-preserved capillary architecture and density, as well as dilated and giant capil- laries. (C) In active scleroderma, it shows numerous giant capillaries and hemorrhages, a moderate loss of capillaries, and disorganized capillary architecture. (D) In late sclero- derma, the capillary architecture is severely disorganized, with “dropouts,” arborized capillaries, and the absence of giant capillaries.

Fenómeno de RaynaudCapilaroscopía

Descrita por Maricq y cols.Altamente específica en espectro de SScDermatoscopio 10x / Oftalmoscopio 20-40dpVideocapilaroscopía 200-600xSensible al cambio. Incrementó Sensibilidad al Dx 67 a 99%

Capilaroscop

ía+

Temprana+

Ac1va+

Tardía+

Asas capilaresHemorragiasAreas avascularesMIcrohemorragiasCapilares arborizados

M. Cutolo et al. Best Practice & Research Clinical Rheumatology Vol. 22, No. 6, pp. 1093–1108, 2008

martes, 10 de septiembre de 13Nailfold capillaroscopy

Normal nailfold capillaries are reassuring, whereas a ‘scleroderma­pattern’ showing capillary dilatation and areas of avascularity, first described by Maricq et al.70 is highly specific for an underlying SSc­spectrum disorder. High magnification videocapillaroscopy (200–600×) has revitalised the interest in capillaroscopy in recent years.71 However, clinicians without access to standard widefield microscopy or videocapillaroscopy, can visual­ ise capillaries using a dermatoscope (magnification in order of 10×) or opthalmoscope,72 which detects more obvious abnormalities.

A method for scoring the scleroderma­pattern, as ‘early’, ‘active’ and ‘late’, has been described.7

Key features of the early pattern, which are highly relevant to early diagnosis of a SSc­spectrum disorder in patients with Raynaud phenomenon, are presence of a small number of giant capillaries and of microhaemorrhages, without obvious capillary loss.

There is considerable interest in expanding clinical applications of capillaroscopy; for example, in improving the prediction of SSc through quantifying the abnormalities, and in predicting the risk of digital ulcera­ tion.

The recent increased emphasis on capillaroscopy is demonstrated in the proposed European criteria for early SSc: a scleroderma­pattern on capillaroscopy is one of the criteria.

(A) Normal nailfold pattern on nailfold capil- laroscopy (magnification ×200). (B) In the early stages of scleroderma, capillaroscopy shows well-preserved capillary architecture and density, as well as dilated and giant capil- laries. (C) In active scleroderma, it shows numerous giant capillaries and hemorrhages, a moderate loss of capillaries, and disorganized capillary architecture. (D) In late sclero- derma, the capillary architecture is severely disorganized, with “dropouts,” arborized capillaries, and the absence of giant capillaries.

Fenómeno de RaynaudCapilaroscopía

Descrita por Maricq y cols.Altamente específica en espectro de SScDermatoscopio 10x / Oftalmoscopio 20-40dpVideocapilaroscopía 200-600xSensible al cambio. Incrementó Sensibilidad al Dx 67 a 99%

Capilaroscop

ía+

Temprana+

Ac1va+

Tardía+

Asas capilaresHemorragiasAreas avascularesMIcrohemorragiasCapilares arborizados

M. Cutolo et al. Best Practice & Research Clinical Rheumatology Vol. 22, No. 6, pp. 1093–1108, 2008

martes, 10 de septiembre de 13Nailfold capillaroscopy

Normal nailfold capillaries are reassuring, whereas a ‘scleroderma­pattern’ showing capillary dilatation and areas of avascularity, first described by Maricq et al.70 is highly specific for an underlying SSc­spectrum disorder. High magnification videocapillaroscopy (200–600×) has revitalised the interest in capillaroscopy in recent years.71 However, clinicians without access to standard widefield microscopy or videocapillaroscopy, can visual­ ise capillaries using a dermatoscope (magnification in order of 10×) or opthalmoscope,72 which detects more obvious abnormalities.

A method for scoring the scleroderma­pattern, as ‘early’, ‘active’ and ‘late’, has been described.7

Key features of the early pattern, which are highly relevant to early diagnosis of a SSc­spectrum disorder in patients with Raynaud phenomenon, are presence of a small number of giant capillaries and of microhaemorrhages, without obvious capillary loss.

There is considerable interest in expanding clinical applications of capillaroscopy; for example, in improving the prediction of SSc through quantifying the abnormalities, and in predicting the risk of digital ulcera­ tion.

The recent increased emphasis on capillaroscopy is demonstrated in the proposed European criteria for early SSc: a scleroderma­pattern on capillaroscopy is one of the criteria.

(A) Normal nailfold pattern on nailfold capil- laroscopy (magnification ×200). (B) In the early stages of scleroderma, capillaroscopy shows well-preserved capillary architecture and density, as well as dilated and giant capil- laries. (C) In active scleroderma, it shows numerous giant capillaries and hemorrhages, a moderate loss of capillaries, and disorganized capillary architecture. (D) In late sclero- derma, the capillary architecture is severely disorganized, with “dropouts,” arborized capillaries, and the absence of giant capillaries.

Fenómeno de RaynaudCapilaroscopía

Descrita por Maricq y cols.Altamente específica en espectro de SScDermatoscopio 10x / Oftalmoscopio 20-40dpVideocapilaroscopía 200-600xSensible al cambio. Incrementó Sensibilidad al Dx 67 a 99%

Capilaroscop

ía+

Temprana+

Ac1va+

Tardía+

Asas capilaresHemorragiasAreas avascularesMIcrohemorragiasCapilares arborizados

M. Cutolo et al. Best Practice & Research Clinical Rheumatology Vol. 22, No. 6, pp. 1093–1108, 2008

martes, 10 de septiembre de 13Nailfold capillaroscopy

Normal nailfold capillaries are reassuring, whereas a ‘scleroderma­pattern’ showing capillary dilatation and areas of avascularity, first described by Maricq et al.70 is highly specific for an underlying SSc­spectrum disorder. High magnification videocapillaroscopy (200–600×) has revitalised the interest in capillaroscopy in recent years.71 However, clinicians without access to standard widefield microscopy or videocapillaroscopy, can visual­ ise capillaries using a dermatoscope (magnification in order of 10×) or opthalmoscope,72 which detects more obvious abnormalities.

A method for scoring the scleroderma­pattern, as ‘early’, ‘active’ and ‘late’, has been described.7

Key features of the early pattern, which are highly relevant to early diagnosis of a SSc­spectrum disorder in patients with Raynaud phenomenon, are presence of a small number of giant capillaries and of microhaemorrhages, without obvious capillary loss.

There is considerable interest in expanding clinical applications of capillaroscopy; for example, in improving the prediction of SSc through quantifying the abnormalities, and in predicting the risk of digital ulcera­ tion.

The recent increased emphasis on capillaroscopy is demonstrated in the proposed European criteria for early SSc: a scleroderma­pattern on capillaroscopy is one of the criteria.

(A) Normal nailfold pattern on nailfold capil- laroscopy (magnification ×200). (B) In the early stages of scleroderma, capillaroscopy shows well-preserved capillary architecture and density, as well as dilated and giant capil- laries. (C) In active scleroderma, it shows numerous giant capillaries and hemorrhages, a moderate loss of capillaries, and disorganized capillary architecture. (D) In late sclero- derma, the capillary architecture is severely disorganized, with “dropouts,” arborized capillaries, and the absence of giant capillaries.

Fenómeno de RaynaudCapilaroscopía

Descrita por Maricq y cols.Altamente específica en espectro de SScDermatoscopio 10x / Oftalmoscopio 20-40dpVideocapilaroscopía 200-600xSensible al cambio. Incrementó Sensibilidad al Dx 67 a 99%

Capilaroscop

ía+

Temprana+

Ac1va+

Tardía+

Asas capilaresHemorragiasAreas avascularesMIcrohemorragiasCapilares arborizados

M. Cutolo et al. Best Practice & Research Clinical Rheumatology Vol. 22, No. 6, pp. 1093–1108, 2008

martes, 10 de septiembre de 13Nailfold capillaroscopy

Normal nailfold capillaries are reassuring, whereas a ‘scleroderma­pattern’ showing capillary dilatation and areas of avascularity, first described by Maricq et al.70 is highly specific for an underlying SSc­spectrum disorder. High magnification videocapillaroscopy (200–600×) has revitalised the interest in capillaroscopy in recent years.71 However, clinicians without access to standard widefield microscopy or videocapillaroscopy, can visual­ ise capillaries using a dermatoscope (magnification in order of 10×) or opthalmoscope,72 which detects more obvious abnormalities.

A method for scoring the scleroderma­pattern, as ‘early’, ‘active’ and ‘late’, has been described.7

Key features of the early pattern, which are highly relevant to early diagnosis of a SSc­spectrum disorder in patients with Raynaud phenomenon, are presence of a small number of giant capillaries and of microhaemorrhages, without obvious capillary loss.

There is considerable interest in expanding clinical applications of capillaroscopy; for example, in improving the prediction of SSc through quantifying the abnormalities, and in predicting the risk of digital ulcera­ tion.

The recent increased emphasis on capillaroscopy is demonstrated in the proposed European criteria for early SSc: a scleroderma­pattern on capillaroscopy is one of the criteria.

(A) Normal nailfold pattern on nailfold capil- laroscopy (magnification ×200). (B) In the early stages of scleroderma, capillaroscopy shows well-preserved capillary architecture and density, as well as dilated and giant capil- laries. (C) In active scleroderma, it shows numerous giant capillaries and hemorrhages, a moderate loss of capillaries, and disorganized capillary architecture. (D) In late sclero- derma, the capillary architecture is severely disorganized, with “dropouts,” arborized capillaries, and the absence of giant capillaries.

Fenómeno de RaynaudCapilaroscopía

Descrita por Maricq y cols.Altamente específica en espectro de SScDermatoscopio 10x / Oftalmoscopio 20-40dpVideocapilaroscopía 200-600xSensible al cambio. Incrementó Sensibilidad al Dx 67 a 99%

Capilaroscop

ía+

Temprana+

Ac1va+

Tardía+

Asas capilaresHemorragiasAreas avascularesMIcrohemorragiasCapilares arborizados

M. Cutolo et al. Best Practice & Research Clinical Rheumatology Vol. 22, No. 6, pp. 1093–1108, 2008

martes, 10 de septiembre de 13Nailfold capillaroscopy

Normal nailfold capillaries are reassuring, whereas a ‘scleroderma­pattern’ showing capillary dilatation and areas of avascularity, first described by Maricq et al.70 is highly specific for an underlying SSc­spectrum disorder. High magnification videocapillaroscopy (200–600×) has revitalised the interest in capillaroscopy in recent years.71 However, clinicians without access to standard widefield microscopy or videocapillaroscopy, can visual­ ise capillaries using a dermatoscope (magnification in order of 10×) or opthalmoscope,72 which detects more obvious abnormalities.

A method for scoring the scleroderma­pattern, as ‘early’, ‘active’ and ‘late’, has been described.7

Key features of the early pattern, which are highly relevant to early diagnosis of a SSc­spectrum disorder in patients with Raynaud phenomenon, are presence of a small number of giant capillaries and of microhaemorrhages, without obvious capillary loss.

There is considerable interest in expanding clinical applications of capillaroscopy; for example, in improving the prediction of SSc through quantifying the abnormalities, and in predicting the risk of digital ulcera­ tion.

The recent increased emphasis on capillaroscopy is demonstrated in the proposed European criteria for early SSc: a scleroderma­pattern on capillaroscopy is one of the criteria.

(A) Normal nailfold pattern on nailfold capil- laroscopy (magnification ×200). (B) In the early stages of scleroderma, capillaroscopy shows well-preserved capillary architecture and density, as well as dilated and giant capil- laries. (C) In active scleroderma, it shows numerous giant capillaries and hemorrhages, a moderate loss of capillaries, and disorganized capillary architecture. (D) In late sclero- derma, the capillary architecture is severely disorganized, with “dropouts,” arborized capillaries, and the absence of giant capillaries.

Fenómeno de RaynaudCapilaroscopía

Descrita por Maricq y cols.Altamente específica en espectro de SScDermatoscopio 10x / Oftalmoscopio 20-40dpVideocapilaroscopía 200-600xSensible al cambio. Incrementó Sensibilidad al Dx 67 a 99%

Capilaroscop

ía+

Temprana+

Ac1va+

Tardía+

Asas capilaresHemorragiasAreas avascularesMIcrohemorragiasCapilares arborizados

M. Cutolo et al. Best Practice & Research Clinical Rheumatology Vol. 22, No. 6, pp. 1093–1108, 2008

martes, 10 de septiembre de 13Nailfold capillaroscopy

Normal nailfold capillaries are reassuring, whereas a ‘scleroderma­pattern’ showing capillary dilatation and areas of avascularity, first described by Maricq et al.70 is highly specific for an underlying SSc­spectrum disorder. High magnification videocapillaroscopy (200–600×) has revitalised the interest in capillaroscopy in recent years.71 However, clinicians without access to standard widefield microscopy or videocapillaroscopy, can visual­ ise capillaries using a dermatoscope (magnification in order of 10×) or opthalmoscope,72 which detects more obvious abnormalities.

A method for scoring the scleroderma­pattern, as ‘early’, ‘active’ and ‘late’, has been described.7

Key features of the early pattern, which are highly relevant to early diagnosis of a SSc­spectrum disorder in patients with Raynaud phenomenon, are presence of a small number of giant capillaries and of microhaemorrhages, without obvious capillary loss.

There is considerable interest in expanding clinical applications of capillaroscopy; for example, in improving the prediction of SSc through quantifying the abnormalities, and in predicting the risk of digital ulcera­ tion.

The recent increased emphasis on capillaroscopy is demonstrated in the proposed European criteria for early SSc: a scleroderma­pattern on capillaroscopy is one of the criteria.

(A) Normal nailfold pattern on nailfold capil- laroscopy (magnification ×200). (B) In the early stages of scleroderma, capillaroscopy shows well-preserved capillary architecture and density, as well as dilated and giant capil- laries. (C) In active scleroderma, it shows numerous giant capillaries and hemorrhages, a moderate loss of capillaries, and disorganized capillary architecture. (D) In late sclero- derma, the capillary architecture is severely disorganized, with “dropouts,” arborized capillaries, and the absence of giant capillaries.

martes, 10 de septiembre de 13Objective. To construct a prognostic index based on nailfold capillaroscopic examinations that is capable of predicting the 5-year transition from isolated Raynaud’s phenomenon (RP) to RP secondary to sclero- derma spectrum disorders (SSDs).

Methods. The study involved 104 consecutive adult patients with a clinical history of isolated RP, and the index was externally validated in another cohort of 100 patients with the same characteristics. Both groups were followed up for 1–8 years. Six variables were examined because of their potential prognostic rele- vance (branching, enlarged and giant loops, capillary disorganization, microhemorrhages, and the number of capillaries).

Results. The only factors that played a significant prognostic role were the presence of giant loops (hazard ratio [HR] 2.64, P<0.008) and microhemorrhages (HR 2.33, P 0.01), and the number of capillaries (analyzed as a continuous variable). The adjusted prognostic role of these factors was evaluated by means of multivariate regression analysis, and the results were used to construct an algorithm-based prognostic index. The model was internally and externally validated.

Conclusion. Our prognostic capillaroscopic index identifies RP patients in whom the risk of developing SSDs is high. This model is a weighted combination of different capillaroscopy parameters that allows physi- cians to stratify RP patients easily, using a relatively simple diagram to deduce the prognosis. Our results suggest that this index could be used in clinical practice, and its further inclusion in prospective studies will undoubtedly help in exploring its potential in predicting treatment response.

martes, 10 de septiembre de 13Objective. To construct a prognostic index based on nailfold capillaroscopic examinations that is capable of predicting the 5-year transition from isolated Raynaud’s phenomenon (RP) to RP secondary to sclero- derma spectrum disorders (SSDs).

Methods. The study involved 104 consecutive adult patients with a clinical history of isolated RP, and the index was externally validated in another cohort of 100 patients with the same characteristics. Both groups were followed up for 1–8 years. Six variables were examined because of their potential prognostic rele- vance (branching, enlarged and giant loops, capillary disorganization, microhemorrhages, and the number of capillaries).

Results. The only factors that played a significant prognostic role were the presence of giant loops (hazard ratio [HR] 2.64, P<0.008) and microhemorrhages (HR 2.33, P 0.01), and the number of capillaries (analyzed as a continuous variable). The adjusted prognostic role of these factors was evaluated by means of multivariate regression analysis, and the results were used to construct an algorithm-based prognostic index. The model was internally and externally validated.

Conclusion. Our prognostic capillaroscopic index identifies RP patients in whom the risk of developing SSDs is high. This model is a weighted combination of different capillaroscopy parameters that allows physi- cians to stratify RP patients easily, using a relatively simple diagram to deduce the prognosis. Our results suggest that this index could be used in clinical practice, and its further inclusion in prospective studies will undoubtedly help in exploring its potential in predicting treatment response.

martes, 10 de septiembre de 13Objective. To construct a prognostic index based on nailfold capillaroscopic examinations that is capable of predicting the 5-year transition from isolated Raynaud’s phenomenon (RP) to RP secondary to sclero- derma spectrum disorders (SSDs).

Methods. The study involved 104 consecutive adult patients with a clinical history of isolated RP, and the index was externally validated in another cohort of 100 patients with the same characteristics. Both groups were followed up for 1–8 years. Six variables were examined because of their potential prognostic rele- vance (branching, enlarged and giant loops, capillary disorganization, microhemorrhages, and the number of capillaries).

Results. The only factors that played a significant prognostic role were the presence of giant loops (hazard ratio [HR] 2.64, P<0.008) and microhemorrhages (HR 2.33, P 0.01), and the number of capillaries (analyzed as a continuous variable). The adjusted prognostic role of these factors was evaluated by means of multivariate regression analysis, and the results were used to construct an algorithm-based prognostic index. The model was internally and externally validated.

Conclusion. Our prognostic capillaroscopic index identifies RP patients in whom the risk of developing SSDs is high. This model is a weighted combination of different capillaroscopy parameters that allows physi- cians to stratify RP patients easily, using a relatively simple diagram to deduce the prognosis. Our results suggest that this index could be used in clinical practice, and its further inclusion in prospective studies will undoubtedly help in exploring its potential in predicting treatment response.

martes, 10 de septiembre de 13Objective. To construct a prognostic index based on nailfold capillaroscopic examinations that is capable of predicting the 5-year transition from isolated Raynaud’s phenomenon (RP) to RP secondary to sclero- derma spectrum disorders (SSDs).

Methods. The study involved 104 consecutive adult patients with a clinical history of isolated RP, and the index was externally validated in another cohort of 100 patients with the same characteristics. Both groups were followed up for 1–8 years. Six variables were examined because of their potential prognostic rele- vance (branching, enlarged and giant loops, capillary disorganization, microhemorrhages, and the number of capillaries).

Results. The only factors that played a significant prognostic role were the presence of giant loops (hazard ratio [HR] 2.64, P<0.008) and microhemorrhages (HR 2.33, P 0.01), and the number of capillaries (analyzed as a continuous variable). The adjusted prognostic role of these factors was evaluated by means of multivariate regression analysis, and the results were used to construct an algorithm-based prognostic index. The model was internally and externally validated.

Conclusion. Our prognostic capillaroscopic index identifies RP patients in whom the risk of developing SSDs is high. This model is a weighted combination of different capillaroscopy parameters that allows physi- cians to stratify RP patients easily, using a relatively simple diagram to deduce the prognosis. Our results suggest that this index could be used in clinical practice, and its further inclusion in prospective studies will undoubtedly help in exploring its potential in predicting treatment response.

martes, 10 de septiembre de 13Objective. To construct a prognostic index based on nailfold capillaroscopic examinations that is capable of predicting the 5-year transition from isolated Raynaud’s phenomenon (RP) to RP secondary to sclero- derma spectrum disorders (SSDs).

Methods. The study involved 104 consecutive adult patients with a clinical history of isolated RP, and the index was externally validated in another cohort of 100 patients with the same characteristics. Both groups were followed up for 1–8 years. Six variables were examined because of their potential prognostic rele- vance (branching, enlarged and giant loops, capillary disorganization, microhemorrhages, and the number of capillaries).

Results. The only factors that played a significant prognostic role were the presence of giant loops (hazard ratio [HR] 2.64, P<0.008) and microhemorrhages (HR 2.33, P 0.01), and the number of capillaries (analyzed as a continuous variable). The adjusted prognostic role of these factors was evaluated by means of multivariate regression analysis, and the results were used to construct an algorithm-based prognostic index. The model was internally and externally validated.

Conclusion. Our prognostic capillaroscopic index identifies RP patients in whom the risk of developing SSDs is high. This model is a weighted combination of different capillaroscopy parameters that allows physi- cians to stratify RP patients easily, using a relatively simple diagram to deduce the prognosis. Our results suggest that this index could be used in clinical practice, and its further inclusion in prospective studies will undoubtedly help in exploring its potential in predicting treatment response.

ORIGINAL ARTICLE

The value of pattern capillary changes and antibodies to predictthe development of systemic sclerosis in patients with primaryRaynaud’s phenomenon

Slavica R. Pavlov-Dolijanovic • Nemanja S. Damjanov •

Nada Z. Vujasinovic Stupar • Snezana Baltic •

Dragan D. Babic

Received: 19 October 2012 / Accepted: 30 July 2013! Springer-Verlag Berlin Heidelberg 2013

Abstract The aim of this study is to assess the prognosticvalue of major provisional criteria for the development of

systemic sclerosis (SSc) in primary Raynaud’s phenome-

non (RP) patients. We retrospectively studied the chart of497 patients with primary RP in whom anticentromere

(ACA) and antitopoisomerase I (ATA) antibodies tests and

a capillary reading were available. Sensitivity, specificity,positive predictive value, negative predictive value, posi-

tive likelihood ratios (LHR?), negative likelihood ratios

(LHR-), odds ratio (OR), and area under the receiveroperating characteristics curve (AUC) of those criteria

were assessed to predict the development of SSc. During

the average follow-up of 2.3 ± 1.9 years, 159 (32 %)patients evolved to SSc, 245 (49.3 %) evolved to other

connective tissue diseases, and 93 (18.7 %) patients did not

progress. The SSc pattern predicted SSc satisfactorily(LHR? 4.12, LHR- 0.07, OR 63, AUC 0.819; P \ 0.001).

ACA were not significantly associated with the develop-ment of SSc (LHR? 1.19, LHR- 0.9, OR 1.32, AUC

0.538, P = 0.156). ATA were significantly associated with

the development of SSc (LHR? 9.32, LHR- 0.67, OR15.13, AUC 0.777; P \ 0.001). Both SSc pattern and ACA

or ATA were significantly associated with the development

of SSc (LHR? 2.98, LHR- 0.70, OR 4.2, AUC 0.674;P \ 0.001 vs. LHR? 16, LHR- 0.68, OR 24, AUC 0.819;

P \ 0.001, respectively). SSc pattern or ATA as indepen-

dent risk factors, as well as following two parameterstogether (SSc pattern and ATA or SSc pattern and ACA)

were good predictors for the development of SSc.

Keywords Systemic sclerosis ! Capillaroscopy !Scleroderma pattern ! Anticentromere antibodies !Antitopoisomerase I antibodies ! Classificationcriteria

Introduction

Provisional criteria for the diagnosis of very early systemic

sclerosis (SSc) proposed by European League AgainstRheumatism (EULAR) Scleroderma Trial and Research

group (EUSTAR) are divided into two groups: (a) major

criteria [Raynaud’s phenomenon (RP), antibodies (antinu-clear, anticentromere, antitopoisomerase I), and abnormal

capillaroscopy with scleroderma pattern] and (b) additional

criteria (calcinosis, puffy fingers, digital ulcers, dysfunc-tion of the esophageal sphincter, telangiectasia, and ground

glass at chest high-resolution computed tomography). The

diagnosis of very early SSc will be achieved when at leastthree major criteria are satisfied or two major plus one

additional criterion is satisfied [1]. These criteria were

validated using consensus procedures, including the Delphi

S. R. Pavlov-Dolijanovic (&) ! S. BalticInstitute of Rheumatology Belgrade, Resavska 69,11000 Belgrade, Serbiae-mail: dolijan@eunet.rs

S. Baltice-mail: baltic.snezana3@gmail.com

N. S. Damjanov ! N. Z. Vujasinovic StuparInstitute of Rheumatology, Faculty of Medicine,University of Belgrade, Resavska 69, 11000 Belgrade, Serbiae-mail: nemanjadamjanov@yahoo.com

N. Z. Vujasinovic Stupare-mail: stuparn@eunet.rs

D. D. BabicInstitute of Medical Statistics and Informatics, Faculty ofMedicine, University of Belgrade, Doctora Subotica 8,11000 Belgrade, Serbiae-mail: babicdra@gmail.com

123

Rheumatol Int

DOI 10.1007/s00296-013-2844-7

SSc Muy temprana(EUSTAR)

Mayores: Fenómeno de Raynaud

AnticuerposCapilaroscopía anormal con patrón

de esclerodermaAdicionales:

CalcinosisDedos GorditosÚlceras DigitalesDisfunción de EII

TelangiectasiaVidrio despulido en TACAR

3 Mayores2 Mayores + 1 adicional

Rheumatol Int. 2013 Aug 11. [Epub ahead of print]

martes, 10 de septiembre de 13The aim of this study is to assess the prognostic value of major provisional criteria for the development of systemic sclerosis (SSc) in primary Raynaud’s phenome- non (RP) patients. We retrospectively studied the chart of 497 patients with primary RP in whom anticentromere (ACA) and antitopoisomerase I (ATA) antibodies tests and a capillary reading were available. Sensitivity, specificity, positive predictive value, negative predictive value, posi- tive likelihood ratios (LHR?), negative likelihood ratios (LHR-), odds ratio (OR), and area under the receiver operating characteristics curve (AUC) of those criteria were assessed to predict the development of SSc.

ORIGINAL ARTICLE

The value of pattern capillary changes and antibodies to predictthe development of systemic sclerosis in patients with primaryRaynaud’s phenomenon

Slavica R. Pavlov-Dolijanovic • Nemanja S. Damjanov •

Nada Z. Vujasinovic Stupar • Snezana Baltic •

Dragan D. Babic

Received: 19 October 2012 / Accepted: 30 July 2013! Springer-Verlag Berlin Heidelberg 2013

Abstract The aim of this study is to assess the prognosticvalue of major provisional criteria for the development of

systemic sclerosis (SSc) in primary Raynaud’s phenome-

non (RP) patients. We retrospectively studied the chart of497 patients with primary RP in whom anticentromere

(ACA) and antitopoisomerase I (ATA) antibodies tests and

a capillary reading were available. Sensitivity, specificity,positive predictive value, negative predictive value, posi-

tive likelihood ratios (LHR?), negative likelihood ratios

(LHR-), odds ratio (OR), and area under the receiveroperating characteristics curve (AUC) of those criteria

were assessed to predict the development of SSc. During

the average follow-up of 2.3 ± 1.9 years, 159 (32 %)patients evolved to SSc, 245 (49.3 %) evolved to other

connective tissue diseases, and 93 (18.7 %) patients did not

progress. The SSc pattern predicted SSc satisfactorily(LHR? 4.12, LHR- 0.07, OR 63, AUC 0.819; P \ 0.001).

ACA were not significantly associated with the develop-ment of SSc (LHR? 1.19, LHR- 0.9, OR 1.32, AUC

0.538, P = 0.156). ATA were significantly associated with

the development of SSc (LHR? 9.32, LHR- 0.67, OR15.13, AUC 0.777; P \ 0.001). Both SSc pattern and ACA

or ATA were significantly associated with the development

of SSc (LHR? 2.98, LHR- 0.70, OR 4.2, AUC 0.674;P \ 0.001 vs. LHR? 16, LHR- 0.68, OR 24, AUC 0.819;

P \ 0.001, respectively). SSc pattern or ATA as indepen-

dent risk factors, as well as following two parameterstogether (SSc pattern and ATA or SSc pattern and ACA)

were good predictors for the development of SSc.

Keywords Systemic sclerosis ! Capillaroscopy !Scleroderma pattern ! Anticentromere antibodies !Antitopoisomerase I antibodies ! Classificationcriteria

Introduction

Provisional criteria for the diagnosis of very early systemic

sclerosis (SSc) proposed by European League AgainstRheumatism (EULAR) Scleroderma Trial and Research

group (EUSTAR) are divided into two groups: (a) major

criteria [Raynaud’s phenomenon (RP), antibodies (antinu-clear, anticentromere, antitopoisomerase I), and abnormal

capillaroscopy with scleroderma pattern] and (b) additional

criteria (calcinosis, puffy fingers, digital ulcers, dysfunc-tion of the esophageal sphincter, telangiectasia, and ground

glass at chest high-resolution computed tomography). The

diagnosis of very early SSc will be achieved when at leastthree major criteria are satisfied or two major plus one

additional criterion is satisfied [1]. These criteria were

validated using consensus procedures, including the Delphi

S. R. Pavlov-Dolijanovic (&) ! S. BalticInstitute of Rheumatology Belgrade, Resavska 69,11000 Belgrade, Serbiae-mail: dolijan@eunet.rs

S. Baltice-mail: baltic.snezana3@gmail.com

N. S. Damjanov ! N. Z. Vujasinovic StuparInstitute of Rheumatology, Faculty of Medicine,University of Belgrade, Resavska 69, 11000 Belgrade, Serbiae-mail: nemanjadamjanov@yahoo.com

N. Z. Vujasinovic Stupare-mail: stuparn@eunet.rs

D. D. BabicInstitute of Medical Statistics and Informatics, Faculty ofMedicine, University of Belgrade, Doctora Subotica 8,11000 Belgrade, Serbiae-mail: babicdra@gmail.com

123

Rheumatol Int

DOI 10.1007/s00296-013-2844-7

Rheumatol Int. 2013 Aug 11. [Epub ahead of print]

martes, 10 de septiembre de 13Despite limitations mentioned above, our data con- firmed SSc pattern or ATA as independent risk factors, as well as following two parameters together (SSc pattern and ATA or SSc pattern and ACA) were good predictors for the development of SSc

23

CHATTERJEE

However, only about 60% of patients have all three color changes. The attacks are associat-ed with paresthesias, an uncomfortable feeling of coldness in the !ngers, and ischemic pain.

Primary Raynaud phenomenonPrimary or idiopathic Raynaud phenomenon is seen in 5% to 10% of the general popula-tion. It more commonly affects women ages 15 to 30, is generally mild, involves the dig-its symmetrically, and is sometimes familial. An increase in alpha-2 adrenergic responses

in the digital vessels leads to arterial vaso-spasm, an exaggerated physiologic response to cold temperatures.2 Geographic variability in prevalence likely represents differences in mean outdoor temperatures,3 which is in part why attacks of primary Raynaud phenomenon tend to be worse in the winter months.4

Secondary Raynaud phenomenonRaynaud phenomenon also often occurs in certain autoimmune rheumatic diseases (sec-ondary Raynaud phenomenon): for example,

A diagnostic algorithm for digital ischemiaDigital ischemia

Exposure to cold temperature or emotional stress that provokes color changes of the fingers and toes

(white followed by blue or red)

Persistent asymmetric or single-digit involvement

Persistent cyanosis of fingers, toes, earlobes, nose; no associated tro-phic skin changes, localized pain, or ulceration

- Females > males- Age 15-30 years- Generally mild episodes- Symmetric involvement- Positive family history (25% of cases)- No digital ulceration or infarction- No history to suggest underlying autoimmune rheumatic or other disease- Normal nailfold capillaroscopy- Negative for antinuclear antibody, other autoantibodies

- Over age 30 at presentation - More severe, prolonged attacks- History and examination suggest underlying autoimmune rheumatic disease (scleroderma, lupus, mixed connective tissue disease, poly- or dermatomyositis, Sjögren syndrome)- Digital pitting scars, ulcers, gangrene- Abnormal nailfold capillaroscopy- Positive for antinuclear antibody, other autoantibodies - Presence of cryoglobulins, cold agglu- tinins, polycythemia, cryofibrinogens- History of cancer, chemotherapy

Precipitating or aggravating factors- Drugs: chemotherapeutic agents,

interferon, estrogen, stimulants (modafinil, methylphenidate, dexamphetamine), anorexiants, sympathomimetics, migraine drugs (triptans, ergotamines, methysergide), clonidine, calcineurin inhibitors

- Toxins: nicotine, cocaine, amphetamines, polyvinyl chloride

- Environmental, occupational factors: frostbite, use of vibrating tools - Entrapment neuropathy: carpal tunnel syndrome

- Large-vessel atherosclerotic disease- Vasculitis (eg, thromboangitis obliterans, Takayasu arteritis)- Thromboembolic disease (endocarditis, cardiac myxoma, atheroemboli, disseminated intravascular coagulation, antiphospholipid syndrome)- Thoracic outlet syndrome

Primary Raynaud phenomenon

Secondary Raynaud phenomenon

Digital artery occlusion

Acrocyanosis

FIGURE 2

on August 28, 2013. For personal use only. All other uses require permission.www.ccjm.orgDownloaded from

Fenómeno de RaynaudDiagnóstico

Herrick, A. L. Nat. Rev. Rheumatol. 8, 469–479 (2012)

martes, 10 de septiembre de 13

F.#Raynaud

#

Primario#

Secundario#

Fenómeno de RaynaudDiagnóstico Diferencial

martes, 10 de septiembre de 13Raynaud’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

F.#Raynaud

#

Primario#

Secundario#

Fenómeno de RaynaudDiagnóstico Diferencial

martes, 10 de septiembre de 13Raynaud’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

F.#Raynaud

#

Primario#

Secundario#

Fenómeno de RaynaudDiagnóstico Diferencial

martes, 10 de septiembre de 13Raynaud’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

F.#Raynaud

#

Primario#

Secundario#

Riesgo de progresión a Enf. Tejido Conectivo

2%a 10 años + > 6.3%

Landry et al. J Vasc Surg 1996; 23: 76–78.

Seropositividad

Fenómeno de RaynaudDiagnóstico Diferencial

martes, 10 de septiembre de 13Raynaud’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

Fenómeno de RaynaudDiagnóstico Diferencial Isquemia Tiempo

Acrocianosis

•Trastorno poco común

•Indoloro, vasoespástico

•Individuos con bajo peso corporal/Anorexia Nervosa

•Coloración azulada en manos y menos frecuente en pies

•Frío lo exacerba

•Involcura TODA la mano o pie

•Diaforesis

•Capilaroscopía normal

Cassidy: Textbook of Pediatric Rheumatology, 6th ed. 2010 Saunders, An Imprint of Elsevier Cap. 29

martes, 10 de septiembre de 13Acrocyanosis is an uncommon, painless, vasospastic disorder causing persistent coldness and bluish discol- oration of the hands (and less commonly of the feet).42 Patients with acrocyanosis have cold and diffusely cya- notic color changes that can involve the entire hand and foot, extending proximally without a sharp demarcation between affected and unaffected tissue. Mild diaphoresis may be present, creating a clammy feel to the extremi- ties. Mild abnormalities may exist but do not show the avascular regions or giant capillaries found in patients with scleroderma.67 Both acrocyanosis and RP are more common in individuals with low body weight or who have anorexia nervosa.68 Evaluation for cyanotic heart disease, eating disorders, or GI malabsorption should be considered.

Fenómeno de RaynaudDiagnóstico Diferencial

Perniosis

•Inducido por frío

•L e s i o n e s p a p u l o n o d u l a r e s ,

eritematosas, DOLOROSAS

•Distal dedos, manos pies, glúteos

•Idiopático o asociado a LES

•Difiere de F. Raynaud en etapa de

“blanqueamiento”

•Tx igual al de F. de Raynaud.

Cassidy: Textbook of Pediatric Rheumatology, 6th ed. 2010 Saunders, An Imprint of Elsevier Cap. 29

martes, 10 de septiembre de 13Perniosis, or chilblains, is a cold-induced condition marked by the appearance of painful, erythematous, pap- ular, or nodular lesions, usually located on the fingers, toes, thighs, and buttocks.69,70 As with RP, perniosis may present as an idiopathic process or in association with systemic disease (i.e. SLE). It is distinguished from RP by the lack of blanching. Although clinically and histologi- cally distinct from RP, the treatment paradigms are simi- lar and based primarily on nonpharmacological lifestyle modifications. Although definitive data are lacking, many of the other agents used for RP can be considered if phar- macological intervention is necessary.

Fenómeno de RaynaudDiagnóstico Diferencial

Perniosis

•Inducido por frío

•L e s i o n e s p a p u l o n o d u l a r e s ,

eritematosas, DOLOROSAS

•Distal dedos, manos pies, glúteos

•Idiopático o asociado a LES

•Difiere de F. Raynaud en etapa de

“blanqueamiento”

•Tx igual al de F. de Raynaud.

Cassidy: Textbook of Pediatric Rheumatology, 6th ed. 2010 Saunders, An Imprint of Elsevier Cap. 29

martes, 10 de septiembre de 13Perniosis, or chilblains, is a cold-induced condition marked by the appearance of painful, erythematous, pap- ular, or nodular lesions, usually located on the fingers, toes, thighs, and buttocks.69,70 As with RP, perniosis may present as an idiopathic process or in association with systemic disease (i.e. SLE). It is distinguished from RP by the lack of blanching. Although clinically and histologi- cally distinct from RP, the treatment paradigms are simi- lar and based primarily on nonpharmacological lifestyle modifications. Although definitive data are lacking, many of the other agents used for RP can be considered if phar- macological intervention is necessary.

Fenómeno de RaynaudDiagnóstico Diferencial

Perniosis

•Inducido por frío

•L e s i o n e s p a p u l o n o d u l a r e s ,

eritematosas, DOLOROSAS

•Distal dedos, manos pies, glúteos

•Idiopático o asociado a LES

•Difiere de F. Raynaud en etapa de

“blanqueamiento”

•Tx igual al de F. de Raynaud.

Cassidy: Textbook of Pediatric Rheumatology, 6th ed. 2010 Saunders, An Imprint of Elsevier Cap. 29

martes, 10 de septiembre de 13Perniosis, or chilblains, is a cold-induced condition marked by the appearance of painful, erythematous, pap- ular, or nodular lesions, usually located on the fingers, toes, thighs, and buttocks.69,70 As with RP, perniosis may present as an idiopathic process or in association with systemic disease (i.e. SLE). It is distinguished from RP by the lack of blanching. Although clinically and histologi- cally distinct from RP, the treatment paradigms are simi- lar and based primarily on nonpharmacological lifestyle modifications. Although definitive data are lacking, many of the other agents used for RP can be considered if phar- macological intervention is necessary.

Fenómeno de RaynaudDiagnóstico Diferencial

Perniosis

•Inducido por frío

•L e s i o n e s p a p u l o n o d u l a r e s ,

eritematosas, DOLOROSAS

•Distal dedos, manos pies, glúteos

•Idiopático o asociado a LES

•Difiere de F. Raynaud en etapa de

“blanqueamiento”

•Tx igual al de F. de Raynaud.

Cassidy: Textbook of Pediatric Rheumatology, 6th ed. 2010 Saunders, An Imprint of Elsevier Cap. 29

martes, 10 de septiembre de 13Perniosis, or chilblains, is a cold-induced condition marked by the appearance of painful, erythematous, pap- ular, or nodular lesions, usually located on the fingers, toes, thighs, and buttocks.69,70 As with RP, perniosis may present as an idiopathic process or in association with systemic disease (i.e. SLE). It is distinguished from RP by the lack of blanching. Although clinically and histologi- cally distinct from RP, the treatment paradigms are simi- lar and based primarily on nonpharmacological lifestyle modifications. Although definitive data are lacking, many of the other agents used for RP can be considered if phar- macological intervention is necessary.

Fenómeno de RaynaudDiagnóstico Diferencial

Perniosis

•Inducido por frío

•L e s i o n e s p a p u l o n o d u l a r e s ,

eritematosas, DOLOROSAS

•Distal dedos, manos pies, glúteos

•Idiopático o asociado a LES

•Difiere de F. Raynaud en etapa de

“blanqueamiento”

•Tx igual al de F. de Raynaud.

Cassidy: Textbook of Pediatric Rheumatology, 6th ed. 2010 Saunders, An Imprint of Elsevier Cap. 29

martes, 10 de septiembre de 13Perniosis, or chilblains, is a cold-induced condition marked by the appearance of painful, erythematous, pap- ular, or nodular lesions, usually located on the fingers, toes, thighs, and buttocks.69,70 As with RP, perniosis may present as an idiopathic process or in association with systemic disease (i.e. SLE). It is distinguished from RP by the lack of blanching. Although clinically and histologi- cally distinct from RP, the treatment paradigms are simi- lar and based primarily on nonpharmacological lifestyle modifications. Although definitive data are lacking, many of the other agents used for RP can be considered if phar- macological intervention is necessary.

Fenómeno de RaynaudDiagnóstico Diferencial

Perniosis

•Inducido por frío

•L e s i o n e s p a p u l o n o d u l a r e s ,

eritematosas, DOLOROSAS

•Distal dedos, manos pies, glúteos

•Idiopático o asociado a LES

•Difiere de F. Raynaud en etapa de

“blanqueamiento”

•Tx igual al de F. de Raynaud.

Cassidy: Textbook of Pediatric Rheumatology, 6th ed. 2010 Saunders, An Imprint of Elsevier Cap. 29

martes, 10 de septiembre de 13Perniosis, or chilblains, is a cold-induced condition marked by the appearance of painful, erythematous, pap- ular, or nodular lesions, usually located on the fingers, toes, thighs, and buttocks.69,70 As with RP, perniosis may present as an idiopathic process or in association with systemic disease (i.e. SLE). It is distinguished from RP by the lack of blanching. Although clinically and histologi- cally distinct from RP, the treatment paradigms are simi- lar and based primarily on nonpharmacological lifestyle modifications. Although definitive data are lacking, many of the other agents used for RP can be considered if phar- macological intervention is necessary.

Fenómeno de RaynaudDiagnóstico Diferencial

Congelamiento

•Inducido por frío

•Hipersensibilidad al frío

•Insensibilidad, adormecimiento

•Vasoespasmo en 20%

Cassidy: Textbook of Pediatric Rheumatology, 6th ed. 2010 Saunders, An Imprint of Elsevier Cap. 29

martes, 10 de septiembre de 13Frostbite is relatively common in cold climates and can have prolonged sequelae including persistent cold sensitivity.

In a study of 30 patients who had suffered moderate (second degree) frostbite, Ervasti and colleagues reported subjective symptoms at 4 to 11 years after injury in 63% of the subjects, including hypersensitivity to cold, numbness, and decreased touch sensitivity. Cold air prov- ocation testing revealed an increased t

Fenómeno de RaynaudDiagnóstico Diferencial

Congelamiento

•Inducido por frío

•Hipersensibilidad al frío

•Insensibilidad, adormecimiento

•Vasoespasmo en 20%

Cassidy: Textbook of Pediatric Rheumatology, 6th ed. 2010 Saunders, An Imprint of Elsevier Cap. 29

martes, 10 de septiembre de 13Frostbite is relatively common in cold climates and can have prolonged sequelae including persistent cold sensitivity.

In a study of 30 patients who had suffered moderate (second degree) frostbite, Ervasti and colleagues reported subjective symptoms at 4 to 11 years after injury in 63% of the subjects, including hypersensitivity to cold, numbness, and decreased touch sensitivity. Cold air prov- ocation testing revealed an increased t

Fenómeno de RaynaudDiagnóstico Diferencial

Congelamiento

•Inducido por frío

•Hipersensibilidad al frío

•Insensibilidad, adormecimiento

•Vasoespasmo en 20%

Cassidy: Textbook of Pediatric Rheumatology, 6th ed. 2010 Saunders, An Imprint of Elsevier Cap. 29

martes, 10 de septiembre de 13Frostbite is relatively common in cold climates and can have prolonged sequelae including persistent cold sensitivity.

In a study of 30 patients who had suffered moderate (second degree) frostbite, Ervasti and colleagues reported subjective symptoms at 4 to 11 years after injury in 63% of the subjects, including hypersensitivity to cold, numbness, and decreased touch sensitivity. Cold air prov- ocation testing revealed an increased t

Fenómeno de RaynaudDiagnóstico Diferencial

Congelamiento

•Inducido por frío

•Hipersensibilidad al frío

•Insensibilidad, adormecimiento

•Vasoespasmo en 20%

Cassidy: Textbook of Pediatric Rheumatology, 6th ed. 2010 Saunders, An Imprint of Elsevier Cap. 29

martes, 10 de septiembre de 13Frostbite is relatively common in cold climates and can have prolonged sequelae including persistent cold sensitivity.

In a study of 30 patients who had suffered moderate (second degree) frostbite, Ervasti and colleagues reported subjective symptoms at 4 to 11 years after injury in 63% of the subjects, including hypersensitivity to cold, numbness, and decreased touch sensitivity. Cold air prov- ocation testing revealed an increased t

Fenómeno de RaynaudDiagnóstico Diferencial

Congelamiento

•Inducido por frío

•Hipersensibilidad al frío

•Insensibilidad, adormecimiento

•Vasoespasmo en 20%

Cassidy: Textbook of Pediatric Rheumatology, 6th ed. 2010 Saunders, An Imprint of Elsevier Cap. 29

martes, 10 de septiembre de 13Frostbite is relatively common in cold climates and can have prolonged sequelae including persistent cold sensitivity.

In a study of 30 patients who had suffered moderate (second degree) frostbite, Ervasti and colleagues reported subjective symptoms at 4 to 11 years after injury in 63% of the subjects, including hypersensitivity to cold, numbness, and decreased touch sensitivity. Cold air prov- ocation testing revealed an increased t

Fenómeno de RaynaudDiagnóstico Diferencial

Congelamiento

•Inducido por frío

•Hipersensibilidad al frío

•Insensibilidad, adormecimiento

•Vasoespasmo en 20%

Cassidy: Textbook of Pediatric Rheumatology, 6th ed. 2010 Saunders, An Imprint of Elsevier Cap. 29

martes, 10 de septiembre de 13Frostbite is relatively common in cold climates and can have prolonged sequelae including persistent cold sensitivity.

In a study of 30 patients who had suffered moderate (second degree) frostbite, Ervasti and colleagues reported subjective symptoms at 4 to 11 years after injury in 63% of the subjects, including hypersensitivity to cold, numbness, and decreased touch sensitivity. Cold air prov- ocation testing revealed an increased t

Fenómeno de RaynaudDiagnóstico Diferencial

Congelamiento

•Inducido por frío

•Hipersensibilidad al frío

•Insensibilidad, adormecimiento

•Vasoespasmo en 20%

Cassidy: Textbook of Pediatric Rheumatology, 6th ed. 2010 Saunders, An Imprint of Elsevier Cap. 29

martes, 10 de septiembre de 13Frostbite is relatively common in cold climates and can have prolonged sequelae including persistent cold sensitivity.

In a study of 30 patients who had suffered moderate (second degree) frostbite, Ervasti and colleagues reported subjective symptoms at 4 to 11 years after injury in 63% of the subjects, including hypersensitivity to cold, numbness, and decreased touch sensitivity. Cold air prov- ocation testing revealed an increased t

Fenómeno de RaynaudDiagnóstico Diferencial

Síndrome del Tunel del carpo

Plexopatías

EritromelalgiaDolor Regional

Complejo

Cassidy: Textbook of Pediatric Rheumatology, 6th ed. 2010 Saunders, An Imprint of Elsevier Cap. 29

martes, 10 de septiembre de 13Carpal Tunnel Syndrome is relatively rare in children and is more often idiopathic or secondary to lysosomal storage disorders, rather than related to overuse as is seen in adults.71 Symptoms are more characteristically numb- ness and reduced manual dexterity, rather than color changes, and are generally not related to cold exposure. Although the wrist-flexion test (Phalen maneuver) and the nerve compression or percussion test (Tinel sign) can be informative, they are often nondiagnostic in pediatric patients, and electrophysiological testing is indicated to confirm a diagnostic suspicion.

Brachial or lumbosacral plexus neuropathies are also rare in children, outside of those related to birth injury, but may present in older adolescents and young adults seen in pediatric clinics.72 The typical presentation of idio- pathic brachial plexus neuritis (Parsonage-Turner syn- drome) or lumbosacral plexopathy includes acute onset of shoulder or proximal leg pain, respectively, associated with weakness and muscle wasting in the extremity and without restricted passive range of motion. Numbness and color changes in the extremity are variable, but fixed and less prominent a complaint than pain and neuromus- cular symptoms. Idiopathic plexus neuropathies often fol- low an upper respiratory infection and may be recurrent. Electromyographic findings are characteristic and diag- nostic. Prognosis is generally good, though recovery may be protracted and may require intensive physical therapy to reduce contractures and restore muscle strength.

Erythromelalgia is a rare condition of paroxysmal vasodilation. Erythromelalgia can be thought of as the opposite of RP. Symptoms manifest as episodic burning pain accompanied by erythema, warmth and swelling of the hands and/or feet; they are often brought on by heat, exercise, or friction, and affected patients report dramatic relief with application of ice or cold water. Erythromelal- gia also presents in both primary and secondary forms. Primary erythromelalgia presents in childhood and can be familial (autosomal dominant) or sporadic. It affects girls more than boys, symptoms are most often symmet- rical, and it is frequently resistant to treatment. Recent studies have attributed a majority of both familial and sporadic cases to gain-of-function mutations of SCN9A, the gene that encodes the voltage-gated sodium chan- nel Na(v)1.7.73 Loss-of-function mutations in the same gene are associated with congenital insensitivity to pain. Secondary erythromelalgia is more common and typi- cally presents in older children and adults. The major- ity of cases are associated with essential thrombocytosis and are characteristically responsive to low dose aspirin therapy.74 Erythromelalgia can also develop in patients with small fiber neuropathies of many sources, including

multiple sclerosis, hypercholesterolemia, mercury and other heavy-metal poisoning, and a variety of autoim- mune diseases. These patients are not responsive to aspi- rin, but the condition typically responds to treatment of the underlying disorder. Management of erythromelalgia includes avoidance of triggers (heat, friction) and appli- cation of cold during acute attacks. If aspirin or treat- ment of associated conditions is unsuccessful, a variety of attempts at interventions have been reported. Although controlled studies are lacking, case studies have reported successful use of a range of pharmacological (e.g., nife- dipine, verapamil, propranolol, nitroprusside), non-phar- macological (e.g., biofeedback, hypnosis), and surgical (sympathectomy, amputation, stereotactic destruction of regions of the hypothalamus) approaches.

Complex regional pain syndrome (CRPS), or reflex sympathetic dystrophy, will often present with altered col- oration of the involved extremity.75 Patients with CRPS usually have unilateral distal limb involvement, with the affected area showing differences in temperature (warmer or colder) and color (red, pale, or mottled) compared with the unaffected side. These patients typically describe severe diffuse allodynia; paresthesia, causalgia or other abnormal sensations; refusal to move the affected region; and unusual positioning of the affected extremity.

martes, 10 de septiembre de 13