Esclerodermia f ry

1. Fenômeno de RaynaudFenômeno de Raynaud
Disciplina Reumatologia
2013

2. Fenômeno de RaynaudFenômeno de Raynaud
Resposta fisiológica exagerada em resposta a exposição ao frio e ao
estresse
Isquemia Cianose Cianose
Reperfusão
Herrick, A. L. Nat. Rev. Rheumatol. 2012

4. Fenômeno de RaynaudFenômeno de Raynaud
NATURE REVIEWS | RHEUMATOLOGY VOLUME 8 | AUGUST 2012 | 471
NO-mediated vasodilatation in Raynaud phenomenon
is highly complex.
14
NO relaxes smooth muscle cells. In
sclerodermatous skin, endo thelial NO synthase (NOS) is
initially increased, whereas in advanced disease, induc-
ible NOS is increased.
15
The roles of the different isoforms
of NOS in cutaneous vasodilatation are currently unclear
10

and reduced NO production via neuronal NOS could also
have a role, at least in SSc,
16
demonstrating the interplay
between ‘vascular’ and ‘neural’ abnormalities. Further
complicating the role of NO, in patients with SSc, the
plasma levels of an endogenous inhibitor of endothelial
NOS—asymmetric dimethylarginine—are increased.
17

However, irrespec tive of whether there is underproduc-
tion or overproduc tion of NO in the digits of patients
with SSc (which could be disease-stage-dependent), NO
supplementation (for example, via topical application of
glyceryl trinitrate) results in vasodilatation. This response
could be as good in patients with SSc as in patients with
primary Raynaud phenomenon and healthy controls.
18
Increased vasoconstriction
Overproduction of vasoconstrictors by endothelial cells
(in particular endothelin-1 and angiotensin II) most
likely contributes to SSc-related Raynaud phenomenon.
The expression of endothelin-1 is increased in sclero-
dermatous skin.
19
An imbalance in the renin– angiotensin
system, in favour of angiotensin II, is thought to occur
in SSc.
20
Although some studies implicated a role for
endothelin-1 in primary Raynaud phe nomenon,
11,21
this
evidence is much weaker than that for SSc. One excit-
ing development in recent years has been the increased
understanding of signal transduction pathways in vas-
cular smooth muscle, as discussed below briefly, which
highlights the fact that ‘vascular’ and ‘neural’ mechanisms
cannot be considered in isolation.
Structural abnormalities
Structural abnormalities of both the microvasculature
and the digital arteries are well studied in SSc,
22,23
and
undoubtedly, contribute to impaired digital perfusion. The
microangiopathy of SSc can be clearly demonstrated non-
invasively by capillaroscopy (Figure 2). Typical changes
are enlarged, widened capillaries (through which the red
blood cells move sluggishly) with areas of avascularity
(Figure 2b). The most striking change in the digital artery
is intimal hyperplasia (Figure 3). The ulnar artery may
also be affected in SSc,
24
and it has been suggested that
the prevalence of proximal large vessel disease is increased
in patients with SSc compared to control population;
25

however, this finding remains controversial.
The pathogenesis of SSc-related microvascular and
digital artery structural vascular disease is well studied.
14,26–28

Although the pathogenesis is not fully under stood, pro-
gress is being made and possible contributors include
endothelial injury (of unknown cause) as a potential early
or initiating mechanism, endothelial cell apoptosis (which
might promote fibrosis
29
), abnormal expression of tran-
scription factors,
28
aberrant production of growth factors
and cytokines, activation of pericytes,
30
and abnormalities
of both angiogenesis and vasculo genesis (with a reduction
in bone- marrow-derived endothelial precursors).
31
A
recent study has shown that the anti-angiogenic vascular
endothelial growth factor (VEGF) isoform VEGF
165
b is
over expressed in SSc.
32
This finding could explain, at least
in part, the marked attrition of microvessels.
By contrast, structural abnormalities do not occur in
primary Raynaud phenomenon: any reported abnor-
malities have been subtle changes
33
and could possi-
bly relate to the unclear distinction between primary
Raynaud phenomenon and SSc. A small proportion of
patients (1–2% per year) with what appears to be primary
Ray naud phenomenon progress to an SSc-spectrum dis-
order or other underlying disease.
34
The thumb is less
affected by Raynaud phenomenon than other digits:
35

the reason for this reduced effect is unknown, but could
imply that its shorter length is in some way protective for
structural (and possibly functional) change.
Neural abnormalities
Several different neurotransmitters and their receptors
are implicated in the pathogenesis of Raynaud phenom-
enon, as many of these neurotransmitters mediate either
vasodilatation or vasoconstriction. Both autonomic and
small sensory nerve fibres are likely to be involved.
Nerve bres
(sympathetic
and sensory)
Smooth muscle cell
Endothelial cell
Endothelin-1
from endothelial cells
Oxidative stress
Endothelial damage
Reduced blood ow/
procoagulant tendency
NO
from endothelial cells
Platelet activation/
aggregation
Reactivity of smooth muscle
α
2
-adrenoceptors (via
Rho/Rho kinase activation)
Thrombin
Viscosity
Fibrinolysis
Red blood cell
deformability
Vasoconstriction Vasodilatation
Vasodilatatory neuropeptides
(e.g. CGRP) from sensory
afferents
Figure 1 | Schematic representation of some of the key elements and
mechanisms contributing to the pathogenesis of Raynaud phenomenon. Some of
the mediators contribute to disease pathogenesis via different mechanisms. For
example, reactive oxygen species (resulting in oxidative stress) may damage the
endothelium via lipid peroxidation, but may also activate Rho/Rho kinase resulting
in increased vasoconstriction. Abbreviations: CGRP, calcitonin gene-related
peptide; NO, nitric oxide. Modified from Herrick, A. L. Pathogenesis of Raynaud’s
phenomenon, Rheumatology 44, 587–596 (2005), by permission of Oxford
University Press.
R E V I E W S
© 2012 Macmillan Publishers Limited. All rights reserved

5. Fenômeno de RaynaudFenômeno de Raynaud
•Primário ou idiopático:
Mulher jovem
Ataques simétricos/ curta duração
Prevalência: 19-11%
Ausência de cicatriz, ulcera ou gangrena digital
Capilaroscopia normal
FAN negativo
PAIs normais
Exame físico normal
Ausência de sintomas sugestivos de DTC
Herrick, A. L. Nat. Rev. Rheumatol. 2012

6. Fenômeno de RaynaudFenômeno de Raynaud
•Secundário
–DTC:
•ESCLEROSE SISTÊMICAESCLEROSE SISTÊMICA
•Miopatias infamatórias
•Lúpus Eritematoso Sistêmico
•Síndrome de Sjogren
•Vasculite

7. Úlcera digitalÚlcera digital

8. Cicatriz e Úlcera DigitalCicatriz e Úlcera Digital

9. Gangrena Gangrena
DigitalDigital

10. Fenômeno de RaynaudFenômeno de Raynaud

11. Esclerodermia LocalizadaEsclerodermia Localizada

12. Esclerodermia LocalizadaEsclerodermia Localizada
•Morféia
–mais comum
–placas de pele espessada com graus variados de pigmentação
–“gutata” e “subcutânea”
•Morféia generalizada
–Área extensa
•Esclerodermia linear
–Podem apresentar envolvimento profundo da pele até atingir os músculos.
–mais comuns nas pernas e nos braços e, quando acometem as articulações, podem acarretar
limitações da função articular.
•Esclerodermia “em golpe de sabre”
–face ou o couro cabeludo
–ocasionalmente pode causar atrofia da face (inclusive língua e a boca)

13. MorféiaMorféia

15. Esclerodermia LinearEsclerodermia Linear

16. Esclerodermia LinearEsclerodermia Linear

17. Golpe de SabreGolpe de Sabre

18. Síndrome de Parry- RombergSíndrome de Parry- Romberg

19. Síndrome de Parry- Romberg
•A síndrome de Parry-Romberg, também
denominada atrofia hemifacial progressiva,
consiste em uma rara condição na qual há
degeneração progressiva e encolhimento dos
tecidos situados abaixo da pele da face,
incluindo, em muitos casos, os ossos.

20. Esclerose SistêmicaEsclerose Sistêmica

21. Esclerose SistêmicaEsclerose Sistêmica
•Prevalência: 1 a 2 casos por 100.000
•Predominio feminino 4:1
•30-50 anos
•Fatores genéticos
•Fatores ambientais
–Sínd. Erasmus (silicose+ES)
–Sínd. ASIA

22. Esclerose SistêmicaEsclerose Sistêmica
•FORMA PRECOCE
–F. Raynaud
–Capilaroscopia SD
–ACA ou SCl-70 +
•SINE ESCLERODERMA
–F. Raynaud
–FAN positivo
–Manifestações viscerais
•LIMITADA
•DIFUSA
•SÍNDROMES DE SUPERPOSIÇÃO

23. Esclerose Sistêmica LimitadaEsclerose Sistêmica Limitada
•Subtipo mais prevalente
•Não acomete: abdome, dorso, braços ou coxa
•Evolução mais lenta
•Mais frequente:
–Dismotilidade Esofágica
–Hipertensão Arterial Pulmonar
–Calcinose
–Telangiectasia
–ACA (padrão de FAN centromérico)

24. Esclerose Sistêmica DifusaEsclerose Sistêmica Difusa
•Subtipo mais grave
•Evolução mais rápida
•Maior mortalidade
•Forma mais comum em crianças
•Mais frequente:
–Fibrose pulmonar
–Miocardite fibrosante
–Crise renal esclerodermica
–SCL-70 (Antitopoisomerase)

25. Esclerose Sistêmica Esclerose Sistêmica
LimitadaLimitada
(CREST)(CREST)

26. Envolvimento Cutâneo DifusoEnvolvimento Cutâneo Difuso

27. CalcinoseCalcinose

28. TelangiectasiasTelangiectasias

29. Capilaroscopia padrão SDCapilaroscopia padrão SD
NATURE REVIEWS | RHEUMATOLOGY VOLUME 6 | OCTOBER 2010 | 581
Raynaud phenomenon (Figure 3c). It has been estimated
that the number of normal capillaries is reduced to 20%
in patients with active SSc.
24
The extensive disappearance
of capillaries can generate large avascular areas, which
have a desert-like appearance in the nail-bed micro-
vascular array. Loss of capillaries could be relevant in
determining the severe tissue hypoxia that is involved
in the development of digital skin ulcers.
11
In patients with
recent onset of Raynaud phenomenon, the appearance of
rapidly prog ressive capillary loss can represent the first
dramatic capillaro scopic evidence of destruction of the
micro vessels and the development of severe SSc.
Ramified capillaries
Capillary loss induces local hypoxia and the consequent
local production of vessel growth factors (such as vascular
endothelial growth factor), which in turn stimulating the
formation of new capillaries—neoangiogenesis.
25
A range
of morphological features of the micro vasculature
attribu table to neoangiogenesis is seen almost exclusively
in patients with late SSc and secondary Raynaud phe-
nomenon (Figure 3d). The main morphological hallmark
of angiogenesis in advanced SSc is the clustering of twisted
capillaries, with pronounced heterogeneity in shape and
size, winding together with bushy capillaries. Highly con-
voluted and branched capillary loop clusters, surrounded
by loss of normal capillary loops, are characteristic
features of neoangiogenesis in advanced SSc.
Characterization of SSc-specific patterns
Historically, the capillaroscopic aspects of vascular
damage in SSc were partially graded into two major pat-
terns: active and slow.
26
Since the year 2000, new classifi-
cations related to selected characteristics of disease
progression have been proposed to improve the diag-
nostic and prognostic power of capillaroscopic analysis.
27

Consequently, microvascular lesions detected by NVC in
patients with SSc can be reclassified into three different
NVC patterns, ‘early’, ‘active’ and ‘late’, which are clearly
distinguishable from the ‘normal’ pattern (Figure 4).
28
The ‘early’ SSc pattern is considered the most important
since it is fundamental to the differentiation of primary
and secondary Raynaud phenomenon. This pattern is
characterized by the presence of a small number of giant
a
c d
b
Figure 3 | Markers of scleroderma patterns. Images obtained by routine nailfold videocapillaroscopy analysis of patients
with systemic sclerosis (magnification × 200) reveal the morphological markers of microvascular disorganization that
characterize overt systemic sclerosis and related nailfold videocapillaroscopy patterns (‘early’,‘active’ and ‘late’ systemic
sclerosis) in the presence of secondary Raynaud phenomenon. a | Giant capillaries (arrows), the earliest and most striking
morphological feature of secondary Raynaud phenomenon, are homogeneously enlarged microvascular loops that serve as
potential markers of microangiopathy. b | Microhemorrhages (arrows) result from the microvascular extravasation of red
blood cells from damaged capillaries. c | Loss of capillaries (arrows) can lead to the presence of avascular areas in the
nailfold bed and subsequent local tissue hypoxia. d | Neoangiogenesis is characterized by the clustering of twisted and
bushy capillaries (arrows) and represents a local reaction to tissue hypoxia.
REVI E WS
nrrheum_104_OCT10.indd 581 10/9/10 15:29:00
© 20 Macmillan Publishers Limited. All rights reserved10
Ectasia
Micro
hemorragia
Perda de capilar
Capilar em arbusto

30. Esclerose SistêmicaEsclerose Sistêmica

31. Esclerose Esclerose
SistêmicaSistêmica
•Manifestações clínicas:
–F. Raynaud (95%)
–Capilaroscopia padrão SD
–Músculo esqueléticas
•artralgia e artrite
•espessamento tendíneo
•miopatia e fraqueza muscular
–Gastrointestinal (90%)
•Dismotilidade esofágica
•Incontinência fecal
•GAVE
•Diarreia crônica e desnutrição
GAVE

32. Esclerose SistêmicaEsclerose Sistêmica
•Manifestações clínicas:
–Pulmonar
•Doença intersticial pulmonar (70%)
•Hipertensão arterial pulmonar
–Coração
•Derrame pericárdico
•Miocardite fibrosante
–Crise Renal esclerodérmica
–Outras
•Síndrome Sicca
•Neuropatia trigêmeo
•Túnel do Carpo
•Mononeurite múltipla e polineuropatia

33. TratamentoTratamento
•Fenômeno de Raynaud:
-orientações gerais para evitar o frio
-bloqueadores de canais de cálcio (nifedipina, diltiazem)
-inibidores da enzima conversora da angiotensina
-inibidor seletivo serotonina
-inibidor da fosfodiesterase
-antagonista do receptor de endotelina 1
-prostanóide
-simpatectomia
•Pele:
–ciclofosfamida em casos graves
–metotrexato

34. TratamentoTratamento
•Doença pulmonar:
–ciclofosfamida
–azatioprina
–Micofenolato mofetil
•Trato gastrointestinal:
-mudar hábitos
-procinéticos
-inibidores de bomba de prótons
•Doença renal: inibidor da ECA
•Transplante Medula Óssea casos graves