Scleroderma Flashcards
three pathogenic processes in systemic scleroderma
immune dysregulation, vascular dysfunction, fibrosis
most important cytokine in scleroderma
TGF-B
mechanism that leads to increased collagen synthesis in scleroderma
increased collagen gene transcription
primary clinical consequences of scleroderma
skin fibrosis & ischemia/fibrosis of visceral organs
what does scleroderma mean?
hard skin
definition of systemic scleroderma
an autoimmune connective tissue disorder of unknown etiology characterized by the triad of fibrosis, vascular dysfunction, and immune dysregulation
gross appearance of skin in patients with scleroderma
tight and shiny. sebacous glands, hair follicles, and sweat glans get occluded. salt and pepper pigment changes.
name when scleroderma affects fingers?
sclerodactyly
raynaud’s phenomenon
spastic effect on vessels in fingers, which completely occlude and blood pools near base. not unique to scleroderma
calcinosis
calcium deposits in tissue. not unique to scleroderma
effect of scleroderma on GI?
esophageal dysmobility. difficulty swallowing and digesting
telangiectasias
dilated ends of vessels. not unique tp scleroderma. most common cause of a GI bleed in scleroderma though
most common cause of death in scleroderma patients?
bilateral interstitial lung fibrosis
classification of scleroderma
Systemic (diffuse, limited, overlap) & localized (morpheme, linear scleroderma)
systemic vs localized scleroderma
in systemic, internal organs are always involved. just the skin is affected in localized scleroderma
diffuse cutaneous scleroderma
symmetric, widespread skin fibrosis that starts at the toes and moves up to head. RAPID progression and early visceral involvement. poor prognosis (10 yrs)
limited cutaneous scleroderma
symmetric skin fibrosis limited to the distal extremities and face. Raynauds manifests ten years before skin and late appearing organ manifestations. SLOW progression. good prognosis
anticentromere antibody
present in limited cutaneous scleroderma
CREST (scleroderma symptoms)
calcinosis, raynauds phenomenon, esophageal dysmotility, sclerodactyly, telangectasias
overlap syndromes (of systemic scleroderma)
mix of diffuse and limited scleroderma. often associated with other rheumatic disease
common facial characteristics of scleroderma
beaking nose, pursed lips, facial muscle atrophy, tightening of skin, telangestasias on forehead
pathogenesis of scleroderma
genetic predisposition + environmental trigger=immune system activation. Causes B cells to start producing autoantibody and T cells to activate and infiltrate skin/vascular epithelium and release profibrotic cytokines (TGF-B).
antibodies produced in scleroderma
ANA (90%), anti-scl, anti-centromere, anti-topoisomerase, anti-RNA polymerase 3
anti-scl 70
antibody indicative of diffuse cutaneous scleroderma (African Americans)
anticentromere antibody
antibody indicative of limited cutaneous scleroderma (Caucasians)
genes whose transcription is unregulated in scleroderma
COL1A2 (type 1 collagen), TGF-B1, Fibrillin-1
tight skin mouse model
mutate fibrillin gene leads to disorganized, unstable microfibrils that inappropriately signal fibroblasts to increase TGF-B and deposit type 1 collagen in ECM
tissue inflammation in early scleroderma
lymphocyte infiltrates skin (mostly CD4 T cells) and release cytokines and growth factors. CD8 T cells predominate in lung tissue
important cytokines released by inflammatory cells of scleroderma
TGF-B, CTGF, PDGF
TGF-B
sensitizes fibroblasts to stay persistently active and decreases the production of collagen degrading metaloproteinases
role of cytokines released by inflammatory cells in scleroderma
induce alterations of the ECM gene expression
CTGF (connective tissue growth factor)
stimulated by TGF-B. sensitizes fibroblasts to stay persistently activated
PDGF (platelet derived growth factor)
TGF-B increases PDGF receptors on fibroblasts, which make them more sensitive to the mitogenic effects of PDGF (which is required for cellular division)
characteristics of damaged vessel walls in scleroderma
thickened and damaged wall, occluded lumen, up regulation of agents that cause vasoconstriction, and down regulation of agents that cause vasodilation. presence of myofibroblasts rather than fibroblasts
how can you easily/quickly test a patient for scleroderma vs Raynauds?
Do exam, get history, test for ANA and ESR. Then look at the capillaries of their nail folds. If someone has autoimmune scleroderma, you will see dilated loops.
tissue fibrosis in scleroderma
overproduction of type 1 collagen and other ECM macromolecules by fibroblasts. (up regulation of COL1A1)
clinical consequences of skin fibrosis in scleroderma
inflammatory infiltrates sparse, thickened dermis, replacement of dermis and subcutaneous fat with collagen bundles, loss of skin appendages, late atrophy of epidermis
clinical consequence of renal necrosis in scleroderma
vascular damage (narrowing/ischemia/cortical hemorrhage/onion skin) leading to scleroderma renal crisis. occurs early with rapidly progressing skin thickening. abrupt onset of malignant hypertension
how to prevent renal damage?
ACE inhibitors forever once symptoms appear. needs to be caught early though
clinical consequence of lung fibrosis in scleroderma?
interstitial lung disease (diffuse fibrotic tissue replacement, anti-topoisomerase) & pulmonary hypertension
GI manifestations of scleroderma
gastroparesis, malabsorption, pseudoobstruction, diverticuli, anorectal sphincter dysfunction, biliary cirrhosis
immune dysregulation in scleroderma
activated b cells, autoantibody production
an early predominant t cell inflammatory infiltrate
vascular abnormalities in scleroderma
initial unknown endothelial cell injury leading to structural damage, local production of GFs and cytokines, thickening of vessel wall, increased contractility of vessel
fibrosis in scleroderma
fibroblast chemotaxis and proliferation, excessive production of type 1 collagen, excessive production of other ECM molecules
most important cytokine in scleroderma
TGF-B
