Scleroderma (Systemic Sclerosis) Flashcards
What is systemic sclerosis?
autoimmune CTD, chronic - females >> males
skin induration is hallmark
multiple organs are involved
vascular and fibrotic changes dominate
high mortality (similar to cancer)
no approved disease - modifying Rx
What are the major clinical subsets of SSc?
limited cutaneous SSc and diffuse cutaneous SSc
characterized by divergent patterns of organ involvement, rate of progression, autoantibody profiles, and survival
What is the pathogenesis of scleroderma?
autoimmunity (autoantibodies)
vasculopathy (small blood vessels) - raynaud, PAH, renal crisis
fibrosis of multiple organs
What is the role of microchimerism in SSc?
cells of maternal origin appear to infiltrate the skin and other affected tissues
What are scleroderma mimicks?
other conditions with skin fibrosis:
localized scleroderma
slceroderma
scleromyxedema
eosinophilia-myalfia syndrome and eosinophilic fasciitis
What are the baseline predictors of increased mortality in dcSSc?
truncal skin involvement
abnormal EKG
reduced diffusing capacity
elevated ESR and presence of serum autoantibodies specific for topoisomerase I and RNA polymerase III
What is the etiology of SSc?
mostly unknown
can be viral infection or reactivation
can also be exposure to silica, vinyl chloride, and organic solvents
What is the epidemiology of SSc?
affects 1 in 4000 adults in the US
female predominance, more frequent in African Americans
10 year survival in dcSSc can be as low as 55%
What is the mechanism of fibrosis?
activation of fibroblasts lead to activation of myofibroblasts
results in excessive deposition of collagen and other ECM proteins, leading to fibrosis
TGFbeta is produced and induces differentiation of fibroblasts, as well as endothelial and epithelial cells
What are the genetic factors in SSc?
non-Mendelian disorder, low concordance rate among twins
SNP studies show that particular alleles in genes for TGFbeta, MCP-1, IL-1alpha, TNF, AIF1, PPAR-gamma, and ACE are linked to disease susceptibility
Describe the vascular damage in SSc.
microvascular obliterative vasculopathy - priminently affects small and medium-sized vessels of digits, lungs, heart, and GI tract
vessel is obliterated and flow ceases
What are the phases of vascular damage in SSc?
1) endothelial cell activation with increased production of ET-1 and decreased prostacyclin release, causing functional changes with initially reversible vasoconstriction, upregulation of adhesion molecules, and generation of ROS
2) vascular wall remodeling follows with intimal proliferation, medial hypertrophy, and adventitial fibrosis
3) platelet aggregation and in situ thrombosis
What happens to the vasculature in patients with long-standing SSc?
vascular rarefaction - paucity of small bood vessels, despite high levels of VEGF and other angiogenic factors
progressive obliteration of vessels results in hypoxia, which is itself a potent stimulus for fibroblast activation
recurrent ischemia-reperfusion leads to increased oxidative stress with generation of harmful ROS such as superoxide radicals, which further exaggerate fibrotic responses
How does immunity factor into SSc?
both innate and adaptive immunity are activated in SSc
under the influence of soluble factors such as MCP-1 and related chemokines, activated immune cells accumulate in the skin, the lungs, and other target tissues
lesional T cells show Th2 polarization of oligoclonality of T cell receptors suggestive of an antigen-driven response
What are the treatments for PS?
IV cytoxan
skin improves by progressive dyspnea develops
develops PFTs
What are the HRCT findings of PS?
lower lobes are affected
peripheral opacities
ground-glass pattern
non-specific interstitial pneumonitis (NSIP)
What is Raynaud phenomenon?
cold-induced reversible vasospasm of the fingers and toes - can be primary or secondary
mostly medium and small vessels
common, occurs up to 15% in healthy women
often progressive
may lead to digital ulcers
What is primary Raynaud Phenomenon?
uncomplicated - functional changes only
nailfold capillaroscopy - sharp loops in normal fingers
infarction of blood vessels can lead to necrosis
What is secondary Raynaud’s Phenomenon?
symptoms of Reynaud’s phenomenon that can be associated with a specific disease
What are the features of PAH as a complication of SSc?
develops in 40% of SSc patients, generally late in the disease
poor 5yr survival
results from obliteration of small arterioles in the lung
endothelin-1 elevated and NO, prostacyclins reduced
block ET-1 or enhance NO/prostacyclin to treat
What are the features of renal crisis as a result of scleroderma?
scleroderma renal crisis (SRC) - precipitates from destruction of medium-sized arteries
microvascular complication of SSc
accelerated or malignant HTN and hyperreninemia
thrombotic microangiopathy (TMA) - mimics TTP, hemolytic uremic syndrome, often presents with microangiopathy (schistocytes, hemolysis)
poor prognosis, high mortality
What is the role of autoantibodies in SSc?
distinct from other autoimmune diseases (lupus, RA,. etc.) - unique set
targets endothelial cells, granzyme or reactive oxidation products
useful for diagnosis, classification - risk stratification (at least 8 different antibodies and depending on which is present, the outcomes can be predicted
role in pathogenesis is unproven
What are the clinical features of the skin in SSc?
cutaneous telangiectasia
lesions themselves don’t do any harm, but is an indication of systemic disease
nailfold capillaries indicate more severe disease
What are the clinical features of the lungs in SSc?
critical target organ in SSc, 90% of patients have ILD at autopsy, and 40% show restrictive changes
interstitial fibrosis (NSIP)
can lead to pulmonary hypertension, which can be life-treatening
drop in FVC in the first few years
