Scleroderma Flashcards
What is scleroderma/systemic sclerosis?
An autoimmune disease belonging to the connective tissue disease family with highly variable and heterogenous clinical manifestations
What are the two major subtypes of scleroderma?
Limited cutaneous SSc and diffuse cutaneous SSc
What is the triad of clinical features present in scleroderma?
Immune dysregulation (autoimmunity/inflammation), vascular damage, and fibrosis
What demographics are most likely to be at risk of developing scleroderma?
female predominance
African-American predominance
What scleroderma symptoms predict increased mortality?
Skin induration on the trunk, tendon friction rubs at large and small joints, abnormal EKG, reduced diffusion capacity, elevated ESR, and presence of autoantibodies for topoisomerase I and RNA polymerase III
What are scleroderma mimics?
Conditions that resemble systemic sclerosis but are not systemic:
localized scleroderma, scleredema, scleromyxedema, eosinophilia-myalgia syndrome, eosinophilic fasciitis
What is the cause of scleroderma?
Unknown, but may be related to viral reactivation or occupational exposures
What is the genetic cause of scleroderma?
Unclear – low twin contractionrate suggests complicted genetic link. There are SNPs that encode risk alleles for scleroderma
What type of vascular damage is caused by scleroderma?
Diffuse vascular damage (microvascular obliterative vasculopathy)
How is vascular damage in scleroderma different from vasculitis or atherosclerosis?
There is little to no inflammation or lipid buildup
What are the three phases of scleroderma vascular damage?
1) endothelial cell activation with increased ET-1 and decreased prostacyclin release
2) vascular wall remodeling
3) blood vessel obliteration and ceased blood flow
What structures are most affected by vascular damage in scleroderma?
Small- and medium-sized vessels of digits, lungs, heart, and GI tract
What changes are associated with phase one of scleroderma vascular damage?
Reversible vasoconstriction, upregulation of adhesion molecules, and generation of ROS
What changes are associated with phase two of vascular damage in scleroderma?
Intimal proliferation, medial hypertrophy, adventitial fibrosis, platelet aggregation, and in situ thrombosis
What is vascular rarifaction?
Paucity of small blood vessels despite high levels of VEGF and angiogenic factors (obliterated blood vessels)
How is fibrotic response exacerbated by vascular damage in scleroderma?
Tissue hypoxia and generation of ROS from oxidative stress both lead to increased fibroblast activation
Which T-cell subtypes and cytokines are implicated in the development of fibrosis in scleroderma?
Th17 subset, Tregs, and IL-17/IL-23 cytokines
What is the role of autoantibodies in scleroderma?
Unclear causal role
What types of autoantibodies are seen exclusively in scleroderma?
topoisomerase-1, RNA polymerase III, and anti-centromere antibodies
What is fibrosis?
An aberrant tissue repair process where the normal mechanisms that limit repair and promote resolution fail, resulitng in uncontrolled and intractable tissue remodeling
What are the key effector cells of fibrosis?
Fibroblasts and myofibroblasts
What cytokines and growth factors are important for fibrosis in scleroderma?
TGF-beta, CTGF, PDGF, Wnt, and endothelin-1
What are the components of the ECM that accumulate during fibrosis?
Collagens, proteoglycans, fibronectin, fibrillin, tenascin, and elastin
What is the role of TGF-beta in fibrosis?
It induces differentiation of fibroblasts, endothelial cells, and epithelial cells into smooth muscle cell-like myofibroblasts
