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
What accounts for the stiffness of fibrotic skin and other tissues?
Crosslinking of secreted collagen into a highly stable, degradation-resistant, and insoluble extracellular matrix
What is the effect of fibrosis on capillaries?
Fibrosis obliterates capillaries (rarifaction), which creates a viscious cycle of hypoxia and fibrosis
What organs are most commonly affected by scleroderma?
Skin, lungs, GI tract, kidneys, and heart
What is a prominent early vascular feature of SSc?
Raynaud phenomenon
What is a scleroderma renal crisis?
Injury to medium-sized arteries that occurs with malignant hypertension and hyperreninemia, microangiopathic hemolytic anemia, and rapidly progressive renal failure
What are risk factors for renal involvement in scleroderma?
Extensive and advancing skin involvement, large joint contractures and tendon friction rubs, presence of autoantibodies to RNA polymerase III
What drug is important for decreasing mortality of scleroderma with renal involvement?
ACE-inhibitors
What is the pressure definition of pulmonary artery hypertension?
mean pulmonary artery pressure > 25 mmHg via right heart catheterization
What is the cardiac involvement of scleroderma like?
It is frequent and can be caused by pulmonary hypertension and cardiac fibrosis
A 45 y.o. previously healthy woman presents with episodic heartburn, increasing in frequency over the past 6 months. Her symptoms are worse at night. She also had several episodes of near-choking on solid food. On further questioning, she notes that she has had “cold sensitivity” in her fingers for 2-3 years; and for the past year, diffuse aching, and a fine rash on her face. Physical exam shows telangiectasia on her lips and cheeks, and erythema around her nailbed. Her laboratory evaluation is most likely to show which of the following?
a) hematuria
b) serum antibody directed to dsDNA
c) elevated level of serum complement 3
d) serum antibody directed to centromere
e) low serum B12
d) serum antibody directed to centromere
A patient with long-standing systemic sclerosis is being treated with the endothelin-1 receptor antagonist bosentan. This class of drugs functions by inhibiting which of the following:
a) gastric acid secretion
b) bronchospasm
c) vasoconstriction
d) synovial inflammation
d) calcium deposition
e) collagen synthesis
c) vasoconstriction
What is a Rondan skin score?
A semi-quantitative measure of the extent of skin induration (fibrosis)
What is CREST for limited cutaneous SSc?
Calcinosis
Raynaud
Esophageal involvement
Sclerodactly
Telangiectasia
What antibody is associated with limited cutaneous SSc?
Anticentromere antibodies
What antibody is diffuse cutaneous SSc associated with?
Antitopoisomerase antibody
