Scleroderma and GVHD Flashcards
What is Limited Cutaneous Scleroderma?
- no skin sclerosis proximal to knees or elbows
- longstanding Raynaud’s phenomenon (typical)
Define Diffuse Cutneous Scleroderma
- cardinal features: skin sclerosis proximal to the kness and elbows
- Raynaud’s phenomenon
What is CREST syndrome?
also known as limited cutaneous form of systemic sclerosis. Multisystem CT disorder.
Calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia.
Autoantibodies associated with scleroderma and CREST and their pattern
60% have antinuclear antibodies (ANA)
pattern: speckled, nucleolar, centromere, or diffuse
Which antibody is very specific for proximal scleroderma? Which is a common antibody found in CREST patients?
Specific for proximal scleroderma (20-40%, CREST = 4%): Anti-topoisomerase I
CREST (40%), Prox scleroderma=12%: Anticentromere Antibody (ACA)
Antibodies to topoisomerase I are associated with the following (3)
1) tight skin (proximal scleroderma) = sclerodactyly
2) severe dieases (i.e. pulm fibrosis)
3) cancer development
[antibodies to centromere (ACA) are associated with the features of CREST]
In terms of the pathogenesis of scleroderma, what are the 3 major components? Which is the most important?
- vascular **most important**
- fibrotic
- immune
Describe the vasculopathy component of Scleroderma.
- loss of endothelial lining layer with intimal proliferation and vascular occlusion
- thinning of muscular layer
- adventitial cuff of connective tissue
Hypothesis of early disease of scleroderma, and following progression
- early disease: activation of endothelial cells, fibroblasts and perivascular inflammatory infiltrate
- endothelial loss, intimal proliferation, luminal narrowing, thrombosis and periadventitial fibrosis of small arteries and capillaries.
which IL has been associated ith pulmonary endothelial injury? What does it react with?
IL-1 ; it reacts with endothelium through expression of ECAM-1 and ICAM-1
these in turn, lead to adhesion of lymphocytes to endothelium and endothelial damage.
Sclerdoerma is a fibortic disease. While the vasculature is a major component, the fibrosis is key. What is the mechanisms of this fibrosis?
Fibroblast activation and proliferation leads to deposition of ECM. Increased collagen production may happen without necesarily fibroblast proliferation, and this may be mediated by TGF-beta.
in patients with diffuse scleroderma, there has been a significant positive correlation between anti-endothelial cell antibodies and these 4 things
- decreased dLCO
- increased pulmonary artery pressures
- digital ulcers
- nail fold capillaroscopy abnormalities
Three main treatment classes for Scleroderma
1, Phosphodiesterase inhibitors: Sildenafil
- Endothelin Rececptor Antagonists: Bosentan, Ambrisentan
- Prostacyclins: Epoprostenol, Iloprost, Treprostenil
What drug was found to be useful in softening the skin in scleroderma?
Cyclophosphamide (immunosuppression), useful in alveolitis.
8 steps for pathogenesis of scleroderma summary
- Unidentified trigger
- Endothelial injury and activation
- Platelet Activation
- Release of PDGF and TGF-B
- Fibroblast activation
- Overproduction of collagen and fibronectin in the dermis
- Fibrosis in skin and organs
- Activation of the immune system
PDGF and TGF-beta, what are their actions?
PDGF: chemo attractant for fibroblasts and smooth mnuscle cells
TGF-beta: most potent inducer of collagen and fibronectin synthesis by FIBROBLASTS.
side effect of scleroderma often misdiagnosed and mistreated to look out for
SCLERODERMA ALVEOLITIS: if misdx as cogestive heart failure, diuresing them is the worst thing you can do– precipitates renal HTN and renal crisis (due to occlusion of renal lumen and inflammation)
Definition of Graft Vs. Host Disease (GVHD)
A syndrome occurring in immune compromised hosts exposed to immunocompetent donor T cells (i.e. bone marrow transplant patients, patients with congenital deficiencies of T lymphocytes)
3 essential requirements for GVHD:
- Graft must contain immunologically COMPETENT T cells
- host must express tissue antigens not present in the donor (or must have an inappropriate response to self)
- The host most be incapable of mounting an immune response that can destroy the transplanted cells.
(recall: in GVHD, the ptmust be immunocompromised)
ACUTE Graft Vs. Host Disease
Triad of complaints: dermatitis, hepatitis, gastroenteritis occurring within the first 100 days following transplantation
CHRONIC Graft Vs. Host Disease
A multi-organ disease occurring more than 100 days after transplantation
GVHD is a consequence of an outpouring of _______
CYTOKINES (TNF-a, IL-1, -2, -3, -4, -6. -11, IFN-B, IFN-gamma, LPS, GM-CSF)
In Acute GVHD, what is essential for this disease? What does target cell injury reveal?
Mature DONOR T cells
Target cell injury reveals: dyskeratotic epithelial cells, mast cell degranulation and lymphocyte infiltration
Satellitosis
Effective lymphocytes surrounding a central degenerating epithelial cell, seen in Acute GVHD
What 3 features in Chronic GVHD are similar to auto immune disease?
- Skin disease: pigment changes and scleroderma like lesions with dermal fibrosis, atrophy, ulceration, fibrosis, and limitation of joint movement
- Liver disease: cholestasis with primary billiary cirrhosis like histopathology
- Sjogrens-like sicca complaints with lymphocytic infiltrates in glandular tissues
