What is the pathologic quartet of Scleroderma?
Patients with systemic sclerosis display evidence of inflammation, autoimmunity, vasculopathy (Raynaud's and others), and fibrosis (IL-4, TGF-b)
Autoimmunity and vasculopathy generally precede the onset and contribute to the progression of fibrosis. Vascular obliteration and interstitial fibrosis perpetuate and further exacerbate chronic autoimmunity and inflammation.
Patient population for Scleroderma?
Young AA, female more than male
connection to coal miners (silica exposure)
Give a general overview of the pathogenesis of scleroderma
The illustrations on the bottom row show examples of, from left to right, the fibrotic process (biopsy of skin), microvascular alterations in pulmonary arterioles, autoantiboides detected by immunoflurosescence, and mononuclear inflammatory cell infiltrates in affected skin.
monocytes needed IFN-y to differentiate into fibroblasts (can interfere with IL-10)
What is one of the earlier pathological changes seen in Scleroderma?
Changes in endothelial cell function with increased apoptosis, upregulation of MHC class II and intercellular adhesion molecule (ICAM)-1 molecule expression on endothelial cells. (persist throughout disease duration)
schistocytes may be seen
Raynaud's phenomenom is a feature of scleroderma. Why?
•Platelets aggregate and microthrombi form in microvasculature leading to digital artery occlusion. (Thrombosis and attempted recanalization of occluded vessels.)
Definition: Episodic attacks (vasospastic attacks) in which the blood vessels of the digits constrict (narrow), usually in response to cold temperatures and/or emotional stress.
Below: You see ballooning of remaining capillaries (in nail fold) due to massive dropout of capillaries due to occlusion (only seen in 2ndary raynaud's)
Describe digital color changes assocated wtih Raynaud's phenomenom
With exposure to cold (typically):
1) fingers become white due to lack of blood flow
2) then blue as vessels dilate as a compensation
3) then back to red as blood flow returns
Raynaud's can present as a primary disease or secondary to other diseases, such as:
SSc, lupus, RA, polymyositis, MCTD
What is a common complication of Raynaud's phenomenon?
Distal ischemia can lead to digital ulcer development
What are two facial skin manifestations of Scleroderma?
Vitilligo-like changes (top) and facial telangiectasias (bottom)- will not blanch
What are the types of Scleroderma?
-localized (morphea or linear)
-systemic (limited, diffuse, or sine (only internal organ invovlvment))
What is the definitional difference between limited and diffuse SSc?
Limited is confined to the extremities (up to knees and elbows) and the head and diffuse can be anywhere
Systemic Involvemnt in SSc
One helpful diagnostic in Scleroderma is the presence (or absence) of autoantibodies in different subsets of disease. What autoantibodies are present only in diffuse SSc? Clinical manifestation?
Topo I (Scl70). Resulting in pulmonary fibrosis and cardiac involvement
What autoantibodies are present only in limited SSc? Clinical manifestation?
Centromere (protein B,C)- several digital ischemia, PAH, sicca syndrome (dryness everywhere), and calcinosis
What autoantibodies are present in an overlap of diffuse and limtied SSc? Clinical manifestation?
PM/Sci- myositis, pulmonary fibrosis, acro-osteolysis
U1-RNP-SLE, pulmonary fibrosis, inflammatory arthritis
1.Scleroderma renal crisis (SRC) is a life-threatening condition that occurs in 5% to 10% of scleroderma patients. What are the known risk factors?
early diffuse skin disease, use of corticosteroids, and the presence of anti-RNA polymerase III antibodies
May present as seziures, papilledema, HTN, elevated creatinine, proteinuira, and anemia
What is the treatment for SRC?
Early pharmacologic intervention with angiotensin-converting enzyme inhibitors is crucial to control and possibly reverse the disease process.
What are other signs/symptoms suggesting that SRC is developing?
-new cardiac events (HF or pericardial effusion)
-prescence of anti-RNA plymerase I and III Abs
-antecedent use of high dose steroids, NSAIDs, or cyclosporin
T or F. Most SSc patients will have some type of GASTROINTESTINAL INVOLVEMENT
What are the most common manifestations of GI involvement in SSc?
1.Manifestations of GUT DYSMOTILITY are universally present in scleroderma and can affect any segment of the gastrointestinal tract.
NOTE about where GI dysfunction occurs most in SSc
Involvement of the upper GI tract is more common and can present with severe symptoms BUT dysfunction and failure of the LOWER GI tract are associated with poor prognosis.
What are some of the more common pulmonary problems in SSc?
-Pleurisy, pleural effusions, pleural scarring
-Malignancy-all cell types
-ILD or PAH
A combined cause 60% of deaths in SSc results from what?
Interstitial lung disease (SSc-ILD) and pulmonary arterial hypertensive (PAH)
When does IPF usually occur in SSc?
late in disease and include dyspnea, fatigue and dry cough
note that methotrexate is a risk factor
Which type of Scleroderma is more associated with PAH development?
limited cutaneous (associated with CREST syndrome- calcinosis, Raynaud, Esophageal dysmotility, Sclerodactyly, and telangiectasia)
PAH associated with diffuse SSc = what Ab? limited SSc?
diffuse= antifibrillarin Ab (U3RNP)
limited= anticentromere Ab
The reported prevalence of PAH in SSc is estimated to be 7 – 15% with a five year cumulative survival of 10% compared with 80% in those without PAH.
Some key points about Scleroderma
There is marked patient-to-patient variability in clinical and laboratory manifestations, disease course, and molecular signatures, suggesting the existence of distinct disease subsets. There are protean clinical manifestations reflecting the underlying early immune dysregulation and microangiopathy, as well as subsequent systemic fibrosis.
Early manifestaitons of SSc?
Vascular lesions in small blood vessels occur early and progress to obliterative vasculopathy that causes tissue hypoxia, oxidative stress, and vascular complications.
Describe localized scleroderma
NONSYSTEMIC skin disease primarily seen in children (5 subtypes)
Subtypes of Limited Scleroderma?
1) Plaque morphea
2) Generalized morphea
3) Keloid morphea
4) Bullous morphea
5) Linear scleroderma
What is this?
Plaque morphea- 1.the most common form of limited scleroderma and is an isolated circular patch of thickened skin.
What is this?
generalized morphea- 1.multiple lesions involving extensive areas of skin and can occasionally coalesce, mimicking skin changes of systemic sclerosis.
What is this?
Keloid morphea- nodular morphea resembling keloids
Bullous morphea is a rare form with subepithelial bullae
Linear scleroderma - A linear streak that crosses dermatomes and is associated with atrophy of muscle, underlying bone and rarely the brain called “en coup de sabre”.
if brain is invovled, seizures can occur
Histopathology of skin lesions in scleroderma characterized by an excessive deposition of collagen, deep fibrosis and perivascular lymphohistiocytic infiltrates.
What's going on here?
Histologic appearance of systemic sclerosis vasculopathy. A pulmonary arteriole showing extensive medial hypertrophy and intimal thickening, leading to narrowing of the vascular lumen
What is this showing?
Raynaud's - 'local asphyxia of the extremities'
A digital artery from a patient with limited cutaneous systemic sclerosis, showing intimal thickening.
The lumen is occluded with visible recanalisation (arrow).
Notes about Raynaud
Structural abnormalities do not occur in primary Raynaud phenomenon: any reported abnormalities have been subtle changes and could possibly relate to the unclear distinction between primary Raynaud phenomenon and SSc.
A small proportion of patients (1–2% per year) with what appears to be primary Raynaud phenomenon progress to an SSc-spectrum disorder or other underlying disease