Systemic Sclerosis (Scleroderma)

Question 1

What is the pathologic quartet of Scleroderma?

Answer 1

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.

Question 2

Patient population for Scleroderma?

Answer 2

Young AA, female more than male

connection to coal miners (silica exposure)

Question 3

Give a general overview of the pathogenesis of scleroderma

Answer 3

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)

Question 4

What is one of the earlier pathological changes seen in Scleroderma?

Answer 4

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

Question 5

Raynaud’s phenomenom is a feature of scleroderma. Why?

Answer 5

•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)

Question 6

Describe digital color changes assocated wtih Raynaud’s phenomenom

Answer 6

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

Question 7

Raynaud’s can present as a primary disease or secondary to other diseases, such as:

Answer 7

SSc, lupus, RA, polymyositis, MCTD

Question 8

What is a common complication of Raynaud’s phenomenon?

Answer 8

Distal ischemia can lead to digital ulcer development

Question 9

What are two facial skin manifestations of Scleroderma?

Answer 9

Vitilligo-like changes (top) and facial telangiectasias (bottom)- will not blanch

Question 10

What are the types of Scleroderma?

Answer 10

• localized (morphea or linear)
• systemic (limited, diffuse, or sine (only internal organ invovlvment))

Question 11

What is the definitional difference between limited and diffuse SSc?

Answer 11

Limited is confined to the extremities (up to knees and elbows) and the head and diffuse can be anywhere

Question 12

Systemic Involvemnt in SSc

Answer 12

Question 13

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?

Answer 13

Topo I (Scl70). Resulting in pulmonary fibrosis and cardiac involvement

Question 14

What autoantibodies are present only in limited SSc? Clinical manifestation?

Answer 14

Centromere (protein B,C)- several digital ischemia, PAH, sicca syndrome (dryness everywhere), and calcinosis

Question 15

What autoantibodies are present in an overlap of diffuse and limtied SSc? Clinical manifestation?

Answer 15

PM/Sci- myositis, pulmonary fibrosis, acro-osteolysis

U1-RNP-SLE, pulmonary fibrosis, inflammatory arthritis

Question 16

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?

Answer 16

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

Question 17

What is the treatment for SRC?

Answer 17

Early pharmacologic intervention with angiotensin-converting enzyme inhibitors is crucial to control and possibly reverse the disease process.

Question 18

What are other signs/symptoms suggesting that SRC is developing?

Answer 18

• new anemia
• 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

Question 19

T or F. Most SSc patients will have some type of GASTROINTESTINAL INVOLVEMENT

Answer 19

T.

Question 20

What are the most common manifestations of GI involvement in SSc?

Answer 20

1.Manifestations of GUT DYSMOTILITY are universally present in scleroderma and can affect any segment of the gastrointestinal tract.

Question 21

NOTE about where GI dysfunction occurs most in SSc

Answer 21

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.

Question 22

What are some of the more common pulmonary problems in SSc?

Answer 22

• Pleurisy, pleural effusions, pleural scarring
• Aspiration pneumonia
• Malignancy-all cell types
• ILD or PAH

Question 23

A combined cause 60% of deaths in SSc results from what?

Answer 23

Interstitial lung disease (SSc-ILD) and pulmonary arterial hypertensive (PAH)

Question 24

When does IPF usually occur in SSc?

Answer 24

late in disease and include dyspnea, fatigue and dry cough

note that methotrexate is a risk factor

Question 25

Which type of Scleroderma is more associated with PAH development?

Answer 25

limited cutaneous (associated with CREST syndrome- calcinosis, Raynaud, Esophageal dysmotility, Sclerodactyly, and telangiectasia)

Question 26

PAH associated with diffuse SSc = what Ab? limited SSc?

Answer 26

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.

Question 27

Some key points about Scleroderma

Answer 27

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.

Question 28

Early manifestaitons of SSc?

Answer 28

Vascular lesions in small blood vessels occur early and progress to obliterative vasculopathy that causes tissue hypoxia, oxidative stress, and vascular complications.

Question 29

Describe localized scleroderma

Answer 29

NONSYSTEMIC skin disease primarily seen in children (5 subtypes)

Question 30

Subtypes of Limited Scleroderma?

Answer 30

1) Plaque morphea
2) Generalized morphea
3) Keloid morphea
4) Bullous morphea
5) Linear scleroderma

Question 31

What is this?

Answer 31

Plaque morphea- 1.the most common form of limited scleroderma and is an isolated circular patch of thickened skin.

Question 32

What is this?

Answer 32

generalized morphea- 1.multiple lesions involving extensive areas of skin and can occasionally coalesce, mimicking skin changes of systemic sclerosis.

Question 33

What is this?

Answer 33

Keloid morphea- nodular morphea resembling keloids

Question 34

Identify

Answer 34

Bullous morphea is a rare form with subepithelial bullae

Question 35

Identify

Answer 35

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

Question 36

Answer 36

Histopathology of skin lesions in scleroderma characterized by an excessive deposition of collagen, deep fibrosis and perivascular lymphohistiocytic infiltrates.

Question 37

Question 38

Question 39

Question 40

What’s going on here?

Answer 40

Histologic appearance of systemic sclerosis vasculopathy. A pulmonary arteriole showing extensive medial hypertrophy and intimal thickening, leading to narrowing of the vascular lumen

Question 41

What is this showing?

Answer 41

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).

Question 42

Notes about Raynaud

Answer 42

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