Scleroderma (Systemic Sclerosis)

Question 1

What is systemic sclerosis?

Answer 1

autoimmune CTD, chronic - females >> males

skin induration is hallmark

multiple organs are involved

vascular and fibrotic changes dominate

high mortality (similar to cancer)

no approved disease - modifying Rx

Question 2

What are the major clinical subsets of SSc?

Answer 2

limited cutaneous SSc and diffuse cutaneous SSc

characterized by divergent patterns of organ involvement, rate of progression, autoantibody profiles, and survival

Question 3

What is the pathogenesis of scleroderma?

Answer 3

autoimmunity (autoantibodies)

vasculopathy (small blood vessels) - raynaud, PAH, renal crisis

fibrosis of multiple organs

Question 4

What is the role of microchimerism in SSc?

Answer 4

cells of maternal origin appear to infiltrate the skin and other affected tissues

Question 5

What are scleroderma mimicks?

Answer 5

other conditions with skin fibrosis:

localized scleroderma

slceroderma

scleromyxedema

eosinophilia-myalfia syndrome and eosinophilic fasciitis

Question 6

What are the baseline predictors of increased mortality in dcSSc?

Answer 6

truncal skin involvement

abnormal EKG

reduced diffusing capacity

elevated ESR and presence of serum autoantibodies specific for topoisomerase I and RNA polymerase III

Question 7

What is the etiology of SSc?

Answer 7

mostly unknown

can be viral infection or reactivation

can also be exposure to silica, vinyl chloride, and organic solvents

Question 8

What is the epidemiology of SSc?

Answer 8

affects 1 in 4000 adults in the US

female predominance, more frequent in African Americans

10 year survival in dcSSc can be as low as 55%

Question 9

What is the mechanism of fibrosis?

Answer 9

activation of fibroblasts lead to activation of myofibroblasts

results in excessive deposition of collagen and other ECM proteins, leading to fibrosis

TGFbeta is produced and induces differentiation of fibroblasts, as well as endothelial and epithelial cells

Question 10

What are the genetic factors in SSc?

Answer 10

non-Mendelian disorder, low concordance rate among twins

SNP studies show that particular alleles in genes for TGFbeta, MCP-1, IL-1alpha, TNF, AIF1, PPAR-gamma, and ACE are linked to disease susceptibility

Question 11

Describe the vascular damage in SSc.

Answer 11

microvascular obliterative vasculopathy - priminently affects small and medium-sized vessels of digits, lungs, heart, and GI tract

vessel is obliterated and flow ceases

Question 12

What are the phases of vascular damage in SSc?

Answer 12

1) endothelial cell activation with increased production of ET-1 and decreased prostacyclin release, causing functional changes with initially reversible vasoconstriction, upregulation of adhesion molecules, and generation of ROS
2) vascular wall remodeling follows with intimal proliferation, medial hypertrophy, and adventitial fibrosis
3) platelet aggregation and in situ thrombosis

Question 13

What happens to the vasculature in patients with long-standing SSc?

Answer 13

vascular rarefaction - paucity of small bood vessels, despite high levels of VEGF and other angiogenic factors

progressive obliteration of vessels results in hypoxia, which is itself a potent stimulus for fibroblast activation

recurrent ischemia-reperfusion leads to increased oxidative stress with generation of harmful ROS such as superoxide radicals, which further exaggerate fibrotic responses

Question 14

How does immunity factor into SSc?

Answer 14

both innate and adaptive immunity are activated in SSc

under the influence of soluble factors such as MCP-1 and related chemokines, activated immune cells accumulate in the skin, the lungs, and other target tissues

lesional T cells show Th2 polarization of oligoclonality of T cell receptors suggestive of an antigen-driven response

Question 15

What are the treatments for PS?

Answer 15

IV cytoxan

skin improves by progressive dyspnea develops

develops PFTs

Question 16

What are the HRCT findings of PS?

Answer 16

lower lobes are affected

peripheral opacities

ground-glass pattern

non-specific interstitial pneumonitis (NSIP)

Question 17

What is Raynaud phenomenon?

Answer 17

cold-induced reversible vasospasm of the fingers and toes - can be primary or secondary

mostly medium and small vessels

common, occurs up to 15% in healthy women

often progressive

may lead to digital ulcers

Question 18

What is primary Raynaud Phenomenon?

Answer 18

uncomplicated - functional changes only

nailfold capillaroscopy - sharp loops in normal fingers

infarction of blood vessels can lead to necrosis

Question 19

What is secondary Raynaud’s Phenomenon?

Answer 19

symptoms of Reynaud’s phenomenon that can be associated with a specific disease

Question 20

What are the features of PAH as a complication of SSc?

Answer 20

develops in 40% of SSc patients, generally late in the disease

poor 5yr survival

results from obliteration of small arterioles in the lung

endothelin-1 elevated and NO, prostacyclins reduced

block ET-1 or enhance NO/prostacyclin to treat

Question 21

What are the features of renal crisis as a result of scleroderma?

Answer 21

scleroderma renal crisis (SRC) - precipitates from destruction of medium-sized arteries

microvascular complication of SSc

accelerated or malignant HTN and hyperreninemia

thrombotic microangiopathy (TMA) - mimics TTP, hemolytic uremic syndrome, often presents with microangiopathy (schistocytes, hemolysis)

poor prognosis, high mortality

Question 22

What is the role of autoantibodies in SSc?

Answer 22

distinct from other autoimmune diseases (lupus, RA,. etc.) - unique set

targets endothelial cells, granzyme or reactive oxidation products

useful for diagnosis, classification - risk stratification (at least 8 different antibodies and depending on which is present, the outcomes can be predicted

role in pathogenesis is unproven

Question 23

What are the clinical features of the skin in SSc?

Answer 23

cutaneous telangiectasia

lesions themselves don’t do any harm, but is an indication of systemic disease

nailfold capillaries indicate more severe disease

Question 24

What are the clinical features of the lungs in SSc?

Answer 24

critical target organ in SSc, 90% of patients have ILD at autopsy, and 40% show restrictive changes

interstitial fibrosis (NSIP)

can lead to pulmonary hypertension, which can be life-treatening

drop in FVC in the first few years

Question 25

What are the clinical features of GI involvement in SSc?

Answer 25

involvement of any part of the GI tract from the mouth to the rectum

the esophagus in particular is particularly important

the liver is not affected

fibrosis in the wall of the intestinal tract that interrupts the tightly choreographed peristaltic activity

patient’s can’t swallow

stomach doesn’t work well either

lower esophageal sphincter is normally tightly closed and only opens with food, but in SSc, it becomes painfully dilaged an opened - allows fro acid reflux and leads to Barett’s esophagus

acid can also end up in the lungs

Question 26

What is the best treatment for SRC?

Answer 26

ACE inhibitors

can avoid dialysis if used aggresively before serum creatinine exceeds 3 mh/dL