Systemic SclerosisSCLERODERMA

ד"ר גבריאל ש ברויארד"ר גבריאל ש ברויאר

היחידה לראומטולוגיההיחידה לראומטולוגיה

המרכז הרפואי שערי צדקהמרכז הרפואי שערי צדק

SCLERODERMA- systemic sclerosisDefinition

1. 1. Systemic sclerosis (scleroderma)Systemic sclerosis (scleroderma)

- a multisystem disorder characterized by- a multisystem disorder characterized by

1) functional and structural 1) functional and structural abnormalities of blood vesselsabnormalities of blood vessels

2) 2) fibrosisfibrosis of the skin and internal organs of the skin and internal organs

3) immune system activation3) immune system activation

4) autoimmunity4) autoimmunity

2. Localized scleroderma2. Localized scleroderma

- morphea, linear scleroderma- morphea, linear scleroderma

Epidemiology

1. 1. PrevalencePrevalence: 19-75 cases per 100,000: 19-75 cases per 100,000

2. Susceptibility: host factor2. Susceptibility: host factor

1) age - peak occurrence: 1) age - peak occurrence: age 35-65age 35-65 years years

2) gender - 2) gender - femalefemale : male = 7-12 : 1 : male = 7-12 : 1

3) genetic background3) genetic background

- Choctaw native Americans in Oklahoma (469 per 100,000)- Choctaw native Americans in Oklahoma (469 per 100,000)

3. Environmental factors3. Environmental factors

1) infection1) infection

2) occupational exposures: 2) occupational exposures: silica dustsilica dust

Classification of systemic sclerosis

1. 1. Diffuse cutaneous systemic sclerosisDiffuse cutaneous systemic sclerosis

1) proximal skin thickening 1) proximal skin thickening

- distal and - distal and proximal extremityproximal extremity and often the and often the trunk and facetrunk and face

2) tendency to 2) tendency to rapid progressionrapid progression of skin change of skin change

3) 3) rapid onsetrapid onset of disease following Raynaud’s phenomenon of disease following Raynaud’s phenomenon

4) early appearance of 4) early appearance of visceral involvementvisceral involvement

5) 5) poor prognosispoor prognosis

Classification of systemic sclerosisClassification of systemic sclerosis

2. Limited cutaneous systemic sclerosis 1) symmetric restricted fibrosis - affecting the distal extremities and face/neck 2) prolonged delay in appearance of distinctive internal manifestation 3) prominence of calcinosis and telangiectasia 4) good prognosis

* CREST syndrome - calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia

2. Limited cutaneous systemic sclerosis 1) symmetric restricted fibrosis - affecting the distal extremities and face/neck 2) prolonged delay in appearance of distinctive internal manifestation 3) prominence of calcinosis and telangiectasia 4) good prognosis

* CREST syndrome - calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia

Pathogenesis 1. 1. Vasculopathy of small artery and capillaryVasculopathy of small artery and capillary - endothelial cell injury - endothelial cell injury - adhesion and activation of platelet- adhesion and activation of platelet - PDGF, thromboxane A2 release - PDGF, thromboxane A2 release - vasoconstriction & growth of endothelial cell and fibroblast- vasoconstriction & growth of endothelial cell and fibroblast - narrowing or obliteration, increased permeability- narrowing or obliteration, increased permeability 2. 2. FibrosisFibrosis - aberrant regulation of fibroblast cell growth - aberrant regulation of fibroblast cell growth - increased production of extracellular matrix- increased production of extracellular matrix (collagen, fibronectin, and glycosaminoglycan)(collagen, fibronectin, and glycosaminoglycan) - thickening of the skin & fibrosis of internal organs- thickening of the skin & fibrosis of internal organs

Pathogenesis 3. 3. Immunologic mechanismImmunologic mechanism 1) cell mediated immunity1) cell mediated immunity - skin: - skin: cellular infiltratescellular infiltrates in perivascular region and dermis in perivascular region and dermis (T cell, Langerhans cell, plasma cell, macrophage)(T cell, Langerhans cell, plasma cell, macrophage)

2) humoral immunity2) humoral immunity - hypergammaglobulinemia- hypergammaglobulinemia - - autoantibodyautoantibody production production antinuclear antibody (+) > 95%antinuclear antibody (+) > 95%

PathogenesisPathogenesis

4. Environmental factors 1) silica dust 2) organic solvents 3) biogenic amines 4) urea formaldehyde 5) polyvinyl chloride 6) rapeseed oil 7) bleomycin 8) L-tryptophan 9) silicone implant (?)

4. Environmental factors 1) silica dust 2) organic solvents 3) biogenic amines 4) urea formaldehyde 5) polyvinyl chloride 6) rapeseed oil 7) bleomycin 8) L-tryptophan 9) silicone implant (?)

FIBROSISFIBROSIS

TGFß, PDGF,IL-4, IL-1, IL-13

adhesion molecules

T cell recruitment,activation?autoantigens

endothelingrowth factors

hypoxia

FIBROSISFIBROSIS

genetic background, microchimerism, environmental stimuli,?infection

Endothelial injury(? oxidation products, immune factors)

Fibroblast autocrine factors, signaling, matrix, selection, imprinting

Mast cells

VASCULAR DISEASEVASCULAR DISEASE

Pathogenesisof SSc

Organ Organ DamageDamage

Review: Evidence That Systemic Sclerosis Is a Vascular Disease

Arthritis & RheumatismVolume 65, Issue 8, pages 1953-1962, 26 JUL 2013 DOI: 10.1002/art.37988http://onlinelibrary.wiley.com/doi/10.1002/art.37988/full#art37988-fig-0002

Clinical features

1. 1. Vascular abnormalitiesVascular abnormalities 1) Raynaud's phenomenon1) Raynaud's phenomenon - cold hands and feet - cold hands and feet with reversible skin color change (white to blue to red)with reversible skin color change (white to blue to red) - induced by cold temperature or emotional stress- induced by cold temperature or emotional stress - initial complaint in 3/4 of patients- initial complaint in 3/4 of patients - 90% in patients with skin change- 90% in patients with skin change (prevalence in the general population: 4-15%)(prevalence in the general population: 4-15%) 2) digital ischemic injury2) digital ischemic injury

Raynaud’s phenomenon

Raynaud’s phenomenon

Terminal digit resorption

Clinical featuresClinical features

2. Skin involvement (1) 1) stage - edematous phase - indurative phase - atrophic phase

2) firm, thickened bound to underlying soft tissue

3) decrease in range of motion, loss of facial expression, inability to open mouth fully

2. Skin involvement (1) 1) stage - edematous phase - indurative phase - atrophic phase

2) firm, thickened bound to underlying soft tissue

3) decrease in range of motion, loss of facial expression, inability to open mouth fully

Edematous phase

Skin Induration

Acrosclerosis

Clinical featuresClinical features

2. Skin involvement (2) 4) ulceration, loss of soft tissue of finger tip, pigmentation, calcific deposit, capillary change 5) pathology - atrophy of dermal appendages - loss of rete pegs - compact bundles of collagen

3. Polyarthritis and flexion contracture

2. Skin involvement (2) 4) ulceration, loss of soft tissue of finger tip, pigmentation, calcific deposit, capillary change 5) pathology - atrophy of dermal appendages - loss of rete pegs - compact bundles of collagen

3. Polyarthritis and flexion contracture

Acrolysis

Digital pitting scars

CREST syndrome: calcinosis cutis

Calcinosis and acrolysis

Facial changes

Telangiectasia

Face / mucous membraneFace / mucous membrane

blanched by pressureblanched by pressure

Calcinosis

Clinical featuresClinical features

4. intestinal involvement

1) esophagus: hypomotility and retrosternal pain,

reflux esophagitis, stricture

2) stomach: delayed emptying

3) small intestine: pseudo-obstruction, paralytic ileus,

malabsorption

4) large intestine: chronic constipation and fecal impaction

diverticula

4. intestinal involvement

1) esophagus: hypomotility and retrosternal pain,

reflux esophagitis, stricture

2) stomach: delayed emptying

3) small intestine: pseudo-obstruction, paralytic ileus,

malabsorption

4) large intestine: chronic constipation and fecal impaction

diverticula

Abnormal motility

Diverticula

Barium enema studyBarium enema study

- multiple wide-mouthed - multiple wide-mouthed

diverticula of colondiverticula of colon

- broad base and neck- broad base and neck

- usually asymptomatic- usually asymptomatic

Diverticula

Clinical featuresClinical features

5. lungs

1) 2/3 of patients affected

- leading cause of mortality and morbidity in later stage

of systemic sclerosis

2) pathology

- interstitial fibrosis

- intimal thickening of pulmonary arterioles

(pulmonary hypertension)

5. lungs

1) 2/3 of patients affected

- leading cause of mortality and morbidity in later stage

of systemic sclerosis

2) pathology

- interstitial fibrosis

- intimal thickening of pulmonary arterioles

(pulmonary hypertension)

סקלרודרמה מעורבות ריאה

Limited cutaneousLimited cutaneous

Pulmonary HypertensionPulmonary Hypertension

Diffuse cutaneousDiffuse cutaneous

Fibrosing alveolitisFibrosing alveolitis

Yearly echo may be considered

Asymptomatic patients

Screening for PAH-SSc: ESC/ERS Guidelines 2009

Symptomatic patients)breathlessness, fatigue, weakness,

angina, syncope, abdominal distension(

Yearly echo is recommended

Confirmation of PAH requires RHC

Galiè et al; Eur Heart J (2009)

Interstitial lung Disease (fibrosing alveolitis)

DiagnosisDiagnosis PFTPFT - -DLCODLCO HRCTHRCT (BAL(BAL -Differential-Differential ( (

Interstitial lung Disease (fibrosing alveolitis)

Treatment: Cyclophosphamide + Prednisone

Micophenolate mofetyl

Clinical featuresClinical features

6. heart (10%)

1) pericarditis

2) heart failure

3) arrhythmia

4) myocardial fibrosis

6. heart (10%)

1) pericarditis

2) heart failure

3) arrhythmia

4) myocardial fibrosis

Clinical featuresClinical features

7. kidney

1) diffuse scleroderma in association with

rapid progression of skin involvement

2) pathology

- intimal hyperplasia of the interlobular artery

- fibrinoid necrosis of afferent arterioles

- glomerulosclerosis

3) proteinuria, abnormal sediment, azotemia,

microangiopathic hemolytic anemia, renal failure

7. kidney

1) diffuse scleroderma in association with

rapid progression of skin involvement

2) pathology

- intimal hyperplasia of the interlobular artery

- fibrinoid necrosis of afferent arterioles

- glomerulosclerosis

3) proteinuria, abnormal sediment, azotemia,

microangiopathic hemolytic anemia, renal failure

Review: Evidence That Systemic Sclerosis Is a Vascular Disease

Arthritis & RheumatismVolume 65, Issue 8, pages 1953-1962, 26 JUL 2013 DOI: 10.1002/art.37988http://onlinelibrary.wiley.com/doi/10.1002/art.37988/full#art37988-fig-0003

Diagnosis 1. 1. major criteria: proximal sclerodermamajor criteria: proximal scleroderma

2. minor criteria: 2. minor criteria:

1) sclerodactyly1) sclerodactyly

2) digital pitting scar or 2) digital pitting scar or

loss of substance from the finger padsloss of substance from the finger pads

3) bibasilar pulmonary fibrosis3) bibasilar pulmonary fibrosis

* one major or 2 or more minor criteria for diagnosis* one major or 2 or more minor criteria for diagnosis

Prognosis

1. 1. quite variable and difficult to predictquite variable and difficult to predict

2. cumulative survival2. cumulative survival

diffusediffuse limitedlimited

5 yr5 yr 70% 70% 90%90%

10 yr10 yr 50% 50% 70%70%

3. 3. major cause of deathmajor cause of death

1) renal involvement1) renal involvement

2) cardiac involvement2) cardiac involvement

3) pulmonary involvement3) pulmonary involvement

סקלרודרמה - מבט לעתיד

טיפול מונע לפיברוזיס ולפיברוגנזה טיפול מונע לפיברוזיס ולפיברוגנזהinterferon gammainterferon gamma קולגנזה וכן נגדנים שוניםקולגנזה וכן נגדנים שונים

חוסמי ציטוקינים כגון חוסמי ציטוקינים כגוןTGF betaTGF betaטיפולים גנטייםטיפולים גנטייםמניעת מפגעים סביבתייםמניעת מפגעים סביבתיים