scleroderma ( systemic sclerosis ). definition systemic sclerosis (scleroderma) a multisystem...

Scleroderma (Systemic Sclerosis)

Scleroderma (Systemic Sclerosis)

DefinitionDefinition

Systemic sclerosis (scleroderma)

a multisystem disorder characterized by

1) functional and structural abnormalities of blood

vessels

2) fibrosis of the skin and internal organs

3) immune system activation

4) autoimmunity Sclero=thickened, derma=skin

Systemic sclerosis (scleroderma)

a multisystem disorder characterized by

1) functional and structural abnormalities of blood

vessels

2) fibrosis of the skin and internal organs

3) immune system activation

4) autoimmunity Sclero=thickened, derma=skin

EpidemiologyEpidemiology

1. Prevalence: 20 new cases per million per year

2. Susceptibility: host factor

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

2) gender - female : male = 4 : 1

3) genetic background

4) enviromental factors

Occurs at a younger age and has a worse prognosis in

African American women

1. Prevalence: 20 new cases per million per year

2. Susceptibility: host factor

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

2) gender - female : male = 4 : 1

3) genetic background

4) enviromental factors

Occurs at a younger age and has a worse prognosis in

African American women

ClassificationClassification

1. Systemic sclerosis

– Diffuse cutaneous systemic sclerosis– Limited cutaneous systemic sclerosis– Overlap syndromes

2. Localized scleroderma

– Morphoea

– Linear scleroderma

• En coup de sabre

1. Systemic sclerosis

– Diffuse cutaneous systemic sclerosis– Limited cutaneous systemic sclerosis– Overlap syndromes

2. Localized scleroderma

– Morphoea

– Linear scleroderma

• En coup de sabre

Classification of systemic sclerosisClassification of systemic sclerosis

1. Diffuse cutaneous systemic sclerosis

1) proximal skin thickening

- distal and proximal extremity and often the trunk and face

2) tendency to rapid progression of skin change

3) rapid onset of disease following Raynaud’s phenomenon

4) early appearance of visceral involvement

5) poor prognosis

1. Diffuse cutaneous systemic sclerosis

1) proximal skin thickening

- distal and proximal extremity and often the trunk and face

2) tendency to rapid progression of skin change

3) rapid onset of disease following Raynaud’s phenomenon

4) early appearance of visceral involvement

5) poor 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) the pacients usually have Raynaud’s phenomenon for years

4) prominence of calcinosis and telangiectasia

5) 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) the pacients usually have Raynaud’s phenomenon for years

4) prominence of calcinosis and telangiectasia

5) good prognosis

* CREST syndrome

- calcinosis, Raynaud's phenomenon, esophageal

dysmotility, sclerodactyly, telangiectasia

Classification of systemic sclerosisClassification of systemic sclerosis

3. Overlap syndromes

– Features of systemic sclerosis together with those of at least one other autoimmune rheumatic disease, e.g. SLE, RA, or polymyositis

3. Overlap syndromes

– Features of systemic sclerosis together with those of at least one other autoimmune rheumatic disease, e.g. SLE, RA, or polymyositis

EtiologyEtiology

Environmental factors1) 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 (?)

Environmental factors1) 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 (?)

Genetic predisposition

Defective immunoregulation

1) cell mediated immunity CD4/CD8 , cytokines

2) humoral immunity

– hypergammaglobulinemia

– autoantibody production

– antinuclear antibody (+) > 95%

Genetic predisposition

Defective immunoregulation

1) cell mediated immunity CD4/CD8 , cytokines

2) humoral immunity

– hypergammaglobulinemia

– autoantibody production

– antinuclear antibody (+) > 95%

PathogenesisPathogenesis

Susceptible host

Exogenous events

Immune system activation

Endothelial cellactivation/damage

Fibroblast activation

End stage pathologyObliterative vasculopathy

Fibrosis

PathogenesisPathogenesis

PathogenesisPathogenesis

1. Vasculopathy of small artery and capillary

- endothelial cell injury

- adhesion and activation of platelet

- PG F, thromboxane A2 release

- vasoconstriction & growth of endothelial cell and fibroblast

- narrowing or obliteration, increased permeability

2. Fibrosis

- aberrant regulation of fibroblast cell growth

- increased production of extracellular matrix

(collagen, fibronectin, and glycosaminoglycan)

- thickening of the skin & fibrosis of internal organs

1. Vasculopathy of small artery and capillary

- endothelial cell injury

- adhesion and activation of platelet

- PG F, thromboxane A2 release

- vasoconstriction & growth of endothelial cell and fibroblast

- narrowing or obliteration, increased permeability

2. Fibrosis

- aberrant regulation of fibroblast cell growth

- increased production of extracellular matrix

(collagen, fibronectin, and glycosaminoglycan)

- thickening of the skin & fibrosis of internal organs

PathogenesisPathogenesis

3. Immune system activation producing autoantibodies:

-anti-topoisomerase I (anti Scl 70)

-anti-centromere

-anti RNA polymerases

-anti U1 RNP

-anti B23

3. Immune system activation producing autoantibodies:

-anti-topoisomerase I (anti Scl 70)

-anti-centromere

-anti RNA polymerases

-anti U1 RNP

-anti B23

Clinical featuresClinical features

1. Vascular abnormalities

1) Raynaud's phenomenon

- cold hands and feet or ears/ nose/ tongue

-with reversible skin color change (white to blue to red)

- induced by cold temperature or emotional stress

- initial complaint in 3/4 of patients

2) digital ischemic injury

1. Vascular abnormalities

1) Raynaud's phenomenon

- cold hands and feet or ears/ nose/ tongue

-with reversible skin color change (white to blue to red)

- induced by cold temperature or emotional stress

- initial complaint in 3/4 of patients

2) digital ischemic injury

Raynaud’s phenomenon-pallor phaseRaynaud’s phenomenon-pallor phase

Raynaud’s phenomenon-cyanotic phaseRaynaud’s phenomenon-cyanotic phase

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, contractures

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, contractures

Edematous phaseEdematous phase

Skin IndurationSkin Induration

AcrosclerosisAcrosclerosis

Facial changesFacial changes

Tight, thin lips with vertical perioral furrowsTight, thin lips with vertical perioral furrows

Salt and pepper pigmentationSalt and pepper pigmentation

Clinical featuresClinical features

2. Skin involvement (2)

ulceration, loss of soft tissue of finger tip, pigmentation, calcific deposit, capillary change

3. Musculoskeletal system

• Polyarthritis and flexion contracture

• Muscle weakness and atrophy (primary /secondary)

2. Skin involvement (2)

ulceration, loss of soft tissue of finger tip, pigmentation, calcific deposit, capillary change

3. Musculoskeletal system

• Polyarthritis and flexion contracture

• Muscle weakness and atrophy (primary /secondary)

Terminal digit resorptionTerminal digit resorption

AcrolysisAcrolysis

Digital pitting scarsDigital pitting scars

CREST syndrome: C is for calcinosisCREST syndrome: C is for calcinosis

CREST :R is for RaynaudCREST :R is for Raynaud

CREST : E is for esophageal dysmotilityCREST : E is for esophageal dysmotility

... actually, you have to imagine this one

CREST : S is for Sclerodactyly

... actually, you have to imagine this one

CREST : S is for Sclerodactyly

CREST: T is for telangiectasiaCREST: T is for telangiectasia

RODNAN scoreRODNAN score

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, weight loss, cachexia

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, weight loss, cachexia

4) large intestine: chronic constipation and fecal impaction

diverticula

Abnormal motility DiverticulaAbnormal motility Diverticula

Clinical featuresClinical features

4. exocrine glands –Xerostomia–xerophthalmia

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)

4. exocrine glands –Xerostomia–xerophthalmia

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)

Pulmonary fibrosisPulmonary fibrosis

Clinical featuresClinical features

6. heart (10%): pericarditis, heart failure, arrhythmia, myocardial

fibrosis

7. kidney-scleroderm renal crisisFeatures: HTN, microangiopathic hemolytic anemia

and oliguric renal failure. Risk Factors: • Diffuse disease within the first five years• Anti-RNA polymerase III antibody• Pericardial effusion• > 15 mg prednisone daily or • Cyclosporin therapy

6. heart (10%): pericarditis, heart failure, arrhythmia, myocardial

fibrosis

7. kidney-scleroderm renal crisisFeatures: HTN, microangiopathic hemolytic anemia

and oliguric renal failure. Risk Factors: • Diffuse disease within the first five years• Anti-RNA polymerase III antibody• Pericardial effusion• > 15 mg prednisone daily or • Cyclosporin therapy

Laboratory findingsLaboratory findings

1. ANA, RF

2. anti-Scl-70 (DNA topoisomerase I) antibody

1) 20-30% in diffuse scleroderma

2) 10-15% in limited scleroderma

3. anticentromere antibody

1) 50-90% in limited scleroderma

2) 5% in diffuse scleroderma

4. Anti RNA polymerase III Ab: 10- 25% in Diffuse SSc,

Renal Disease.

1. ANA, RF

2. anti-Scl-70 (DNA topoisomerase I) antibody

1) 20-30% in diffuse scleroderma

2) 10-15% in limited scleroderma

3. anticentromere antibody

1) 50-90% in limited scleroderma

2) 5% in diffuse scleroderma

4. Anti RNA polymerase III Ab: 10- 25% in Diffuse SSc,

Renal Disease.

Subsets of systemic sclerosisSubsets of systemic sclerosis

Diagnosis- ACR criteriesDiagnosis- ACR criteries

1. major criteria: proximal scleroderma

2. minor criteria:

1) sclerodactyly

2) digital pitting scar or

loss of substance from the finger pads

3) bibasilar pulmonary fibrosis

*the major or 2 or more minor criteria for diagnosis

1. major criteria: proximal scleroderma

2. minor criteria:

1) sclerodactyly

2) digital pitting scar or

loss of substance from the finger pads

3) bibasilar pulmonary fibrosis

*the major or 2 or more minor criteria for diagnosis

Scoring Systems for Severity (?!?)Scoring Systems for Severity (?!?)

• Disease burden: The Systemic Sclerosis Severity Scale Includes nine organ systems.

• Functional Assessment: Scleroderma Health Assessment Questionnaire Disability Index (SHAQ) and Scleroderma Functional Score.

• Quality of Life: Short Form Health Survey (SF-36) for psychological and mental functioning

• Disease burden: The Systemic Sclerosis Severity Scale Includes nine organ systems.

• Functional Assessment: Scleroderma Health Assessment Questionnaire Disability Index (SHAQ) and Scleroderma Functional Score.

• Quality of Life: Short Form Health Survey (SF-36) for psychological and mental functioning

Differential dignosisDifferential dignosis

• Raynaud phenomenon: primary Raynaud’s syndrome, SLE, systemic vasculitis, medication-induced.

• Skin thickening: scleredema, scleromyxedema, POEMS syndrome, diabetic cheiroarthropathy, morphea

• Overlapping clinical features: SLE, Sjogren syndrome, RA, inflammatory myopathies.

• Raynaud phenomenon: primary Raynaud’s syndrome, SLE, systemic vasculitis, medication-induced.

• Skin thickening: scleredema, scleromyxedema, POEMS syndrome, diabetic cheiroarthropathy, morphea

• Overlapping clinical features: SLE, Sjogren syndrome, RA, inflammatory myopathies.

TreatmentTreatment

A wide spectrum of clinical manifestations and severity

- spontaneous improvement occurs frequently

• Disease modifying interventions (?)

- methotrexate

- immunosuppressive agent: cyclosporin, cyclophosphamide,mycophenolate mophetil

- recombinant human relaxin

• Symptomatic (organ-specific) treatment

A wide spectrum of clinical manifestations and severity

- spontaneous improvement occurs frequently

• Disease modifying interventions (?)

- methotrexate

- immunosuppressive agent: cyclosporin, cyclophosphamide,mycophenolate mophetil

- recombinant human relaxin

• Symptomatic (organ-specific) treatment

TreatmentTreatment

Raynaud’s phenomenon and ischemia

1) avoid cold exposure

layers of warm, loose-fitting clothing

2) quit smoking

3) vasodilator therapy

- calcium channel blocker (nifedipine), prazosin, ACE-i

4) finger / toe necrosis

- intravenous prostaglandin (PGE1, PGI2)

- amputation

Raynaud’s phenomenon and ischemia

1) avoid cold exposure

layers of warm, loose-fitting clothing

2) quit smoking

3) vasodilator therapy

- calcium channel blocker (nifedipine), prazosin, ACE-i

4) finger / toe necrosis

- intravenous prostaglandin (PGE1, PGI2)

- amputation

TreatmentTreatment

Gastrointestinal

1) reflux esophagitis and dysphagia

- elevation of head of bed

- small frequent meal

- avoid lying down within 3-4 hours of eating

- abstaining from caffeine-containing beverages,

cigarette smoking

- H2 blocker, proton-pump inhibitor

2) gastroparesis: promotility agent (metoclopramide)

3) malabsorption syndrome: broad spectrum antibiotics

Gastrointestinal

1) reflux esophagitis and dysphagia

- elevation of head of bed

- small frequent meal

- avoid lying down within 3-4 hours of eating

- abstaining from caffeine-containing beverages,

cigarette smoking

- H2 blocker, proton-pump inhibitor

2) gastroparesis: promotility agent (metoclopramide)

3) malabsorption syndrome: broad spectrum antibiotics

TreatmentTreatment

Pulmonary 1) Interstitial fibrosis - corticosteroid

- cyclophosphamide, azathioprine

2) pulmonary artery hypertension

- calcium channel blocker

- prostacyclin

-sildenafil

- transplantation

Renal renal crisis: -early detection and ACE inhibitor

1 year survival without captopril 15%

1 year survival with captopril 76%

- dialysis

Pulmonary 1) Interstitial fibrosis - corticosteroid

- cyclophosphamide, azathioprine

2) pulmonary artery hypertension

- calcium channel blocker

- prostacyclin

-sildenafil

- transplantation

Renal renal crisis: -early detection and ACE inhibitor

1 year survival without captopril 15%

1 year survival with captopril 76%

- dialysis

PrognosisPrognosis

1. quite variable and difficult to predict

2. cumulative survival

diffuse limited

5 yr 70% 90%

10 yr 50% 70%

3. major cause of death

1) renal involvement

2) cardiac involvement

3) pulmonary involvement

1. quite variable and difficult to predict

2. cumulative survival

diffuse limited

5 yr 70% 90%

10 yr 50% 70%

3. major cause of death

1) renal involvement

2) cardiac involvement

3) pulmonary involvement