Download Systemic Sclerosis (Scleroderma)

Scleroderma
(Systemic Sclerosis)
Definition
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
Epidemiology
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
Classification
1. Systemic sclerosis
2.
–
Diffuse cutaneous systemic sclerosis
–
–
Limited cutaneous systemic sclerosis
Overlap syndromes
Localized scleroderma
–
Morphoea
–
Linear scleroderma
•
En coup de sabre
Classification 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
Classification 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
Classification 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
Etiology
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 (?)
Genetic predisposition
Defective immunoregulation
1) cell mediated immunity CD4/CD8 ,
cytokines
2) humoral immunity
– hypergammaglobulinemia
– autoantibody production
– antinuclear antibody (+) > 95%
Pathogenesis
Susceptible host
Exogenous events
Immune system
activation
Fibroblast activation
Endothelial cell
activation/damage
End stage pathology
Obliterative vasculopathy
Fibrosis
Pathogenesis
Pathogenesis
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
Pathogenesis
3. Immune system activation producing
autoantibodies:
-anti-topoisomerase I (anti Scl 70)
-anti-centromere
-anti RNA polymerases
-anti U1 RNP
-anti B23
Clinical 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
Raynaud’s phenomenon-pallor phase
Raynaud’s phenomenon-cyanotic phase
Clinical 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
Edematous phase
Skin Induration
Acrosclerosis
Facial changes
Tight, thin lips with vertical perioral furrows
Salt and pepper pigmentation
Clinical 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)
Terminal digit resorption
Acrolysis
Digital pitting scars
CREST syndrome: C is for calcinosis
CREST :R is for Raynaud
CREST : E is for esophageal dysmotility
... actually, you have to imagine this one
CREST : S is for Sclerodactyly
CREST: T is for telangiectasia
RODNAN score
Clinical 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
Abnormal motility
Diverticula
Clinical 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)
Pulmonary fibrosis
Clinical features
6. heart (10%): pericarditis, heart failure, arrhythmia, myocardial
fibrosis
7. kidney-scleroderm renal crisis
Features: 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 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.
Subsets of systemic sclerosis
Diagnosis- 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
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
Differential dignosis
• Raynaud phenomenon: primary Raynaud’s
syndrome, SLE, systemic vasculitis, medicationinduced.
• Skin thickening: scleredema, scleromyxedema,
POEMS syndrome, diabetic cheiroarthropathy,
morphea
• Overlapping clinical features: SLE, Sjogren
syndrome, RA, inflammatory myopathies.
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
Treatment
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
Treatment
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
Treatment
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
Prognosis
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