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6 Limited Cutaneous Previously called CREST Involvement of distal extremities and face/neck Raynaud’s phenomenon for years prior to skin thickening Occasionally pulmonary hypertension w

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TS BS Hoàng Thị Lâm

Phó Trưởng Bộ môn Dị ứng - MDLS, Đại học Y Hà nội Khoa khám bệnh, bệnh viện Đại học Y Hà nội

1 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

1 Prevalence : Rare disease

4-12 new cases per million per year

prevalence of 19-75/100,000

2 Susceptibility: host factor

age - peak occurrence: age 35-65 years rare in children

gender - female : male = 3-12 : 1

genetic background:

(Systemic Sclerosis)

Morphea Scleroderma Linear Scleroderma Limited Scleroderma Diffuse Scleroderma Sine

5

Limited and Diffuse SSc—

Skin Involvement

Limited Diffuse

6

Limited Cutaneous

Previously called CREST

Involvement of distal extremities and face/neck

Raynaud’s phenomenon for years prior to skin thickening Occasionally pulmonary hypertension with or without

interstitial lung disease

Majority anti-centromere antibody positive

(80–90%)

Nailfold capillaroscopy—dilated capillary loops

* CREST syndrome

- c alcinosis, R aynaud's phenomenon, e sophageal

dysmotility, s clerodactyly, t elangiectasia

Truncal and acral skin involvement

Absent for anti-centromere antibody

Nailfold capilaroscopy—capillary dilatation and destruction

8

Diffuse Cutaneous

Associated with substantial morbidity and

mortality resulting from—

– Vascular dysfunction

– Organ fibrosis and inflammation

– Gastrointestinal dysmotility

– Myocardial involvement

1) cell mediated immunity CD4/CD8 , cytokines

2) humoral immunity – hypergammaglobulinemia – autoantibody production – antinuclear antibody (+) > 95%

Pathogenesis

1 Vasculopathy of small artery and capillary

- endothelial cell injury

- adhesion and activation of platelet

- aberrant regulation of fibroblast cell growth

- increased production of extracellular matrix

(collagen, fibronectin, and glycosaminoglycan)

- thickening of the skin & fibrosis of internal organs

Vascular abnormalities

1) Raynaud's phenomenon

- cold hands and feet

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

- induced by cold temperature or emotional stress

- initial complaint in 3/4 of patients

- 90% in patients with skin change

(prevalence in the general population: 4-15%)

2) digital ischemic injury

Raynaud’s phenomenon

Causes of Raynaud’s

Occlusive arterial disease

Rheumatic

diseases:Scleroderma,CREST,MCTD,SLE ,RA, Myositis

Repetitive vascular injury

Hyperviscosity

:Polycythemia,Cryoglobulinemia

Thoracic outlet syndrome

Telangiectasia

• local disruption of

angiogenesis

• blanched by pressure

Dilated capillaries seen

over the face

2) firm, thickened bound to underlying soft tissue

3) decrease in range of motion, loss of facial expression,

inability to open mouth fully, contractures

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

Edematous phase

Skin Induration

Acrosclerosis

Skin changes,and flexion contactures

Facial changes

Tight, thin lips with vertical perioral furrows

Salt and pepper pigmentation

Musculoskeletal system

• Polyarthritis and flexion contracture

• Muscle weakness and atrophy (primary /secondary)

Terminal digit resorption

Digital pitting scars

CREST syndrome:

calcinosis cutis

Calcinosis and acrolysis

Acrolysis

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

Pulmonary fibrosis

Interstitial Lung disease

Pathogenesis of PAH

Disease of the small arteries and arterioles of the pulmonary circulation

Imbalance between mediators of

vasoconstriction and proliferation

Over expression of endothelin-1, serotonin and thromboxane A2

Under expression of prostacyclin and

prostacyclin synthase , nitric oxide and nitric

oxide synthase

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

Renal crises and hypertension

in scleroderma

Major complication

Early in disease first few years

Acute onset hypertension

Renal impairment

Microangiopathic hemolytic

anemia,Thrombocytopenia

Renal failure can be reversible if BP treated

Drug of choice Angiotensin converting enzyme inhibitor

Kidney arteriogram

Exocrine glands

– Xerostomia

– xerophthalmia

Developedduring pregnancy

Not recorded

n=101

It is possible that patients with

Scleroderma can achieve pregnancy although there is increased sub-

fertility in such patients

There are conflicting reports about the increased abortion rate.

•It can not be predicted as available evidence is very limited

•Third trimester is the dangerous period with the risks

of rapidly developing hypertension, renal failure and

of interruption of pregnancy

•Reflux esophagitis may increase

•Small bowel involvement may cause malabsorption /

•Changes of pregnancy may cause increased

constipation in already diseased large bowel

Most of the times, baby is born healthy

Parents should be informed that the risks are certainly greater that baby might be growth effected or born

with congenital anomalies due to underlying maternal visceral involvement and the treatment she had been taking during pregnancy

Pre-pregnancy advice:

Ante-natal care:

Complete evaluation early in the pregnancy

Fortnightly antenatal examination until 3rd

trimester and thereafter weekly

If there is evidence of Renal disease, Pulmonary hypertension or myocardial fibrosis -

Termination of Pregnancy should be offered

Post Natal Management:

Postnatal period should be monitored carefully as acute hypertension with renal and cardiac failure may occur

Anticentromere antibody positive in

CREST and limited scleroderma

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

* one major or 2 or more minor criteria for diagnosis

Treatment

A wide spectrum of clinical manifestations and severity

- spontaneous improvement occurs frequently

• Disease modifying interventions (?)

- penicillamine

- methotrexate

- immunosuppressive agent: cyclosporin, IFN-

- recombinant human relaxin

• Symptomatic (organ-specific) treatment

Treatment

Skin thickening

– No clinically significant effect of any treatment – D Penicillamine – used in the past but

controlled studies show no benefit

– MTX – some benefit in small studies

– Oral cytoxan – benefit seen but risk to benefit ratio needs to be assessed carefully

Treatment

Raynauds

– Behavioral

Maintain warmth of digits

Maintain warmth of body

Avoid aggravating factors

– Smoking

– Drugs – OTC decongestants

Treatment

Raynauds

– Direct vasodilators

Calcium channel blockers

Alpha adrenergic inhibitors

Endothelial receptor blockers - Bosentan

Anticoagulants and low dose aspirin

Treatment

Ulcers

– Optimize raynauds treatment

– Antibiotics

– Endothelian receptor blocker – Bosentan is

associated with a 50% reduction in the development

of new digital ulcers

– In cases of critical ischemia

Parenteral prostacyclin

PDE5 inhibitor – Sildenafil

Endothelin receptor blocker

Selective digital sympathectomy

Cervical sympathetic block

Treatment

ILD

– Oral cytoxan at 2mg/kg with oral prednisone particularly in patients with evidence of

alveolitis ie inflammation > fibrosis

– Supplemental Oxygen to maintain Spo2 > 90%

– Pulmonary rehab

Treatment of PAH

Endothelin receptor antagonist

Phosphodiesterase 5 inhibitor

PGI2 ( Prostacyclin) and analogues

Vasodilators – response extremely rare in

CTD associated PAH

Treatment of PAH

Endothelin receptor antagonist

– Dual ETA / ETB receptor antagonist

Bosentan

– Selective ETA receptor antagonist

Situxentan and ambrisentan are in phase three clinical trials

Treatment

For patients with aggressive disease

– High dose immunosuppressive therapy with autologous hematopoietic stem cell transplant

92% complete or partial remision

35% relapse rate within one yr

9% transplant related mortality

Scleroderma cyclophosphamide or transplant trial

Prognosis

Mortality

– Diffuse SSc mortality is 5 to 10 fold higher

– Limited SSc mortality is 2 fold higher

80% of deaths attributable to ILD and PAH Risk factors

– Extent of skin involvement

– Severity of sclerosis

– Presence of pulmonary HTN

Limited SSc

– 2 yr survival without PAH – 80%

– 2 yr survival with PAH – 40%

Thank you very much for your attention!