XƠ CỨNG BÌ 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 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 Epidemiology Prevalence: Rare disease 4-12 new cases per million per year prevalence of 19-75/100,000 Susceptibility: host factor age - peak occurrence: age 35-65 years rare in children gender - female : male = 3-12 : genetic background: Classification Scleroderma Localized Scleroderma Morphea Linear Scleroderma Systemic Scleroderma (Systemic Sclerosis) Limited Scleroderma Diffuse Scleroderma Sine Scleroderma Limited and Diffuse SSc— Skin Involvement Limited Diffuse 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 - calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia Diffuse Cutaneous Widespread with early involvement of internal organs Raynaud’s phenomenon Truncal and acral skin involvement Absent for anti-centromere antibody Nailfold capilaroscopy—capillary dilatation and destruction Diffuse Cutaneous Associated with substantial morbidity and mortality resulting from— – Vascular dysfunction – Organ fibrosis and inflammation – Gastrointestinal dysmotility – Myocardial involvement 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 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 NTG / nitrate patches Losartan - ARB – Perfusion enhancing Pentoxifylline, cilostazol, serotonin reuptake inhibitors – Endothelial integrity 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 GI Tract – Aggressive treatment of reflux – Prokinetic agents – Rotating Abx for malabsorption secondary to bacterial overgrowth Treatment Scleroderma renal crisis – Strict monitoring of BP – Avoid high dose steroids - > 15mg – ACEI is first line treatment – Dialysis – Renal transplant 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 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 of PAH Phosphodiesterase inhibitor – Sildenafil marketed as Revatio Prostacyclin analogues – Epoprostenol Continuous IV infusion – Treprostinil SQ or IV infusion – Iloprost Inhalation 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 quite variable and difficult to predict cumulative survival diffuse limited yr 70% 90% 10 yr 50% 70% major cause of death 1) renal involvement 2) cardiac involvement 3) pulmonary involvement Prognosis Mortality – Diffuse SSc mortality is to 10 fold higher – Limited SSc mortality is 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 – yr survival without PAH – 80% – yr survival with PAH – 40% Prognosis Causes of death in SSc – – – – – – – PAH : 30% Pulmonary fibrosis : 28% Cardiac : 11% Renal : 9% G.I : 7% Multiorgan : 11% Other : 3% Thank you very much for your attention! [...]... 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,... Abnormal motility Diverticula • Barium enema study - multiple widemouthed diverticula of colon - broad base and neck - usually asymptomatic Diverticula 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) 3) Complains - dry cough, breathlessness... arteries - proximal vessels, arcades and metacarpal vessels are widely patent 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 Skin involvement... 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)... 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 Raynaud’s phenomenon Raynaud’s phenomenon • Arteriogram... cough, breathlessness 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) 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 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 ... capillaroscopy—dilated capillary loops * CREST syndrome - calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia Diffuse Cutaneous Widespread with early involvement... of Raynaud’s Occlusive arterial disease Rheumatic diseases:Scleroderma,CREST,MCTD,SLE ,RA, Myositis Repetitive vascular injury Hyperviscosity :Polycythemia,Cryoglobulinemia Thoracic outlet syndrome... substantial morbidity and mortality resulting from— – Vascular dysfunction – Organ fibrosis and inflammation – Gastrointestinal dysmotility – Myocardial involvement Etiology Environmental factors