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Systemic Sclerosis (Scleroderma)

Systemic Sclerosis (Scleroderma). N.Movaffagh MD Rheumatologist. Systemic sclerosis ( SSc ) is an uncommon connective tissue disorder characterized by multisystem involvement, heterogeneous clinical manifestations.

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Systemic Sclerosis (Scleroderma)

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  1. Systemic Sclerosis (Scleroderma) N.Movaffagh MD Rheumatologist

  2. Systemic sclerosis (SSc) is an uncommon connective tissue disorder characterized by multisystem involvement, heterogeneous clinical manifestations.

  3. The early stage of the disease is associated with prominent inflammatory features. • Over time, functional and structural alterations in multiple vascular beds and progressive visceral organ dysfunction due to fibrosis dominate the clinical picture.

  4. Although thickened skin (scleroderma) is the distinguishing hallmark of SSc, skin induration can occur in localized forms of scleroderma and other disorders

  5. SSc grouped into : • diffuse cutaneous • limited cutaneous

  6. Diffuse cutaneousSSc (dcSSc) • extensive skin induration • starting in the fingers • ascending from distal to proximal limbs and the trunk • Often have early interstitial lung disease and acute renal involvement

  7. limited cutaneousSSc (lcSSc) • skin involvement limited to the fingers(sclerodactyly) distal limbs, and face • trunk is not affected

  8. CREST syndrome • calcinosis cutis • Raynaud’s phenomenon • Esophageal dysmotility • sclerodactyly • Telangiectasia

  9. lcSSc • Visceral organ involvement (insidious progression) • pulmonary arterial hypertension (PAH) • interstitial lung disease • hypothyroidism • primary biliary cirrhosis

  10. SSc sine scleroderma • Raynaud’s phenomenon and other characteristic features of SSc occur in the absence of skin thickening

  11. EPIDEMIOLOGY • acquired sporadic disease • worldwide distribution • affecting all races • prevalence of 286 cases per million • incidence is estimated at 9–19 cases per million per year(United States)

  12. Important factor in disease susceptibility: • Gender • Age • Ethnicity

  13. EPIDEMIOLOGY • female:male 4.6: 1 • Increase in the childbearing years • declines after menopause • peak age of disease onset : 30–50 years

  14. EPIDEMIOLOGY • incidence is higher in blacks than whites, and disease onset occurs at an earlier age • blacks with SScare more likely to have diffuse cutaneous disease associated with interstitial lung involvement and a worse prognosis

  15. GENETIC CONSIDERATIONS • Genetic associations identified to date make only a small contribution to disease susceptibilit y • Concordance rates for SSc are low in monozygotic twins • concordance for ANA positivity is significantly higher

  16. The risk of Raynaud’s phenomenon, ILD and other autoimmune diseases, including SLE ,RAand autoimmune thyroiditisis increased • associations with multiple gene variants, many related to B and T lymphocyte activation (…PTPN22) • MHC locus alleles, non-HLA-linked genes(STAT4…)

  17. ENVIRONMENTAL AND OCCUPATIONAL RISK FACTORS • infectious agents(EBV, hCMV) • intestinal microbiota • occupational, dietary, and drug exposures

  18. molecular mimicry as a possible mechanistic link between hCMV infection and SSc • toxic oil syndrome (contaminated rapeseed oils) • eosinophilia-myalgia syndrome or EMS( consumption of l-tryptophan-containing dietary supplements)

  19. Occupational exposures: • silica dust • polyvinyl chloride • aromatic hydrocarbons (including toluene and trichloroethylene) • Drugs:bleomycin, pentazocine, and cocaine, and appetite suppressants

  20. PATHOGENESIS • Three cardinal pathophysiologic processes: • (1) diffuse microangiopathy • (2) inflammation and autoimmunity • (3) visceral and vascular fibrosis

  21. Humoral Autoimmunity • B cells also present antigen, secrete IL-6 and TGF-β, and modulate T cell and dendritic cell function.

  22. regulatory T cells is elevated in SSc, their immunosuppressive function is defective.

  23. MICROANGIOPATHY • clinical sequelae: • Raynaud’s phenomenon • ischemic digital ulcers • scleroderma renal crisis • PAH

  24. Raynaud’s phenomenon • an early disease manifestation • Altered blood-flow response to cold challenge • Association with autonomic and peripheral nervous system alterations including : • 1.impaired production of the neuropeptidecalcitonin gene-related peptide from sensory afferent nerves • 2.heightened sensitivity of α2-adrenergic receptors on vascular smooth-muscle cells

  25. FIBROSIS • distinguishing feature of SSc, is characterized by: • progressive replacement of normal tissue architecture with dense, stiff, and acellular connective tissue.

  26. FIBROSIS • fibrotic mediators such as: • hypoxia,ROS, thrombin Wnt ligands lysophosphatidic acid CTGF, PDGF endothelin-1

  27. Myofibroblasts: • contribute to scar formation via production of collagen and TGF-β

  28. PATHOLOGY • pathologic hallmark of SSc is: • capillary loss and obliterativemicroangiopathy

  29. early disease: lymphocytes, perivascular inflammatory cell composed of T cell, monocytes/macrophages, plasma cells, mast cells, and occasionally B cells • late disease: • obliterativevasculopathy

  30. SKIN • Collagen fiber accumulation is most prominent in the reticular dermis • Intradermal adipose layer is diminished • Epidermis is atrophic

  31. LUNG • The most common histologic pattern in SSc-associated ILD is: NSIP

  32. GASTROINTESTINAL TRACT • lower esophagus: • atrophy of the muscular layers and characteristic vascular lesions • Upper third of the esophagus is generally spared

  33. KIDNEY • vascular lesions affecting the interlobular and arcuate arteries predominate • Acute scleroderma renal crisis is associated with: • thrombotic microangiopathic pathology

  34. thrombotic microangiopathy • reduplication of elastic lamina • marked intimal proliferation • narrowing of the lumen in small renal arteries • accompanied by thrombosis and hemolysis

  35. HEART • involvement of the myocardium and pericardium • Fibrosis of the conduction system is common • especially at the sinoatrial node • the frequency of atherosclerotic coronary artery disease is comparable to the general population

  36. INITIAL CLINICAL PRESENTATION • dcSSc : • Raynaud’s phenomenon • interval between Raynaud’s phenomenon and onset of other disease manifestations is typically brief (weeks to months) • dcSSc have edematous” &“fibrotic” phase • Soft tissue swelling and intense pruritus are signs of the early inflammatory “edematous” phase

  37. fingers, hands, distal limbs, and face are usually affected first • Diffuse skin hyperpigmentation and carpal tunnel syndrome • Arthralgias, muscle weakness, fatigue, and decreased joint mobility are common

  38. “fibrotic” phase compose of : • skin induration associated with hair loss reduced production of skin oils decline in sweating capacity

  39. The initial 4 years from disease onset is the period of rapidly evolving pulmonary and renal damage

  40. LcSSc : course of lcSSc is characteristically more indolent • interval between Raynaud’s phenomenon and onset of manifestations such as GERD, cutaneous telangiectasia or soft tissue calcifications can be several years • scleroderma renal crisis and severe pulmonary fibrosis are uncommon

  41. lcSSc have overlap with: Keratoconjunctivitissicca polyarthritis cutaneous vasculitis biliary cirrhosis

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