Scleroderma - PDF Document

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  1. Scleroderma Edward Dwyer, M.D. Division of Rheumatology Scleroderma

  2. Nomenclature Synonyms Scleroderma Progressive Systemic Sclerosis Systemic Sclerosis Scleroderma

  3. Scleroderma ? Chronic systemic autoimmune disease characterized by fibrosis of the skin as well as internal organs, e.g., lung, heart, gastrointestinal tract, and kidneys. Scleroderma

  4. Limited vs. Diffuse Scleroderma ? Cutaneous criteria: ? Limited: involves skin distal to elbows and knees, as well as face ? Diffuse: involves skin of proximal extremities and face, as well as trunk ? Implications regarding natural history and prognosis Scleroderma

  5. Mortality in Scleroderma ? Limited scleroderma ? 90% 5-year survival ? 75% 10-year survival ? Diffuse scleroderma ? 70% 5-year survival ? 50% 10-year survival Scleroderma

  6. Swollen Digits in Scleroderma Scleroderma

  7. Sclerodactyly Scleroderma

  8. Scleroderma Facial Appearance Scleroderma

  9. Diffuse Scleroderma Scleroderma

  10. Dermatopathology Excessive Dermal Deposition of Collagen and ECM proteins Scleroderma

  11. Raynaud’s Phenomenon ? Early manifestation of disease in >97% of scleroderma patients, preceding sclerodactyly by months to years ? Vasospasm of the digital microvasculature resulting in: ? Digital ischemia (pallor) ? Digital hypoxia (cyanosis) ? Digital reactive hyperemia (erythema) Scleroderma

  12. Raynaud’s Phenomenon Scleroderma

  13. Raynaud’s Phenomenon Scleroderma

  14. Digital Arteriogram in Raynaud’s Disease Scleroderma

  15. Digital Capillary Microscopy in Scleroderma Normal Capillary dilatation Capillary “dropout” Scleroderma

  16. Facial Telangiectasias in Limited Scleroderma Scleroderma

  17. Epidemiology of Scleroderma ? Incidence: 2 per 100,000 ? Prevalence: 25-75 per 100,000 ? Sex: F:M 3:1 ? Racial Distribution ? Occurs in all populations ? African Americans > Caucasians (2:1) ? Choctaw Native Americans (Oklahoma) • Prevalence: 450 per 100,000 Scleroderma

  18. Autoantibodies in Scleroderma ? > 98% exhibit antinuclear antibodies (+ANA) ? Limited Scleroderma ? 60-70% exhibit anticentromere Ab ? Diffuse scleroderma ? 30% exhibit antitopoisomerase 1 Ab (anti-Scl 70 Ab) ? 20-30% exhibit anti-RNA polymerase Ab Scleroderma

  19. Autoantibodies in Scleroderma Anti-PDGF Receptor Antibodies Tan F. N Engl J Med 2006;354:2709-2711 Scleroderma

  20. Immunogenetics of Scleroderma ? HLA associations: ? Limited scleroderma (anticentromere Ab) • HLA-DRβ1*0101 • HLA-DQβ1*0501 ? Diffuse scleroderma (antitopoisomerase 1 Ab) • HLA-DRβ1*1101 (African Americans, Caucasians) • HLA-DRβ1*1104 (African Americans, Caucasians) • HLA-DQβ1*0301 (African Americans, Caucasians) • HLA-DRβ1*1502 (Japanese) • HLA-DRβ1*1602 (Choctaw Native Americans) Scleroderma

  21. Pathogenesis of Scleroderma ? Endothelial activation ? Vasospasm in Raynaud’s disease ? Immune activation ? B cells and autoantibody generation ? T cells and HLA associations ? Macrophages and cytokine secretion • TGF-β, PDGF, TNFα, IL-1 ? Fibroblast activation ? Tissue fibrosis by excessive collagen deposition Scleroderma

  22. Pathogenesis of Scleroderma Scleroderma

  23. Limited vs. Diffuse Scleroderma Limited Scleroderma Diffuse Scleroderma ? Kidney ? Acute renal failure 2° renovascular hypertension ? Pulmonary ? Pulmonary ? Pulmonary Hypertension ? Kidney disease uncommon ? Heart disease uncommon ? Gastrointestinal ? Pulmonary Hypertension ? Pulmonary Fibrosis ? Heart ? Esophageal dysmotility and gastroesophageal reflux disease ? Myocardial Fibrosis ? Gastrointestinal ? Esophageal dysmotility and gastroesophageal reflux ? Gastroparesis ? Small bowel stasis and bacterial overgrowth ? Colonic diverticular disease Scleroderma

  24. Kidney Disease in Diffuse Scleroderma ? Renovascular disease causing hypertensive crisis resulting in acute renal insufficiency ? Usually an early manifestation Scleroderma

  25. Renal Arteriogram Normal Scleroderma Scleroderma

  26. Scleroderma Kidney Infarctions Scleroderma

  27. Kidney Histopathology vessel lumen occlusion Scleroderma

  28. Approach to Scleroderma Kidney Diseasae ? Prophylactic administration of Angiotensin Converting Enzyme Inhibitors (ACE inhibitors) ? Prior to ACE inhibitors: >90% mortality within one year ? After ACE inhibitors: >60% survival after 10 years Scleroderma

  29. Pulmonary Disease* ? Parenchymal involvement (interstitial lung disease) ? Pulmonary fibrosis ? Vascular involvement ? Pulmonary hypertension *Major cause of mortality in Scleroderma Scleroderma

  30. Pulmonary Fibrosis Scleroderma

  31. Pulmonary Fibrosis Chest CT scan Scleroderma

  32. Interstitial Lung Disease Scleroderma

  33. Pulmonary Artery Involvement Scleroderma

  34. Therapy of Pulmonary Hypertension ? Calcium channel blockers (e.g., diltiazem) ? Endothelin receptor blockers ? Bosentan (Tracleer) ? Ambrisentan (Letairis) ? Phosphodiesterase 5 inhibitor ? Sildenafil (Revatio) ? Prostacyclin analogs ? Epoprostenol (Flolan) intravenous ? Treprostinil (Remodulin) intravenous ? Iloprost (Ventavis) inhalation Scleroderma

  35. Therapy of Interstitial Lung Disease ? Corticosteroids plus cyclophosphamide? ? Autologous stem cell transplant? Scleroderma

  36. Gastrointestinal Involvement ? Principal cause of symptoms is a fibrosing process of the medial layer of the GI tract resulting in the replacement of smooth muscle with collagen ? Can involve the entire gastrointestinal tract ? Significant cause of morbidity in scleroderma Scleroderma

  37. Esophageal Involvement ? Esophageal Dysmotility ? Dysphagia ? Gastroesophageal Reflux due to incompetence of the lower esophageal sphincter ? Dyspepsia or heartburn Scleroderma

  38. Esophageal Disease Scleroderma

  39. Esophageal Histopathology Scleroderma

  40. Duodenal Histopathology Brunner’s glands Scleroderma

  41. Normal GI Manometry Scleroderma

  42. GI Manomety in Scleroderma Scleroderma

  43. Small Intestine Involvement ? Hypomotility ? Stasis of intestinal contents ? Bacterial Overgrowth ? Malabsorption ? Pseudo-obstruction ? Abdominal pain Scleroderma

  44. Dilatation of Proximal Jejunum Scleroderma

  45. Large Intestine Involvement ? Diverticuli ? Perforation ? Hypomotility ? Constipation ? Pseudo-obstruction ? Abdominal pain Scleroderma

  46. Colonic Diverticuli Scleroderma

  47. Colonic Diverticuli Scleroderma

  48. Approach to Gastrointestinal Disease ? Gastroesophageal reflux ? Antisecretory agents, e.g., proton pump inhibitors ? Malabsorption 2° to bacterial overgrowth ? Antibiotic therapy ? Hypo- or dysmotility related symptoms ? Symptom control • e.g., constipation ? laxatives Scleroderma

  49. Scleroderma Edward Dwyer, M.D. Division of Rheumatology Scleroderma