Scleroderma
SclerodermaEdward Dwyer, M.D.
Division of Rheumatology
Scleroderma
Scleroderma
Progressive Systemic Sclerosis
Systemic Sclerosis
Nomenclature Synonyms
Scleroderma
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
Limited vs. Diffuse Scleroderma
Cutaneous criteria:
Limited: involves skin distal to elbows and knees, as well as faceDiffuse: involves skin of proximal extremities and face, as well as trunk
Implications regarding natural history and prognosis
Scleroderma
Mortality in Scleroderma
Limited scleroderma90% 5-year survival75% 10-year survival
Diffuse scleroderma70% 5-year survival50% 10-year survival
Scleroderma
Swollen Digits in Scleroderma
Scleroderma
Sclerodactyly
Scleroderma
Scleroderma Facial Appearance
Scleroderma
Diffuse Scleroderma
Scleroderma
Dermatopathology
Excessive Dermal Deposition of Collagen and ECM proteins
Scleroderma
Raynaud’s PhenomenonEarly 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
Raynaud’s Phenomenon
Scleroderma
Raynaud’s Phenomenon
Scleroderma
Digital Arteriogram in Raynaud’s Disease
Scleroderma
Digital Capillary Microscopy in Scleroderma
Normal Capillary dilatation Capillary “dropout”
Scleroderma
Facial Telangiectasias in Limited Scleroderma
Scleroderma
Epidemiology of SclerodermaIncidence: 2 per 100,000
Prevalence: 25-75 per 100,000
Sex: F:M 3:1
Racial DistributionOccurs in all populationsAfrican Americans > Caucasians (2:1)Choctaw Native Americans (Oklahoma)
• Prevalence: 450 per 100,000
Scleroderma
Autoantibodies in Scleroderma> 98% exhibit antinuclear antibodies (+ANA)
Limited Scleroderma60-70% exhibit anticentromere Ab
Diffuse scleroderma30% exhibit antitopoisomerase 1 Ab (anti-Scl 70 Ab)20-30% exhibit anti-RNA polymerase Ab
Scleroderma
Tan F. N Engl J Med 2006;354:2709-2711
Anti-PDGF Receptor Antibodies
Autoantibodies in Scleroderma
Scleroderma
Immunogenetics of SclerodermaHLA 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
Pathogenesis of SclerodermaEndothelial activation
Vasospasm in Raynaud’s disease
Immune activationB cells and autoantibody generationT cells and HLA associationsMacrophages and cytokine secretion
• TGF-β, PDGF, TNFα, IL-1
Fibroblast activationTissue fibrosis by excessive collagen deposition
Scleroderma
Pathogenesis of Scleroderma
Scleroderma
Limited vs. Diffuse SclerodermaLimited Scleroderma Diffuse Scleroderma
KidneyAcute renal failure 2°renovascular hypertension
PulmonaryPulmonary HypertensionPulmonary Fibrosis
HeartMyocardial Fibrosis
GastrointestinalEsophageal dysmotility and gastroesophageal refluxGastroparesisSmall bowel stasis and bacterial overgrowthColonic diverticular disease
PulmonaryPulmonary Hypertension
Kidney disease uncommonHeart disease uncommonGastrointestinal
Esophageal dysmotility and gastroesophageal reflux disease
Scleroderma
Kidney Disease in Diffuse Scleroderma
Renovascular disease causing hypertensive crisis resulting in acute renal insufficiency
Usually an early manifestation
Scleroderma
Renal Arteriogram
Normal Scleroderma
Scleroderma
Scleroderma Kidney Infarctions
Scleroderma
Kidney Histopathology
vessel lumen occlusion
Scleroderma
Approach to Scleroderma Kidney Diseasae
Prophylactic administration of AngiotensinConverting Enzyme Inhibitors (ACE inhibitors)
Prior to ACE inhibitors: >90% mortality within one year
After ACE inhibitors: >60% survival after 10 years
Scleroderma
Pulmonary Disease*Parenchymal involvement (interstitial lung disease)
Pulmonary fibrosis
Vascular involvementPulmonary hypertension
*Major cause of mortality in Scleroderma
Scleroderma
Pulmonary Fibrosis
Scleroderma
Pulmonary Fibrosis
Chest CT scan
Scleroderma
Interstitial Lung Disease
Scleroderma
Pulmonary Artery Involvement
Scleroderma
Therapy of Pulmonary HypertensionCalcium channel blockers (e.g., diltiazem)
Endothelin receptor blockersBosentan (Tracleer)Ambrisentan (Letairis)
Phosphodiesterase 5 inhibitorSildenafil (Revatio)
Prostacyclin analogsEpoprostenol (Flolan) intravenousTreprostinil (Remodulin) intravenousIloprost (Ventavis) inhalation
Scleroderma
Therapy of Interstitial Lung Disease
Corticosteroids plus cyclophosphamide?
Autologous stem cell transplant?
Scleroderma
Gastrointestinal Involvement
Principal cause of symptoms is a fibrosingprocess 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
Esophageal Involvement
Esophageal DysmotilityDysphagia
Gastroesophageal Reflux due to incompetence of the lower esophageal sphincter
Dyspepsia or heartburn
Scleroderma
Esophageal Disease
Scleroderma
Esophageal Histopathology
Scleroderma
Duodenal Histopathology
Brunner’s glands
Scleroderma
Normal GI Manometry
Scleroderma
GI Manomety in Scleroderma
Scleroderma
Small Intestine Involvement
HypomotilityStasis of intestinal contents
Bacterial OvergrowthMalabsorption
Pseudo-obstructionAbdominal pain
Scleroderma
Dilatation of Proximal Jejunum
Scleroderma
Large Intestine Involvement
DiverticuliPerforation
HypomotilityConstipation
Pseudo-obstructionAbdominal pain
Scleroderma
Colonic Diverticuli
Scleroderma
Colonic Diverticuli
Scleroderma
Approach to Gastrointestinal DiseaseGastroesophageal reflux
Antisecretory agents, e.g., proton pump inhibitors
Malabsorption 2° to bacterial overgrowthAntibiotic therapy
Hypo- or dysmotility related symptomsSymptom control
• e.g., constipation laxatives
Scleroderma
SclerodermaEdward Dwyer, M.D.
Division of Rheumatology