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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