scleroderma (diffuse cutaneous systemic sclerosis)

Introduction

A systemic disorder of unknown etiology characterized by thickening & hardening of the skin & visceral organs, risk of hypertensive renal crisis, & shortened survival. The CREST syndrome represents a limited form of scleroderma.

Etiology

• unknown
• autoimmune
• agents which may induce some manifestations of scleroderma
  • exposure to polyvinyl chloride (PVC)
  • exposure to silica (coal miners)
  • bleomycin

Pathology

• microangiopathy & fibrosis of skin & visceral organs
• arterial vasospasm of small arteries, arterioles
  • repeated episodes of ischemia-reperfusion injury
  • fibrosis
  • Raynaud's phenomenon
• gastrointestinal
  • atrophy & fibrosis of smooth muscle from pharynx to colon
  • lower esophageal sphincter incompetence
  • esophageal dysmotility, esophageal hypomotility
  • esophageal strictures
  • enteric telangiectasias
  • gastric antral venous ectasia
• myocardial fibrosis
• microangiopathic hemolytic anemia
• skin:
  • thickening of reticular dermis with excessive collagen deposition
  • atrophy of papillar dermis & epidermal rete pegs
  • cutaneous vessels show intimal proliferation, collagen deposition in the vessel wall & mild perivascular inflammation
• pulmonary:
  • diffuse interstitial fibrosis (75% at autopsy)
  • progressive restrictive lung disease

* histopathology images

Clinical manifestations

• skin (also see vascular)
  • skin thickening, tightening (induration)
  • millet size calcifications may develop
  • pruritus & ulceration may occur
  • distribution:
    • fingers (sclerodactyly), digital ulceration
      • nailfold capillary changes, pitting
    • dorsum of hand proximal to MCP joints
    • forearms, face, legs, trunk
    • limited disease involves face & skin distal to elbows & knees
    • diffuse disease involves skin proximal to elbows & knees
  • nail fold capillary changes
  • edema & erythema of the hands & forearms may precede induration in early scleroderma
  • salt & pepper skin changes described
    • areas of depigmentation with relative sparing ofvperifollicular areas & preservation of pigmentation overveins
• joints
  • joint contractures
  • synovitis (arthritis)
  • tendon sheath inflammation (tendonitis)
• vascular
  • most manifestations have a vascular basis
  • vasculitis is rare
  • Raynaud's phenomenon (95%)
    • initial presentation in 70% of patients
    • absence of Raynaud's phenomenon should prompt consideration of another diagnosis
  • telangiectasias on hands, cheeks & lips are common
  • nail fold capillary changes
  • microangiopathic hemolytic anemia
• cardiac
  • conduction disturbances & arrhythmias
  • congestive heart failure
  • coronary vasospasm
  • accentuated P2 heart sound
  • may be asymptomatic (for heart disease)
  • myocardial fibrosis
  • pericardial disease
• pulmonary (80%)
  • pulmonary basilar crackles
  • diffuse interstitial fibrosis (75% at autopsy)
  • pulmonary hypertension (50%)
  • cor pulmonale
  • pulmonary complications are more severe in the CREST syndrome
  • aspiration pneumonia secondary to esophageal dysfunction & gastroesophageal reflux
  • pleural involvement (pleurisy, pleural effusion) is rare
• renal
  • nephrosclerosis
  • hypertension, including hypertensive crisis
  • renal insufficiency
  • scleroderma renal crisis occurs almost exclusively in patients with early cutaneous disease
    • severe hypertension
    • renal failure
    • microangiopathic hemolytic anemia
• gastrointestinal (50-90%)
  • may precede skin manifestations of scleroderma
  • esophageal dysfunction is the most common visceral organ manifestation
    • reflux esophagitis (GERD)
    • esophageal strictures
    • esophageal dysmotility, dysphagia
  • upper GI bleed
    • gastric antral ectasia (also see complications)
  • decreased bowel motility
    • altered peristalsis due to fibrosis
  • bacterial overgrowth syndrome
    • blind loop syndrome
  • malabsorption
  • bloating
  • abdominal distension
  • diverticulosis
  • pseudotoxic megacolon
• myositis
• CREST syndrome

* images

Diagnostic criteria

• sclerodermatous skin changes that extend proximal to the MCP joints or
• 2 of the following
  • sclerodactyly
  • digital pitting
  • basilar fibrosis visible of chest X-ray

Laboratory

• serology for autoantibodies
  • antinuclear antibodies (ANA)
    • present in about 95% of patients
    • usually speckled or homogenous pattern
    • nucleolar & centromere patterns, less common, but more specific for systemic sclerosis
    • centromere pattern most common with limited cutaneous scleroderma
  • anti Scl-70 Ab
    • speckled pattern
    • 20-50% in diffuse scleroderma
    • associated with diffuse cutaneous disease & interstitial lung disease
    • associated with pulmonary fibrosis, cadiac fibrosis & poor prognosis
  • anti-centromere Ab (70-80% in CREST)
    • centromere pattern
    • Ab against kinetichore proteins
    • associated with diffuse cutaneous disease & pulmonary hypertension
  • anti RNA polymerase I (4-20%)
  • anti RNA polymerase II (4%)
  • anti RNA polymerase III (23%)
    • anti-POLR3C
  • fibrillarin Ab in serum (U3-snRNP Ab)
    • speckled pattern
    • associated with diffuse cutaneous disease, pulmonary hypertension & myositis
  • anti PM-ScL (PMSCL1, PMSCL2)
    • nucleolar pattern
    • associated with myositis
  • anti To
    • nucleolar pattern
    • associated with diffuse cutaneous disease & pulmonary hypertension
  • anti NOR-90
  • Sjogren's syndrome/scleroderma autoantigen 1
  • RPP38
• other autoantigens associated with scleroderma
  • SPOP, TEX101, EXOSC9, EXOSC10, RPP30, UBF1, SSSCA1,
• hypergammaglobulinemia (50%)
• complete blood count (CBC)
  • mild eosinophilia (5-10%)
  • anemia is generally mild
    • iron studies
    • serum folate, serum vitamin B12
• serum creatinine is generally normal in the absence of hypertension & renal crisis
• see ARUP consult

Diagnostic procedures

• pulmonary function testing (every 6-12 months)
  • progressive restrictive lung disease
  • low diffusion capacity (DLCO) is earliest manifestation
  • all patients at initial diagnosis
• echocardiogram to evaluate pulmonary artery pressure & to assess septal fibrosis or pericardial effusions (30% of patients have asymptomatic pericardial effusions)
  • annual monitoring for pulmonary hypertension in patients without interstitial lung disease
• right heart catheterization if further evaluation of pulmonary hypertension if needed
• upper gastrointestinal endoscopy if iron-deficiency anemia
• nailfold capillarioscopy can distinguish Raynaud's phenomenon secondary to systemic sclerosis from primary Raynaud's phenomenon

Radiology

• chest X-ray may show
  • adequate sensitivity to assess interstitial lung disease
  • basilar fibrosis
• high-resolution CT to evaluate
  • assess interstitial lung disease
  • alveolitis (may precede interstitial lung disease)
  • pulmonary fibrosis
• barium swallow if dysphagia

* images

Complications

• patients with limited cutaneous scleroderma confined to the face & distal extremities are at increased risk for pulmonary hypertension
• patients with diffuse cutaneous scleroderma are at increased risk for interstitial lung disease, serositis, & scleroderma renal crisis
• progressive diffuse parenchymal lung disease
  • interstitial pneumonitis
  • pulmonary fibrosis: 35% of scleroderma-related deaths
  • major cause of death in scleroderma
• cardiovascular & renal
  • systemic hypertension
    • sclerodermal renal crisis (glucocorticoids a risk factor)
      • do not use glucocorticoids to treat scleroderma
  • pulmonary hypertension: 26% of scleroderma-related deaths
  • cardiomyopathy due to coronary vasospasm, myocardial fibrosis
    • 5 year mortality 75%
    • 26% of scleroderma-related deaths
  • pericardial disease
• gastrointestinal
  • gastric antral ectasia -> GI bleed -> iron deficiency
  • intestinal bacterial overgrowth -> malabsorption -> vitamin B12 deficiency (serum folate is increased)
• pregnancy is associated with increased risk of miscarriage, preterm birth & intrauterine growth retardation
• increased 5 year risk for all-type of cancers vs general population

Differential diagnosis

• eosinophilic fasciitis
• eosinophilia myalgia syndrome
• scleroderma variants
  • morphea (localized cutaneous scleroderma)
  • limited cutaneous systemic sclerosis
  • systemic sclerosis sine scleroderma
  • CREST
• graft versus host disease
• mycosis fungoides
• primary biliary cirrhosis
• pulmonary hypertension, primary
  • idiopathic pulmonary fibrosis
• reflex sympathetic dystrophy
• mixed connective tissue disease
• nephrogenic systemic fibrosis
• Buschke scleredema
• scleromyxedema

Management

• No curative therapy
  • myeloablative autologous stem-cell transplantation for severe scleroderma with renal or pulmonary involvement may improve long-term event-free survival
• problem-oriented (organ-specific) approach
  • do not use glucocorticoids to treat scleroderma
• Raynaud's phenomenon
  • cessation of smoking
  • cold avoidance, central warmth
  • calcium channel blockers
  • anti-platelet agents, low-dose aspirin
  • prazosin losartan, sildenafil, topical nitrates
  • phenoxybenzamine, reserpine, guanethidine
  • bosentan may be useful for preventing recurrences of digital ulcers
  • intravenous epoprostenol for acutely ischemic digit(s)
  • sympathetic ganglion blockade for patients with digital ulceration that have failed conservative management
• skin
  • physical therapy
  • methotrexate, mycophenolate, cyclophosphamide
  • rituximab appears to be beneficial for both skin fibrosis & pulmonary function
  • antihistamines, low-dose prednisone for pruritus
  • penicillamine
  • laser therapy for telangiectasias
  • adipocyte transplantation (CPT)
• gastrointestinal
  • reflux esophagitis (GERD)
    • proton pump inhibitor (omeprazole, lansoprazole)
    • H2 receptor antagonists
    • sucralfate
    • promotility agent for diminished esophageal peristalsis: metoclopramide
    • Ca+2-channel antagonists may worsen reflux
    • lifestyle changes
    • fundoplication for patulous lower esophageal sphincter contraindicated
  • esophageal strictures - dilation
  • gastric antral vascular ectasia: laser ablation
  • gut motility, bloating & abdominal distension
    • metoclopramide, erythromycin
      • long-term therapy can cause tardive dyskinesia, limit therapy to 12 weeks
    • octreotide for ileus
  • bacterial overgrowth
    • rotating antibiotics: tetracycline, metronidazole
    • cholestyramine for fat malabsorption
  • correct iron deficiency
  • correct folate deficiency, vitamin B12 deficiency
  • fiber, polyethylene glycol, &/or senna for constipation
• renal
  • aggressive blood pressure control with ACE inhibitor
  • high-dose glucocorticoids increase risk of renal crisis
  • ACE inhibitor for renal crisis regardless of serum creatinine
  • ACE inhibitor for renal insufficiency
  • hemodialysis as needed
• cardiovascular
  • standard therapies for specific problems
  • ACE inhibitor for hypertension
  • vasodilators for pulmonary artery hypertension
    • phosphodiesterase-5 inhibitors
    • prostacyclin analogues
    • endothelin receptor antagonists
• pulmonary
  • standard therapies for specific problems
  • treatment of pulmonary alveolitis with mycophenolate or cyclophosphamide may improve symptoms & delay progression of interstitial lung disease
  • rituximab appears to be beneficial for both skin fibrosis & pulmonary function
  • pulmonary hypertension
    • supplemental oxygen
    • treat right-sided heart failure
    • prostanoids, endothelin receptor antagonists, PDE5 inhibitors, soluble guanylate cyclase inhibitors (nitric oxide inhibitors)
  • lung transplantation
  • glucocorticoids may increase risk for scleroderma renal crisis
• arthritis, tendonitis & myositis
  • weekly methotrexate
  • prednisone
• pregnancy is high risk
  • increased risk of small full-term infants
  • increased risk of premature births
  • avoid pregnancy in women with pulmonary hypertension or severe restrictive lung disease
• prognosis:
  • progressive disease
  • 45% 10 year survival for diffuse form

More general terms

• systemic sclerosis

More specific terms

• scleroderma in pregnancy
• scleroderma renal crisis

Additional terms

• CREST syndrome
• morphea; localized cutaneous scleroderma; linear scleroderma
• scleredema (Buschke disease)
• scleromyxedema; lichen myxedematosus; papular mucinosis
• systemic sclerosis sine scleroderma

Patient information

scleroderma patient information