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A. Characteristics

  1. Chronic disease of diffuse fibrosis and degenerative changes
  2. Sclerosis of skin, articular structures and internal organs, particularly GI tract
  3. Skin Changes
    1. Sclerodactyly - involvement distal to MCP joints
    2. Acrosclerosis - involvement distal to elbows and knees
    3. Diffuse Scleroderma - generalized involvement
  4. Categories of Disease
    1. Diffuse Scleroderma - progressive systemic sclerosis (PSS)
    2. Limited Scleroderma - formerly called CREST syndrome
    3. Localized Scleroderma-like Disease
  5. Raynaud phenomenon is most common complaint
  6. Uncommon disease, prevalence <25 per 100,000 population (~25,000 patients in USA)
  7. No association or increased risk with breast implants, including silicone types [3]

B. Disease Categories

  1. Limited Scleroderma (CREST Syndrome)
    1. Calcinosis, Raynaud's, Esophageal dysfunction, Sclerodactyly, Telangiectasia
    2. Usually occurs in older patients
    3. Pulmonary hypertension ("Pulmonary Raynaud's", P-HTN) quite common [4]
    4. Associated with anti-centromere antibodies
  2. Progressive Systemic Sclerosis (Diffuse Scleroderma)
    1. May involve any organ in the body
    2. Usually occurs in younger patients
    3. True scleroderma begins in hands (feet) and may progress proximally
    4. Later stages with prominent P-HTN usually due to pulmonary fibrosis
    5. Associated with anti-topoisomerase I antibodies
  3. Sclerodermatomyositis
    1. Tight skin and muscle weakness
    2. Indistinguishable from polymyositis except for autoantibodies (such as anti-Jo1 Abs)
    3. Mixed connective tissue disease (MCTD) may have similar features (anti-U1 RNP Abs)
  4. Undifferentiated Connective Tissue Disease (UCTD)
    1. Overlap syndrome usually with Raynaud's Disease
    2. Aspects of SLE, Myositis, Systemic Sclerosis
    3. Majority of patients progress to a more defined syndrome with 3-5 years
    4. May have pulmonary hypertension (HTN) [4]
  5. Scleredema
    1. Thick indurated skin
    2. Often truncal, back, shoulders, neck, face
    3. Unlike scleroderma, does not affect hands or have systemic symptoms
    4. May be associated with diabetes, hypothyroidism (scleromyxedema), multiple myeloma
    5. No association with known autoantibodies
  6. Scleromyxedema [21,22]
    1. Papular mucinous deposits, plaques and nodules can also occur
    2. Monoclonal paraproteinemia
    3. Dermal fibroblast proliferation with sclerotic skin, increased mucin
    4. Lymphoplasmacellular infiltrates
    5. Differentiate from myxedema associated with hypothyroidism (myxedema)
    6. Gastrointestinal, cardiac, pulmonary and neurologic symptoms can occur
  7. Morphea [22]
    1. Ivory colored, plaque-like distribution of indurated skin, erythematous border
    2. Localized lesions, usually on arms or shoulders, upper back
    3. Homogenized collagen, mucin normal
    4. May be associated with plasma cell dyscrasias, diabetes mellitus
    5. Usually resolves on its own
  8. Nephrogenic Systemic Fibrosis (NSF) [22,25,26]
    1. Previously called nephrogenic fibrosing dermopathy
    2. Scleroderma-like fibrotic disease with indurated plaques, hyperpigmentation, sclerodactyly
    3. Occurs in patients with end-stage renal disease (ESRD) from any cause
    4. Rare condition primarily in patients on dialysis (but some transplant or acute renal failure)
    5. Painful tightening of skin with tethering to underlying fascia
    6. Usually begins on hands and feet and extends proximally
    7. Woody induration, brawny hyperpigmentation, peau d'orange changes of skin
    8. Contractures of elbow, finger, knee and ankle; facial involvement not reported
    9. Skipped areas of induration with smooth transition to indurated plaques
    10. Hyperpigmentation very common
    11. Histology shows dermal CD34+ spindle-cell proliferation, variable mucin
    12. Must rule out scleromyxedema, ß2-microglobulin amyloidosis, systemic sclerosis
    13. Gadolinium contrast agents (Magnavist®, MultiHance®, Omniscan®, OptiMARK®, ProHance®) for MRI rarely can cause NSF in CRF patients [25]
    14. Typically relentless progressive disease leading to death
    15. If Gad must be used in patients with renal failure, dose should be substantially limited
    16. Unclear if dialysis following Gad use is of any benefit (syndrome is very rare)
    17. Reduce/eliminate Gad use in any patient with glomerular filtration rate <30cc/min
    18. Poorly treated; physical therapy and thalidomide may be helpful

C. Symptoms and Signs [1,2]

  1. Raynaud's Phenomenon
  2. Swelling of acral parts of extremities with joint dysfunction
  3. Thickening of skin over fingers, induration (symmetric)
  4. Gastrointestinal Tract Dysmotility
    1. One of major esophageal dysmotility disorders
    2. Reflux esophagitis with pain is major symptoms
    3. Small intestinal dysmotility may lead to obstruction or malabsorption
  5. Pulmonary Disease
    1. Lung Fibrosis - usually late stage but may occur early in aggressive disease
    2. Begins as inflammatory alveolitis and leads to fibrosis (fibrosing alveolitis)
    3. Pure P-HTN is more common in localized scleroderma (CREST Syndrome)
    4. Progressive severe P-HTN may occur leading to right sided heart failure
  6. Cardiac Disease
    1. Involvement of conduction system most common
    2. High grade heart block is sometimes seen
    3. Constrictive (pericardial) and/or restrictive cardiomyopathy develops later
    4. Right sided heart failure, Cor Pulmonale, death
  7. Renal Disease
    1. Renovascular HTN
    2. Renal Artery Stenosis
    3. Renal Crisis
  8. Renal Crisis [5]
    1. Acute increase in renin for unclear reasons
    2. Malignant HTN often develops
    3. Severe glomerular damage can occur
    4. Intravascular hemolysis with schizocytes and hemoglobinuria is found
  9. Calcinosis (Dystrophic Calcification)
    1. Pathological calcification of soft tissues
    2. Normal calcium and phosphate metabolism
    3. Found mainly in CREST (limited scleroderma)
    4. Occasionally found in systemic lupus erythematosus and polymyositis
  10. Thyroid Abnormalities
    1. Elevated levels of antithyroid antibodies
    2. Clinical and subclinical hypothyroidism common

D. Autoantibodies [2,6]

  1. Serum ANA (usually high titer) positive >90%
  2. Rheumatoid Factor (RF) Positive 33% of patients
  3. Autoantibodies in PSS
    1. Anti-RNA Polymerase III Abs 45% (associated with renal disease)
    2. Anti-Topoisomerase I (Anti-Scl70) Abs ~40% (highly specific for limited form)
    3. Anti-Centromere Abs 10%
    4. Anti-Endothelial Abs 80%
  4. Limited Scleroderma (CREST Syndrome)
    1. Anti-Centromere Abs 50-70% (highly specific for limited form)
    2. Anti-U1-RNP Abs ~35%
    3. Anti-Th/To Nucleolar Abs ~15%
    4. Anti-Endothelial Abs 40%
  5. Anti-centromere and andti-topoisomerase I are found together in <1% of cases
  6. Mixed Connective Tissue Disease (MCTD): anti-U1-RNP Abs
  7. Overlap Syndromes: anti-Jo1, other anti-tRNA synthetases

E. Pathophysiology [2]

  1. Components of Systemic Sclerosis
    1. Severe cutaneous and visceral fibrosis
    2. Exaggerated deposition of extracellular matrix
    3. Chronic inflammation / immune activation mainly in early stage disease
    4. Inflammation mainly macrophages and T cells; autoantibodies produced
    5. Microvascular disease with intimal proliferation, deposition of subendothelial collagen and mucinous material, narrowing and thrombosis of vessel lumen
  2. Histopathologic Changes in Skin
    1. Marked thickening of dermis with epidermal atrophy, flattening of rete pegs
    2. Also replacement of sebaceous and sweat glands and hair follicles
    3. Prominant inflammation in early lesions at dermal adipose interface
    4. Small vessels in lower dermis have fibrous thickening without vasculitis
  3. Altered Collagen Biosynthesis
    1. Stimulatory autoantibodies against platelet derived growth factor (PDGF) receptor found in 46/46 sera from patients with PSS, and none of 75 non-scleroderma controls [7]
    2. Stimulatory PDGF receptor antibodies indluce collagen expression and myofibroblast phenotype conversion in normal human primary fibroblasts [7]
    3. TGFß (transforming growth factor ß) stimulates extracellular matrix synthesis
    4. Connective tissue growth factor also plays a crucial role in fibrosis
    5. Fibrous tissue expansion, particularly in subendothelial areas
    6. Increased types I, III, VI, and VII collagens in diseased skin
    7. Reduced collagenase expression (? increased collagenase inhibitor production)
  4. Development of fibrosis appears to be preceded by inflammatory cell infiltrates
    1. Mainly macrophages and T cells
    2. Activation of T helper cells and reduction in T suppressor cells
    3. High expression of transforming growth factor ß (TGFß) involved in fibrosis
  5. Vasodilator Dysfunction
    1. SS associated with imbalance of vasconstrictors and dilators
    2. Increased levels of potent vasoconstrictor endothelin-1
    3. Angiotensin converting enzyme (ACE) alleles associated with SS
    4. ACE D allele more prevalent in patients with SS than controls [9]
    5. Endothelial nitric oxide synthetase (eNOS) alleles associated with SS
    6. Exon 7 (Glu298->Asp), but not a promoter, polymorphism in eNOS associated with SS [9]
  6. Endothelin-1
    1. Endothelin 1 levels do not correlate with pulmonary fibrosis or pulmonary HTN
    2. Increased endothelin 1 levels may be a marker for active PSS
    3. Blockade of endothelin receptors leads to improvement in pulmonary HTN in SS
  7. Defective Vasculogenesis [8]
    1. Low capillary density and vascular obliteration typically found in SS
    2. Formation and repair of blood vessels is defective in SS
    3. ~75% reduction in circulating endothelial precursors (CEP) in SS versus normals or RA
    4. Circulating concentrations of VEGF, ß-FGF, hepatocyte growth factor, EPO elevated
    5. CEP from SS do not differentiate properly in vitro compared with normal or rheumatoid arthritis (RA) derived CEP
  8. Role of Fetal-Maternal Interactions [10]
    1. Fetal and maternal cells of various types are exchanged between mother and fetus
    2. Fetal erythrocytes and leukocytes are found ~70% of women sometime during pregnancy
    3. Fetal hematopoietic stem cells found in women up to 27 years post partum
    4. In women with PSS who have had male children, Y chromosome sequences found in 46%
    5. In control group (women without PSS with male children), Y sequences found in 4%
    6. In addition, Y chromosome sequences found in 58% of skin lesions from women with PSS
    7. No clear association with microchimerism in followup studies
  9. Similar mechanisms probably exist in other chronic fibrotic diseases
    1. Pulmonary fibrosis - initially inflammatory alveolitis
    2. Hepatic Cirrhosis
    3. Chronic glomerulonephritis
    4. Arterial restenosis after angioplasty
    5. Surgical Adhesions
    6. Graft versus host disease

F. Evaluation

  1. General Testing
    1. Complete blood count
    2. Renal function and electrolytes (including anion gap)
    3. Thyroid Function Tests
  2. Urine for microscopic examination, creatinine and protein concentration
  3. Pulmonary Function Tests
    1. Diffusion capacity (DLCO) Is likely of greatest prognostic value
    2. Full PFTs with lung volumes should be performed at initial and some followup visits
    3. Radiography of the lungs should be considered (chest radiograph and/or CT scan)
    4. Gallium scan to evaluate neutrophil infiltration in the lungs
    5. Lung biopsy or bronchoalveolar lavage (BAL) may identify high risk patients [11]
  4. Cardiac Assessment
    1. Echocardiography for screening for P-HTN, right sided heart failure
    2. Right heart catheterization may be useful in difficult cases
    3. P-HTN is treatable, progression can be slowed with current agents
    4. Subclinical pericarditis may be assessed as well
    5. Electrocardiogram (ECG) for all patients to assess heart block
  5. Esophageal Studies - as dictated by symptoms
  6. Autoantibody testing - as above Card "Autoantibodies"

G. Treatment [1]

  1. Glucocorticoids
    1. Very effective for myositis; some efficacy in pulmonary inflammation
    2. Prednisone, initially 1-2mg/kg qd po, then slow taper
    3. Concern for development of glucocorticoid myopathy
    4. High doses (500-1000mg iv x 3 days methylprednisolone) for severe lung disease
    5. The actual long term efficacy of this therapy is questionable
  2. Skin Disease
    1. No agent has been shown to prevent progression of sclerderma changes
    2. D-Penicillamine originally used but now in general disfavor
    3. Trials of various immune modulators under way
    4. Human relaxin 25µg/kg showed positive phase II but negative Phase III effects [12]
    5. Oral cyclophosphamide 1mg/kg qd initially then 2mg/kg po x 1 year in patients with lung disease reduced skin thickening [23]
    6. Methotrexate and/or cyclosporin have shown some efficacy [13]
  3. Renal Crisis [14]
    1. Acute hypertensive emergency
    2. ACE Inhibitors (ACE-I) should be used for renal dysfunction and in renal crisis
    3. ACE-I may prevent progressive renal damage
    4. ACE-I inhibitors should be continued during dialysis as they may permit return of renal function and dialysis discontinuation
    5. In patients treated with ACE-I requiring dialysis for renal crisis, >50% will not require dialysis in long term
    6. Angiotensin II receptor blockers are recommended in patients intolerant of ACE-I
    7. Other anti-hypertensives may be used as well
    8. Renal function returns in >60% of patients with renal crisis
  4. Raynaud's Symptoms [1]
    1. Nifedipine long acting as blood pressure tolerates (may control hypertension as well)
    2. Other dihydropyridine calcium blockers are likely as effective
    3. Nitrates (including topical) may be effective
    4. Bosentan (Tracleer®), an oral nonselective endothelin blocker, has shown efficacy
    5. Bosentan 62.5mg po bid resolved digital ulcers in a scleroderma patient [20]
    6. Sildenafil (Revatio®, Viagra®), an oral PDE5 inhibitor, has shown efficacy
    7. Intravenous iloprost (prostacyclin analog) has shown efficacy
    8. Pentoxyphylline (Trental®) has reported efficacy
    9. Keeping extremities warm is best initial preventive
  5. Reflux Esophagitis and Dysmotility
    1. Proton pump inhibitors (PPI) in moderate to high doses are effective for esophagitis
    2. H2-blockers in high doses may be effective in less severe cases
    3. Metaclopramide (Reglan®) is somewhat effective for dysmotility
    4. Other 5-HT4 agonists such as tegaserod (Zelnorm®) may be helpful
    5. Combination of agents may be required
    6. Nitrates, Nifedipine and calcium blockers can worsen reflux symptoms
  6. Calcinosis
    1. Warfarin, 1mg po qd may reduce nodules in mild to moderate cases
    2. Colchicine may also be tried in difficult cases
    3. Intralesional glucocorticoids may be effective in calcinosis confied to skin
    4. Diltiazem at 240-480mg po qd has shown modest benefit in calcinosis
  7. Somatostatin analogue (Sandostatin®) shown to help with diarrhea in scleroderma
  8. Pulmonary Fibrosis [13]
    1. Often cause of death in diffuse SS
    2. Glucocorticoids do not appear to alter the chronic course of lung disease
    3. Cyclophosphamide improves lung function and mortality in PSS with lung inflammation [11]
    4. Cyclophosphamide IV then azathioprine has reduced progression of lung disease in PSS [1]
    5. Cyclophosphamide po (1mg/kg qd initially then 2mg/kg qd if tolerated) x 1 year slightly reduced lung function (FVC) decline at 2 year endpoint [23]
    6. Cyclophosphamide po caused increased overall but not severe adverse events [23]
    7. increased risk of hemorrhagic cystitis, bladder fibrosis, certain cancers, gonadal failure with oral cyclophosphamide [24]
    8. Oral cyclophosphamide is beneficial in scleroderma with interstitial lung disease [23,24]
    9. Autologous stem cell transplant after immunoablation is undergoing clinical trials
  9. Pulmonary Hypertension (P-HTN) [1,4]
    1. Pure P-HTN is more common in CREST than in PSS
    2. More common in patients with Raynaud's Disease
    3. Echocardiographic evaluation of right ventricular pressures and function is required
    4. Right heart catheterization may be needed when Doppler echocardiography is insufficient
    5. Vasodilators may be beneficial but may reduce systemic blood pressures
    6. Bosentan an oral nonselective endothelin receptor blocker, improves function and outcomes in P-HTN of various causes including scleroderma (FDA approved) [15,16]
    7. Sildenafil, an oral PDE5 inhibitor that elevates nitric oxide and does not affect systemic blood pressure, is FDA approved for P-HTN secondary to SS [1]
    8. Three prostacyclin derivatives are also beneficial but costly
    9. Epoprostenol (prostacyclin, continuous IV) improved scleroderma related P-HTN exercise capacity and NYHA heart failure class improved considerably [17]
    10. Iloprost, a long-acting prostacyclin analog, is beneficial in some patients [18,19]
    11. Aerosolized iloprost may be effective in treatment resistant patients [18]
    12. Patients who respond to iloprost have low baseline NO and increase it after drug [19]
    13. Iloprost may prevent progression of pulmonary HTN by preventing vascular remodeling
  10. Severe Disease
    1. Immuno-ablative therapy with stem cell rescue is being evaluated for severe patients
    2. These patients have early pulmonary fibrosis at a young age
    3. Chemotherapy is used to ablate the bone marrow, and stem cell rescue is performed
    4. Appears that T cell depletion of the stem cells is important
    5. Mortality is 3-5% and efficacy is being evaluated

H. Prognosis [1]

  1. Death usually due to cardiac or pulmonary failure
  2. Estimated overall 5 year (yr) survival rate is >80% and 10 yr survival >70%
    1. In general, older age, male sex, and black race trend towards poorer outcomes
    2. Bimodal distribution of mortality, with long term (>10 yrs) and short term (<5 yrs) mortality peaks
  3. Poor prognostic features
    1. Baseline (at diagnosis) cardiopulmonary signs
    2. Abnormal urine sediment (pyuria, hematuria)
    3. Anti-Topo I+ / Anti-Pol III± Ab: poorer prognosis for cardiac, lung and myopathic disease
  4. No relationship between pulmonary function and Gastroesophageal reflux disease

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  21. Pomann JJ and Rudner EJ. 2003. Int J Dermatol. 42(1):31 abstract
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