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Scleroderma

A. Scleroderma is a multisystem disorder involving proliferative vascular lesions, obliterative microvascular disease leading to atrophy and fibrosis.

B. Characteristic finding is hidebound fibrotic skin.

C. Commonly thought to be untreatable.

1. Not all patients have progressive course - counseling and reassurance.

2. Symptomatic treatment is often beneficial.

D. Epidemiology

1.Rare disease with incidence of about 19/yr and prevalence of about 200 per 1,000,000 people. More common in U.S.

B. Localized scleroderma

1. Morphea

2. Linear scleroderma.

C. Scleroderma-like syndromes.

1. Occupational - polyvinyl chloride, vibration, silicosis.

2. Eosinophilic fasciitis and Eosinophilic myalgia syndrome (L-tryptophan). 

3. Scleredema of Buschke - often postinfectious. 

4. Metabolic - porphyria, amyloid.

5. Immunologic - graft vs. host reaction in bone marrow transplant patients.

D. Scleroderma-associated syndromes.

E. Werner's syndrome, PKU, Carcinoid syndrome.

III. Etiology and pathogenesis

A. Etiology is unknown but environmental factors are likely important. 

1. Organic solvents. 

2. Epoxy resins. 

3. Silica.

4.Silicone prostheses - no association with scleroderma or other connective tissue diseases.

B. Vascular - reaction to repeated injury of endothelial cells.

1. Etiology of vascular injury unknown.

a. Endothelial cytotoxin found in the serum of some scleroderma patients (granzyme 1 from T cells?).

b. Anti-endothelial antibodies found in some scleroderma patients; unlikely to be primary cause of injury.

c. Increased levels of yon Willebrand factor and tissue plasminogen activator are indicative of endothelial cell injury.

2.Vascular injury due to vasoconstriction and ischemia may be induced by cold exposure, platelet or coagulation system activation.

a. Reactive oxygen species (free radicals) are produced during reversible ischemia causing further vascular damage.

b. Reactive oxygen species in combination with metal ions (Fe, Cu) results in fragmentation of nucleolar components (metal-catalyzed oxidation) resulting in autoantigen expression.

3. Vascular injury leads to pathologic changes.

a. Small arteries- myointimal cell proliferation, medial thickening, adventitial scarring. 

b. Capillaries - decreased budding, devascularization, atrophy, telangiectasias.

C. Immune - indirect evidence.

1. Autoimmune phenomenon.

a. ANA especially nucleolar pattern. 

b. Anti-Scl-70 (DNA topoisomerase I) antibodies. 

c. Anti-nucleolar antibodies.

(1) Anti-RNA polymerase I.

(2) Anti-fibrillarin.

(3) Anti-nucleolar 4-65 RNA.

(4) Anti-U2 RNP. 5 ) Anti-PM-Scl.

d. Anticentromere antibodies.

e. Abnormalities of cellular immunity - result in activation of fibroblasts.

2.Coexistence of scleroderma with other autoimmune diseases.

3.Occurrence of scleroderma-like illness in graft vs. host disease.

D. Connective tissue

1.Activation of connective tissue fibroblasts in response to immunologically mediated inflammation - increased collagen synthesis and fibrosis.

2.Cytokines IL-1, TGF-13 and CTGF (connective tissue growth factor) may play a role in proliferative and fibrotic stages of scleroderma.

3.Scleroderma skin fibroblasts are hyperresponsive to TGF-13 exhibiting increased proliferation and increased production of CTGF.

E. Genetic factors.

1. Little familial tendency.

2. Scleroderma associated with HLA-DR1, 2 and 5 and supertypic determinant DRw52. 

3. Stronger association with C4A null allele and HLA-DQ2.

4.Associations between HLA and specific autoantibodies.

a. HLA-DQBI*0501 and anticentromere.

b. HLA-DRBI *1104, 1502 and 0802 and anti-Scl-70.

5. Increased chromosomal instability and breakage.

A. Presentation.

1. Onset in the 30s to 40s, more common in females.

2.History of Raynaud's phenomenon in >90% of patients.

a. Usually antedates other features.

3.Development of puffiness in hands and face especially in AM.

4.Physical examination shows skin to be puffy or taut, slight pigmentation changes, scars on finger tufts, telangiectasias on face, chests, hands.

5.May have esophageal and or pulmonary manifestations early in course.

6.Will develop hidebound skin in weeks to months.

7.Occasionally present with symmetric polyarthritis causing diagnostic confusion.

8.Occasionally present with myositis.

9.May present with hypertension due to early renal involvement.

V. Organ system involvement

A. Peripheral vascular- Raynaud's phenomenon.

1. Cold or stress induced peripheral vasoconstriction with associated color changes. 

2. Found in >90% of all scleroderma patients. 

3. Of diagnostic but not prognostic significance.

B. Isolated Raynaud's phenomenon

1. Epidemiology.

a. Mild Raynaud's phenomenon is very common;, 2-10% of general population.

(1) Young women tend to have Raynaud's disease or associated with connective tissue disease; older women and men often have occlusive arterial disease.

b. Of all patients with Raynaud's phenomenon- 5%/yr develop connective tissue disease - usually scleroderma but also RA and SLE.

(1) Raynaud's phenomenon that is severe, has a later age of onset, is associated with autoantibodies and/or abnormal nailfold capillaries is more likely to be associated with underlying connective tissue disease.

c. 80% have serologic abnormalities; usually + ANA.

d. Raynaud's phenomenon associated with vasospasm organs; lungs heart, kidneys, brain, and certain disorders such as migraine headaches.

e. Other associated conditions; fibromyalgia, mitral valve prolapse, irritable bowel syndrome, CTS.

2.Pathophysiology of Raynaud's.

a. Vasospastic arterial occlusion:

(1) Sympathetic hyperactivity (increased sensitivity of a-2 adrenoreceptor). 

(2) Altered blood viscosity. 

(3) Mediator release.

(a) Increased endothelin 1, decreased calcitonin gene-related peptide (CGRP). 

(4) Endothelial abnormality.

b. Obstructive arterial occlusion.

3.Classification of Raynaud's phenomenon.

a. Vasospastic.

(1) Primary Raynaud's phenomenon.

(2) Drug induced -vasoconstrictors, b-blockers, cytotoxic agents, IFN-a, oral contraceptives.

(3) Pheochromocytoma, carcinoid syndrome.

b. Structural

(1) Small arteries and arterioles:

(a) Connective tissue diseases; ie, Scleroderma. Atherosclerosis, Thromboangiitis obliterans, Vibration, Cold injury, PVC, Chemotherapy

(2) Large and medium arteries:

(a) Thoracic outlet syndrome, Crutch injury.

c. Hemorheologic

(1) Cryoglobulinemia, Cryofibrinogenemia.

(2) Hyperviscosity syndromes, cold agglutinins.

(3) Polycythemia, Thrombocythemia.

4. Conditions associated with Raynaud's phenomenon.

a. Systemic connective tissue diseases:

(1) Scleroderma, SLE, RA, PM/DM, vasculitis, UCTD.

b. Obstructive arterial diseases: Atherosclerosis, thromboangiitis obliterans. 

c. Occupation: Vibration, cold injury, direct arterial trauma. 

d. Drug-induced: Ergotamine, ß-blockers, cytotoxic drugs, oral contraceptives. 

e. Miscellaneous: PVC exposure, cold agglutinins, cryoglobulinemia, neoplasia, neurologic disorders, endocrinopathies.

5. Frequency of associated conditions with Raynaud's phenomenon.

 

6. Evaluation of patient with Raynaud's phenomenon.