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Systemic sclerosis (scleroderma) from Standard of Care

Posted Mar 29 2011 10:45pm
Systemic autoimmune inflammatory connective tissue disease characterized by excessive production of extracellular matrix by fibroblasts as well as damage of small blood vessel endothelium with intimal hyperplasia, tissue ischemia and activation of the immune system.

Symptoms result from inflammation and tissue fibrosis leading to occlusion of the micro vasculature by excess production and deposition of types I and III collagen.

Levels of macromolecules such as fibronectin, glycoaminoglycans, and tenascin are also increased in the connective tissue.
Vascular changes are predominantly in the small arteries and arterioles.

Alterations in the small blood vessels of the skin and internal organs, including fibrosis and perivascular infiltration of activated T cells our present in this process.

Progressive fibrosis of tissues is the pathological hallmark.

Fibrosis is found in both the clinically affected and unaffected tissues.

Skin fibroblasts are persistently activated with higher levels of the gene encoding for type I procollagen and down regulation of fibroblast collagen synthesis by collagen amino-terminal peptides is impaired.

Mononuclear infiltration of the blood vessels, and dermal appendages precede fibrosis.

Infiltrate inflammation associated with predominantly CD4 lymphocytes and suppressor T cells are diminished in number.
Inflammatory infiltrates have large numbers of macrophages, eosinophils, basophils, mast cells and B cells.

Inflammatory cells secrete cytokines, which are important in producing fibrosis.

Visceral involvement can involve the lungs, heart, kidneys and gastrointestinal tract.

40% of patients have restrictive lung disease as a result of interstitial lung disease.

Leading causes of death from scleroderma are from pulmonary hypertension and ventilatory restriction.

Vascular dysfunction is the key pathologic element.

Median survival about 11 years.

Mean age at diagnosis 46 years.

Prevalence and incidence higher in blacks than in whites.

The two major variants of the disease are localized scleroderma with fibrosis limited to the skin and systemic scleroderma with fibrosis affecting internal organs.

Localized disease may be noted to have linear scleroderma with band-like thickening of the skin affecting one area such as the arm, leg, face forehead or scalp.

Localized disease can also manifest as morphia with circumscribed sclerotic plaques on the skin, in a limited or generalized fashion, and can be an intermittent process.

Morphia lesions are round or oval with purple edges and a wax-like appearance.

Black patients have 1.86 times greater risk of having diffuse rather than limited disease.

Young black females have a 10 times the risk than the general population.

Incidence higher in African-Americans than in Nigerians, and incidence is quite significantly elevated in Choctaw Indians.
Annual incidence estimated to be approximately 19 cases per million adults per year.

Prevalence estimated to be 240 cases per million population, with a range of 138 to 286 cases per million population.
Prevalence may be as high as 400 cases per million for women ages 35 to 65 years.

Prevalence has been increasing because of earlier detection related to better diagnostic techniques and increased survival time.

Frequently misdiagnosed entity.

Affects 2-10 million people, with four times as many women involved than men.

About 300,000 Americans have this disease and 75-100,000 have systemic variants of the disease.

Uncommon in Asians.

Juvenile onset rare.

Several variants of the disease exist.

Criteria of American College Of Rheumatology for classification of systemic sclerosis require one major criterion or two minor criteria, as follows: major criteria-proximal scleroderma characterized by symmetric thickening, tightening and in duration of the skin of the fingers and the skin is proximal to the metacarpophalangeal or metatarsophalangeal joints.

Minor criteria, include sclerodactyly characterized by thickening, and duration, and tightening of the skin, limited to the fingers, digital pitting scars or loss of substance from the finger pad from ischemia, bilateral pulmonary basilar fibrosisas seen on chest x-ray.

Classification criteria proposed by Nadashkevich et al include autoantibodies to centromere proteins, Scl-70 and fibrillarin, bibasilar pulmonary fibrosis, contractures of digital joints, dermal thickening proximal to the wrists, calcinosis cutis, Raynaud phenomenon, esophageal, distal hypo-motility or reflux esophagitis, sclerodactyly, and telangiectasia: three or more criteria indicates definite systemic scleroderma.

Maricq and Valter classification: Type I-diffuse skid involvement proximal to elbows/knees; includes trunk Type II-intermediate skin involvement proximal to the metacarpal phalangeal/metatarsal phalangeal joints, distal to the elbows/knees; trunk not involved. Type III-Digital sclerodactyly only. Type IV-capillary pattern or pitting scars and visceral involvement, no anticentromere antibodies, no telangiectasia. Type V-undifferentiated connective tissue disease with two of three of the following: sclerodactyly, pitting scars, or scleroderma capillary pattern, or one of these features along with one of the following: Raynaud phenomenon, pulmonary fibrosis, visceral involvement of the esophagus, a heart, kidney; but does not meet the criteria of groups III and IV, no anticentromere antibodies, no telangiectasia. Type VI-CREST; no skin involvement, or sclerodactyly only, telangiectasia or anticentromere antibodies required.

Patients may complain of diffuse pruritus, skin tightness, and induration.

Hyperpigmentation and hypopigmentation may be present.

70% of patients present with the Raynaud phenomenon, up to 95% eventually develop this process.

Cutaneous and mucosal telangiectasia and pitting ulcers in the fingertips indicate vascular involvement.

Telangiectasia most common in the perioral area of the face, hands and anterior chest, but can be in any area in the dermis of the skin.

The skin of the hands are swollen and subsequently may become indurated with sclerosis.

The longer the time between edema to the sclerosis phase indicates a better prognosis.

Rapid onset of sclerosis associated with an impaired prognosis, and often with more expensive and aggressive visceral involvement with an increased risk of renal crisis.

Gastroesophageal reflux disease is a common phenomenon, as is dyspepsia, bloating and early satiety.

With respiratory involvement progressive dyspnea occurs as those chest discomfort related to pulmonary hypertension, and a persistent dry cough may occur related to restrictive lung disease.

Fatigue and weight loss are common.

Arthralgias, myalgia, carpal tunnel syndrome, loss of joint range of motion and muscle weakness may occur with involvement of the musculoskeletal system.

Involvement of the cardiovascular system may be too much cardio fibrosis, congestive heart failure, and pericardial effusions arrhythmias, and syncope related to conduction abnormalities.

Dyspareunia in women and erectile dysfunction may occur in men.
The sicca syndrome may occur and may be related to poor dentition.

Hoarseness may occur related to GERD and vocal cord fibrosis.

Renal crisis, hypertension and chronic renal insufficiency may occur.

The presence of peripheral entrapment neuropathy may be present due to facial pain and hand paresthesias.

Most frequent causes of mortality are pulmonary hypertension and renal disease.

Cutaneous subtype of disease associated with a tenuous arrival rate of 71%.

Diffuse subtype of disease has a 10 year survival rate of only 21%.

The presence of pulmonary hypertension a poor prognostic marker.

Oral cyclophosphamide in patients with symptomatic interstitial lung disease have small but statistical improvement in lung function and decreased symptoms over the course of one year of therapy.

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