Scleroderma overview

# Overview
Scleroderma is an autoimmune connective tissue disease. The hallmark of the disease is the presence of autoantibodies against various cellular antigens, which results in small vessel vasculopathy, excessive collagen deposition and fibrosis of skin and internal organs. Growth factors and cytokines play an important role in the underlying pathogenesis. The word scleroderma is greek in origin and translates in to hard skin, describing the skin fibrosis. Scleroderma is classified into 2 subtype, limited cutaneous scleroderma and diffuse cutaneous scleroderma. CREST syndrome is a variant of limited cutaneous scleroderma. Choctaw native Americans have a much higher prevalence of scleroderma than the general population. Scleroderma must be differentiated from other diseases that cause skin thickening, sclerodactyly, edema and symptoms of gastroesophageal reflux disease. Common risk factors for scleroderma that have been described in literature are exposure to silica, chlorinated and aromatic solvents and welding fumes. Since there is a possibility of internal organ involvement, screening for fatal complications such as scleroderma renal crisis, pulmonary arterial hypertension, and cardiovascular involvement must be carried out in patients with scleroderma. Scleroderma is mainly diagnosed based on clinical presentation and the new American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) classification criteria has been published. The new criteria is more sensitive and is better for detecting disease earlier, so that the fatal renal and pulmonary complications can be screened for and prevented. Nailfold video capillaroscopy is the diagnostic study of choice to confirm Raynaud's phenomenon and scleroderma microangiopathy. The mainstay of treatment for scleroderma is medical therapy. Pharmacologic medical therapies for scleroderma include topical tacrolimus for morphea, methotrexate for diffuse sclerosis of the skin, minocycline for calcinosis cutis, nifedipine for Raynaud's phenomenon, captopril for scleroderma renal crisis.

# Historical Perspective
The word scleroderma comes from greek words; skleros (hard) and derma (skin). Scleroderma was first described by Carlo Curzio in Naples, Italy in 1753. The association between abnormal vasoconstriction and diffuse scleroderma was made in 1865 by Raynaud.

# Classification
Scleroderma (systemic sclerosis) is classified into 2 subtypes, limited cutaneous scleroderma and diffuse cutaneous scleroderma. Morphea and CREST syndrome are variants of limited cutaneous scleroderma. Scleroderma was previously classified according to American College of Rheumatology (ACR) 1980 preliminary scleroderma criteria. Scleroderma (systemic sclerosis) is now classified according to the new American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) criteria.

# Pathophysiology
Scleroderma is an autoimmune connective tissue disease. The hallmark of the underlying pathophysiology is production of autoantibodies against various cellular antigens, small vessel vasculopathy, fibrosis of skin and internal organs, and excess collagen deposition in the skin and internal organs. Circulating autoantibodies found in patients with scleroderma are anti-topoisomerase I (Scl-70) antibody, anti-centromere antibody, anti-RNA polymerase III antibody, anti-nucleolar antibody. Growth factors and cytokines play an important role in the underlying pathogenesis of scleroderma. Increased fibroblast activity leads to the excessive collagen deposition in scleroderma. Although the hallmark of this disease is skin fibrosis, internal organ involvement is a fatal complication and includes, esophageal dysmotility, interstitial lung disease, pulmonary arterial hypertension, scleroderma renal crisis, myocardial fibrosis, pericardial fibrosis and pericardial effusion. Although scleroderma occurs in a sporadic pattern in the general population, variations in the human leukocyte antigen (HLA) genes can predispose an individual to developing scleroderma. On gross pathology, sclerodactyly, skin fibrosis, edema and calcinosis are characteristic findings of scleroderma. On microscopic histopathological analysis, characteristic findings of scleroderma include microvascular damage, perivascular infiltrates of immune cells, loss of microvasculature, perivascular edema, fibrosis, densely packed collagen in the lower dermis and upper subcutaneous layer, atrophy and loss of cells in the later stages of the disease. The endothelial cell dysfunction allows the chemokine- and cytokine-mediated attraction of inflammatory cells and fibroblast precursors (fibrocytes) from the bloodstream and bone marrow and their transmigration into the surrounding tissues, resulting in the establishment of a chronic inflammatory process with participation of macrophages and T and B lymphocytes, with further production and secretion of cytokines and growth factors from these cells.The immunological alterations include innate immunity abnormalities, tissue infiltration with macrophages and T and B lymphocytes; production of numerous disease-specific autoantibodies; and dysregulation of cytokine, chemokine, and growth factor production. The released cytokines and growth factors induce the activation and phenotypic conversion of various cellular types, including resident fibroblasts, epithelial cells, endothelial cells, and pericytes into activated myofibroblasts, the cells ultimately responsible for initiation and establishment of the fibrotic process.

# Causes
The cause of scleroderma has not been identified. There is a possibility of an underlying immunologic abnormality. To review risk factors for the development of scleroderma click here.

# Differentiating Scleroderma from other Diseases
Scleroderma must be differentiated from other diseases that cause skin thickening, sclerodactyly, edema and symptoms of GERD such as scleredema, scleromyxedema, eosinophilic fasciitis, chronic graft-versus-host disease, drug induced scleroderma, scleroderma overlap syndromes, diabetic cheiroarthropathy, myxedema and nephrogenic systemic fibrosis.

# Epidemiology and Demographics
The majority of cases of scleroderma have been reported from the United States. The prevalence of scleroderma is approximately 24 cases per 100,000 individuals in the United States. Scleroderma commonly affects individuals between 20 to 50 years of age. Choctaw native Americans have a much higher prevalence of scleroderma than the general population. Females are more commonly affected than males. Familial clustering of scleroderma has been reported in United States and Australia.

# Risk Factors
Common risk factors in the development of scleroderma include occupational and environmental exposure to certain chemicals, certain genetic variations and infectious agents. Most commonly implicated occupational and environmental risk factors are exposure is to silica, chlorinated and aromatic solvents as well as welding fumes.

# Screening
There is insufficient evidence to recommend routine screening for scleroderma, however screening is recommended for pulmonary arterial hypertension and malignancy in scleroderma patients. Regular blood pressure monitoring at home is encouraged in patients with scleroderma to screen for renal involvement and prevention of scleroderma renal crisis

# Natural History, Complications and Prognosis
If left untreated, patients with scleroderma may progress to develop pulmonary arterial hypertension (PAH), interstitial lung disease and severe gastrointestinal disease. Common complications of scleroderma include pulmonary fibrosis, pulmonary arterial hypertension, interstitial lung disease and scleroderma renal crisis. The 10-year survival rate of patients with scleroderma is approximately 70%-80%.

# Diagnosis

## Diagnostic Study of Choice
There is no single diagnostic study of choice for the diagnosis of scleroderma. Scleroderma is mainly diagnosed based on clinical presentation, though scleroderma (systemic sclerosis) maybe diagnosed based on the new American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) classification criteria. The new criteria is more sensitive and is better for detecting disease earlier, so that the fatal renal and pulmonary complications can be screened for and prevented.

## History and Symptoms
The hallmark of scleroderma is sclerodactyly. A positive history of progressive skin tightening and hardening is suggestive of scleroderma. The most common symptoms of scleroderma include skin tightening or induration, Raynaud's phenomenon, and symptoms of gastroesophageal reflux disease (GERD). Less common symptoms of scleroderma include shiny skin appearance and restricted movement of affected areas of the skin.

## Physical Examination
Patients with scleroderma usually appear anxious. Physical examination of patients with scleroderma is usually remarkable for sclerodactyly, Raynaud's phenomenon, digital ulcers, skin fibrosis and telangiectasias.

## Electrocardiogram
An ECG may be helpful in the diagnosis of scleroderma heart disease. Findings on an ECG suggestive of scleroderma heart disease include left bundle branch block, right bundle branch block and septal infarction pattern. It is recommended to screen for myocardial fibrosis with an annual electrocardiogram in patients with scleroderma.

## Chest X-Ray
An x-ray of the chest may be helpful in the diagnosis of scleroderma interstitial lung disease and pulmonary fibrosis.Although it is usually not as sensitive as HRCT, findings on an x-ray suggestive of scleroderma interstitial lung disease include, interstitial opacification, reticular areas of attenuation, ground glass opacity greatest at lung bases.

## CT Scan
High-resolution CT (HRCT) scan of the chest may be helpful in the diagnosis of scleroderma interstitial lung disease and pulmonary hypertension. Findings on HRCT suggestive of interstitial lung disease include architectural distortion due to pulmonary fibrosis, reticular interlobular interstitial thickening, increased ground glass opacity and accentuated reticular markings on juxtapleural, posterior and basilar portion of the lungs, traction bronchiectasis, and honeycomb cystic change

## MRI
There are no MRI findings associated with scleroderma.

## Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with scleroderma. However, a transthoracic echocardiography (TTE) may be helpful in the diagnosis of complications of scleroderma, which include pulmonary arterial hypertension (PAH).

## Other Imaging Findings
Nail-fold video capillaroscopy (NVC) may be helpful in the diagnosis of scleroderma. Findings on nail-fold video capillaroscopy diagnostic of raynaud's phenomenon (RP) and scleroderma microangiopathy include nail-fold capillary abnormalities, capillary dilatation, and capillary loop drop-out. Findings on nail-fold video capillaroscopy diagnostic of scleroderma microangiopathy are graded into 3 phases; early, active and late.

## Other Diagnostic Studies
There are no other diagnostic study associated with scleroderma.

# Treatment

## Medical Therapy
The mainstay of treatment for scleroderma is medical therapy. Pharmacologic medical therapies for scleroderma include topical tacrolimus for morphea, methotrexate for diffuse sclerosis of the skin, minocycline for calcinosis cutis, nifedipine for Raynaud's phenomenon, captopril for scleroderma renal crisis, treatment of gastroesophageal reflux disease and pulmonary hypertension. Localized phototherapy with ultraviolet light is preferred for the treatment of morphea.

## Surgery
Surgical intervention is not recommended for the management of scleroderma. However, surgical procedures such as debulking and lung transplantation are needed to treat complications of scleroderma which include calcinosis cutis and pulmonary hypertension.

## Primary Prevention
Effective measures for the primary prevention of scleroderma include avoiding occupational and environmental exposure to crystalline silica, epoxy resins, welding fumes and hand-arm vibration.

## Secondary Prevention
There are no established measures for the secondary prevention of scleroderma. However, effective measures for the secondary prevention of pulmonary arterial hypertension and scleroderma renal crisis in patients with scleroderma include screening.