Systemic sclerosis (scleroderma)


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.

Patients may present with Raynaud’s symptoms, fatigue, weight loss, polyarthritis, swollen hands and/or legs, carpal tunnel syndrome, and tendon friction rubs.

A complex heterogeneous fibrosing autoimmune disorder.

Associated with fibrosis of the dermis and visceral organs.

Associated with immune dysregulation, micro vascular damage and organ fibrosis.

Microvascular complications are primarily result of obliterated vasculopathy involving intimate proliferation in the small arteriloes and manifest is Raynaud’s phenomenon, pulmonary hypertension, and scleroderma renal crisis.

Raynaud’s phenomenon Is present in 95% of patients with systemic sclerosis and can proceed the development of scleroderma up to 30 years, with mean duration of 10 years.
In patients with Raynaud’s phenomenon who have abnormal nail capillaries and a scleroderma specific autoantibody, 80% transition to systemic sclerosis within two years of initial presentation.
The vascular pathology associated with Raynaud’s phenomenon in systemic sclerosis is characterized by endothelial dysfunction, intimal fibrosis, ischemia/re-perfusion injury from cyclical vasodpasm and can ultimately progressed to digital ulcers and gangrene.


Digital ulcers occur in 30% of patients each year and are a marker of internal organ involvement, and if severe, associated with increases in mortality.

Scleroderma renal crisis is associated with hypertension and renal dysfunction and can be fatal.

An estimated 4-6% of patients develop scleroderma renal crisis, and most of these have diffuse cutaneous sclerosis.

Some 90% of patients with Scleroderma renal crisis have a blood pressure higher than 150/90 mmHg with signs mirroring those seen in malignant hypertension including hypertensive encephalopathy, congestive heart failure, and arrhythmia.

Scaleroderma renal crisis is life-threatening and the use of angiotensin-converting enzyme inhibitors has improved outlook, reducing mortality from 76% to less than 10%.

Of unknown pathogenesis.

Varying geographical prevalence of 50-300 per million persons per year.

Incidence 2.3-22.8 per million persons per year.

Affects women four times as often as men.

Prevalence is estimated at 50-300 cases per 1 million persons.

Onset between 30 and 60 years of age.

Associated with both genetic and environmental factors involving cellular and hormonal immunity.

Three major pathological hormone features include fibrosis, vasculopathy, and immune dysfunction which are interconnected.

An autoimmune connective tissue disease causing skin thickening as well as destruction of the microvasculature due to immunologic and cytotoxic activities.

There is an increased risk of myocardial infarction and stroke in patients, especially within the first year of diagnosis.

A generalized fibrotic destruction caused by accumulation of scleroproteins in skins and other organs.

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.

Probably related to intimal thickening of the renal interlobular and arcuate arteries secondary to endothelial cell injury and abnormal oxidative stress leading to fibrosis.

The above process narrows arterial vessels decreasing renal perfusion and progressing to hyperplasia of the juxtaglomerular apparatus and increased renin release, microangiopathic hemolytic anemia, and high levels of cellular adhesion molecules.

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.

Classified into two major subtypes on the basis of the extent of cutaneous fibrosis: limited cutaneous and diffuse cutaneous systemic sclerosis.

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.

Classified as either a limited cutaneous or defuse cutaneous disease determined by the extent of cutaneous manifestations.

Localized scleroderma is generally restricted to distal aspects of the body, distal to the elbows and knees and is characterized by sclerodactyly and acrosclerosis.

Truncal and acral areas tend to be affected in patients with diffuse cutaneous systemic sclerosis.

Patients with greater skin involvement generally have more severe disease, that is, gdiffuse cutaneous systemic sclerosis is tied to higher incidence of visceral organ involvement and lower survival rate.

Localized scleroderma can be manifested with Raynaud disease, dysphasia, calcinosis cutie, telangiectasia but such cases are uncommon.

Localized scleroderma can progress insidiously to include pulmonary hypertension and biliary cirrhosis

Magnitude of skin and organ involvement predicts clinical course and ultimately the morbidity and mortality.

Autoantibodies to titin are produced in patients with the autoimmune disease scleroderma.


Most dismal prognosis is associated with diffuse disease.

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.

A progressive damage of internal organs occurred due to this autoimmune disorder is associated with chronic inflammation and systemic immunological abnormalities.

Fibrosis of the lungs and pulmonary arterial hypertension are the two most serious complications among all the major causes of death among patients.

Nearly half of one hundred thousand patients with scleroderma have interstitial lung disease .

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

Interstitial lung disease tends to occur early in the course of illness.

Interstitial lung disease is the leading cause of death related to systemic sclerosis.

Seizures and other neurological symptoms are not uncommon and up to 42% of patients with localized scleroderma have experienced seizures and up to 14% of patients with systemic sclerosis have reported seizures.

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

Rare, approximately 10 cases per 100,000 population in industrialized nations in North America and Europe.

Sclerosis involving major organs such as the heart, kidneys, lungs, may occur early and rapidly.

May result in significant morbidity and mortality.

Carries an increased risk of death compared to age- and sex-matched controls, with a mortality ratio of PSS compared to the general population estimated to be at least 1.5 and as high as 7.2.

There is an increased incidence of cancer in PSS patients compared with the general population.

The highest increased risk is for lung cancer, with a relative risk ratio of 4.3, with a predominance of adenocarcinoma and squamous cell carcinoma.

The second highest increased risk is associated with hematologic malignancy, and esophageal cancer.

Active surveillance of scleroderma patients for early detection of cancer is advisable.

Vascular dysfunction is the key pathologic element.

Diffuse cutaneous scleroderma involves more proximal aspect of the extremities and trunk as well as vital organs including cardiac, pulmonary, gastrointestinal and renal systems.

The risk of myocardial infarction is 8.2-fold greater in SSc patients than controls during the first year after diagnosis and 3.5 times greater during years 1-5 after diagnosis, but once patients got more than 5 years out from diagnosis there was no longer any significant increase in MI risk.

Median survival about 11 years.

Has a mortality of 30-50% at five 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.

Typically presents between ages 30-60 years.

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.

87% of patients with diffuse cutaneous systemic sclerosis test positive for the anti-SCL-70 antibody.

Antibodies often have high specificity, but sensitivity is modest.

Clinical features are primary to diagnosis and antibody profiles provide additional diagnostic support.

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.

Pulmonary involvement is responsible for 60% of the mortality in patients with systemic sclerosis.

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

Calcinosis cutis, also known as subcutaneous calcifications, may be present in all forms of systemic sclerosis but is most commonly in limited scleroderma.

The calcinosis is of the dystrophic type and occurs primarily in the areas of sclerodactyly but maybe seen in the hip, shoulders, lower limbs , elbows and forearms.

Calcinosis cutis characterized by a deposition of calcium in the subcutaneous tissues at sites of micro trauma such as the phalanges, feet, elbows, and forearms.

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.

Renal crisis in the era before renin-angiotensin-aldosterone inhibitors associated with nearly 100% mortality, and presently early survival rates 70-80%.

Early warning signs of renal crisis include onset of diffuse skin disease subtype of scleroderma, rapidly progressive skin disease, presence of RNA-polymerase antibodies, and increased doses of glucocorticoids of greater than 15 mg/day.

Late warning signs of renal crisis include: progressive hypertension, decreasing GFR, encephalopathy, new onset of proteinuria or microscopic hematuria.

Scleroderma renal crisis is a life-threatening complications commonly associated

with diffuse scleroderma.

Renal crisis is characterized by accelerated hypertension, acute renal failure and is also associated with a high mortality rate.

Mild elevations of serum creatinine and hypertension developing 50% of all

patients with scleroderma and from 10-20% of patients will go on to develop renal crisis.

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

Associated with sicca syndrome, sclerodactyly, Raynaud’s phenomenon, and dysphagia.

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 associated with cardiac fibrosis, congestive heart failure, and pericardial effusions arrhythmias, and syncope related to conduction abnormalities.

Patients with systemic sclerosis have a greater than two fold increased risk for developing a cardiovascular event compared with persons without systemic sclerosis.

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.

Smoking associated with more severe systemic sclerosis.

Conventional immunosuppressive therapy has limited efficacy and a few data support survival benefit.

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.

Hematopoietic stem cell transplant improves skin involvement and functional ability, and some studies suggest it can ameliorate vasculopathy, improve lung involvement and correct immune abnormalities.

In a randomized clinical trial comparing autologous hematopoietic stem cell transplantation versus intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis autologous hematopoietic stem cell transplantation was associated with increased treatment related mortality in the first year, however it conferred a significant long-term event free survival benefit (EBMT/EULAR Study Group).

In the above study autologous hematopoietic stem cell transplant used high-dose cyclophosphamide ATG and reinfusion of CD34 selected cells.

The annual rate of decline in FVC in patients with interstitial lung disease from systemic sclerosis is lower with nintedanib than with placebo.

With nintedanib the annual rate of decrease in forcibly exhaled air after a single deep breath, was significantly lower in the nintedanib damage group compared with placebo.

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