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Tufts OpenCourseware
Author: Elena Massarotti, M.D.
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1. Introduction

Scleroderma is a rheumatic disease of unknown cause that is characterized by excess fibrosis. Like many of the rheumatic diseases, multiple organ systems can be involved, and the extent, expression, and autoantibody profiles can help differentiate the forms of scleroderma from one another. However, like most of the rheumatic diseases, it is a combination of the history, physical examination and laboratory features that best clinches the diagnosis, not the antibody profiles alone. Because scleroderma is a disease of connective tissue, and connective tissue is part of the anatomy of joints and periarticular structures, this disease is considered a rheumatic disease.

(Major reference for this section is “Following the Molecular Pathways toward an Understanding of the Pathogenesis of Systemic Sclerosis” by Sergio Jiminez MD and Chris Derk MD. Annals of Internal Medicine 2004; 140:37-50.)

2. Learning Objectives

  1. The student will be able to describe current theories regarding the pathogenesis of scleroderma.
  2. The student will be able to distinguish the clinical and serological features of scleroderma from other connective tissue diseases.
  3. The student will be able to define Raynaud’s phenomenon, and describe the pathophysiologic mechanisms and treatments.

3. Pathogenesis

There are three major processes that contribute to the clinical manifestations of scleroderma: (1) severe tissue fibrosis with excessive deposition of collagen and connective tissue components in the extracellular matrix, (2) chronic inflammation characterized by infiltration of T cells and macrophages in affected tissues, and (3) microvascular disease, characterized by intimal proliferation of blood vessels. (Jiminez and Derk, see reference above) The immune features are clinically characterized by the presence of autoantibody formation, and the vascular features are clinically characterized by digital ischemia. Fibroblast activation leads to excessive collagen deposition, clinically characterized by thickening of the skin.

Endothelial cell activation and injury is one of the major triggers of the fibrotic process. Microvascular injury initiates the pathogenic process in scleroderma, but the specific mechanisms by which the injury takes place have not been identified. A cytotoxic factor, granzyme I (an enzyme that breaks down collagen, or a collagenase), degrades the basal lamina and is found in cytolytic T cells. Many patients with scleroderma also possess anti-endothelial cell antibodies that may also injure the endothelium. These two processes contribute to the endothelial cell damage seen in scleroderma. Once the endothelium has been injured, ischemia and vascular constriction follow. The diseased endothelium then produces lower amounts of an important vasodilator and inhibitor of platelet aggregation, prostacyclin. The damaged endothelium then attracts platelets which then release another important vasoconstrictor, thromboxane. Platelet derived growth factor (PDGF) is also released by activated platelets, and attract fibroblasts, smooth muscle cells and transforming growth factor β (TGFβ). TGFβ then triggers the activation of fibroblasts and excessive collagen synthesis. Activation of adhesion molecules (ICAM-1, VCAM-1) has also been demonstrated in the sera of these patients. One of the most common clinical manifestations of vascular disease in patients with scleroderma is Raynaud’s phenomenon, characterized by peripheral vasoconstriction and ischemic pain.

Fibrosis and microvascular occlusion underlies the pathologic findings in the involved organs of patients with this disease. The clinical hallmark of this disease is thickened and taut skin. The development of this disfiguring process is linked to the excessive accumulation of types I and II collagens in the extracellular matrix of the dermis of these patients. The extent and degree of skin involvement differentiates the different forms of scleroderma, as do the antibody profiles and organs involved. For example, progressive systemic sclerosis (PSS) is characterized by extensive skin thickening. Morphea is characterized by skin thickening in localized, discrete patches and limited scleroderma (formerly known as CREST), is characterized by thickening primarily over the distal extremities alone (fingers). Increased amounts of other connective tissue molecules like fibronectin, tenascin, and glycosaminoglycans are also found in these patients. Excess deposition of collagen in the dermis leads to marked thickening of the dermis with a leathery feeling. The pliability and movement of skin is greatly restricted, leading to physiological and cosmetic disturbances. The cutaneous glands found within this diseased dermis are secondarily affected, leading to dryness. T cells populate the perivascular areas of the cellular infiltrate found in these vascular areas. Intimal proliferation and luminal narrowing of the arteries and arterioles in the vascular lesion is also present.

Both the humoral and cell mediated immunity contribute to the pathogenesis of this disease. Examples of abnormalities seen in humoral immunity include higher than average levels of rheumatoid factor (immunoglobulin directed against the Fc portion of IgG) in the serum of these patients, cryoglobulins (immunoglobulins which precipitate in the cold), and polyclonal hypergammaglobulinemia. However, the immune markers may not have any direct pathogenic role, but are evidence of some disruption in immune surveillance in these patients. Autoantibody formation is commonly found with 95% of patients having detectable antinuclear antibodies. These antibodies are directed against nuclear antigens; their staining pattern and antigenic specificity may help to differentiate different scleroderma subtypes. Patients with the PSS express antibody to Topoisomerase I (anti Scl 70), while those patients with the limited form of the disease (also known as CREST) express antibody to the centromere (anti centromere antibody). The nucleolar pattern of antinuclear antibody staining is commonly seen in patients with scleroderma. Though other autoantibodies have been found in the sera of these patients, not all have clinical significance.

The evidence for the role of cell-mediated immunity in the pathogenesis of scleroderma is based upon studies of the affected skin of these patients that show lymphocytic infiltrates early on in the disease process. (Jiminez and Derk, see reference above) Furthermore, the degree and extent of lymphocytic infiltration correlates with the severity of skin sclerosis. The lymphocytes seen are mostly CD4+ T cells, and express the MHC II antigen, DR. This would suggest that an antigen driven process is partially responsible for the subsequent events, though antigen is not known. The T cells isolated from the lymphocytic areas of infiltration can stimulate fibroblast production. It is unknown how these T cells migrate to the affected tissues, and how they are retained but are known to be mediated by integrins and cell adhesion molecules. There is a normal ratio of T cell to B cells but an increased ratio of T helper to T suppressor cells and absolute lymphopenia. Levels of interleukin-2 and interleukin-2 receptors are elevated and correlate with disease activity.

There are other important cells that contribute to the pathogenesis of this disease. Mast cells, which have granules containing substances that affect the function of endothelial cells and fibroblasts, are found in the affected microvasculature of scleroderma patients. Fibronectin, a component of the extracellular matrix, is made by fibroblasts. Increased numbers of macrophages are seen in the alveoli of affected patients and in vitro, secrete large amounts of fibronectin when compared with macrophages from normal individuals. Cytokines, which are produced by activated macrophages, include transforming growth factor ß (TGF-ß), tumor necrosis factor (TNF), interleukins 6 and 1ß, and platelet derived growth factor. Macrophages are also seen in the dermal cell mononuclear cell infiltrates of patients with scleroderma.

The fibrotic lesion in scleroderma is characterized excess collagen production by fibroblasts. This has been found in the heart, lungs, gastrointestinal tract, and skin of patients with scleroderma; clinical correlates of the fibrotic lesion include interstitial pulmonary fibrosis, diffuse skin thickening, cardiomyopathy, esophageal dysmotility, and pseudodiverticula of the colon. Excess collagen production is not due to neoplasia of the fibroblast; dysregulation of collagen and matrix component biosynthesis underlies the pathogenesis. Fibroblasts in scleroderma produce excessive amounts of extracellular matrix molecules. This production is caused by increased transcription rates of their corresponding genes.

In sum, the etiologic trigger of scleroderma is unknown. This trigger leads to endothelial cell injury and activation. The activated endothelial cell releases components of platelet granules that lead to fibroblast activation. The activated fibroblast leads to the overproduction of collagen and fibronectin. Cytokines are involved in the induction of collagen, production of TGF-ß, and endothelial cell injury.

4. Clinical Features

Scleroderma is a rare disease that primarily affects women between the ages of 45 and 65. Genetics are thought to play some role because it is not uncommon for patients with scleroderma to have family members with other autoimmune diseases but familial aggregation is rare and the disease does not occur with higher frequency in twins. The cause is unknown, but scleroderma like illness has followed exposure to rapeseed oil, silica, and tryptophan.

Scleroderma is classically divided into localized or generalized forms. The major distinguishing feature of these two forms of the disease is the extent of skin involvement though an excess of collagen deposition is at the root of both forms of the disorder. In addition to cutaneous involvement, the generalized form of the disease exhibits visceral organ changes as well. The localized forms of the disease do not exhibit visceral manifestations or autoantibody formation.

Localized scleroderma, the more benign condition, describes a heterogenous group of disorders that are usually circumscribed or focal. They may be patchy or linear, and can affect children or young adults. Two forms of localized scleroderma are morphea and linear scleroderma.

Morphea can occur on any part of the body and is characterized by small discrete spots (guttate morphea) or larger patches. The scalp can also be involved. Involutional atrophy occurs and leads to cosmetic deformities, which is the most serious consequence. Constitutional symptoms (fever, malaise) are rarely if ever present.

Linear Scleroderma usually occurs on a single extremity or on the face (also known as the coup de saber). The entire extremity may be affected, leading to a secondary joint contracture. The disease usually remains active for two to three years and then involutes.

The treatment of the localized forms of scleroderma is usually supportive (meaning that symptoms are managed either with medications or other modalities) though ultraviolet light treatments with or without use of the immunosuppressive drug methotrexate has been used in cases where skin involvement may result in limb dysfunction or unwanted cosmetic effects.

5. Generalized Scleroderma

In contradistinction to the localized forms of scleroderma, the generalized forms of scleroderma exhibit systemic features that may involve major organ systems. These systemic diseases may also accompany features of other autoimmune diseases like inflammatory myopathies (polymyositis), lupus, or rheumatoid arthritis.

6. Progressive Systemic Sclerosis (PSS)

This is a systemic fibrotic disease in which uncontrolled fibrosis of the skin and major organs take place. Characteristic microvascular compromise occurs and specific autoantibodies are also found.

Virtually all patients with PSS have Raynaud's Phenomenon, a clinical manifestation of microvascular compromise. This phenomenon refers to episodic pallor, cyanosis, suffusion, and pain in the fingers, toes, nose or ears in response to the cold. Its presence is a strong indication that the disease has a vascular component. Though it is normal for the muscular digital arteries of the fingers to contract in the cold, in patients with scleroderma, this response is heightened and they lack the reactive hyperemia seen in normal persons. This puts the digits of patients with scleroderma at risk for ischemic necrosis. The endothelium is injured, causing secondary platelet activation. These platelets then adhere to the subendothelium, aggregate, and induce the release of vasoconstrictors (thromboxane A2, 5-hydrosytryptamine, adenosine diphosphate). Normal, healthy endothelium opposes these effects but the diseased endothelium cannot respond as well, and more constrictors are released. This cascade of events leads to occlusion of the vessel, and intimal hyperplasia.

Though Raynaud’s phenomenon is present in the vast majority of patients with scleroderma, it is also commonly found in the normal female population. Primary Raynaud’s is found in about ten percent of the normal female population, and usually begins in the teenage years. The diagnosis of Raynaud's phenomenon rests upon eliciting the characteristic biphasic response upon cold exposure and can be confirmed with nailfold microscopy and/or serum autoantibody determinations. The Raynaud’s process associated with PSS patients is often associated with clinical manifestations of fixed ischemia: digital pitting, and necrosis. These problems are never seen in the benign, common form of Raynaud’s. Nailfold microscopy may help to distinguish the severity of Raynaud’s phenomenon. In PSS, nailfold microscopy reveals dilated, distorted capillaries with irregular spacing (capillary dropout). The criteria that distinguish primary Raynaud's phenomenon (unassociated with connective tissue disease) from secondary Raynaud's phenomenon (associated with connective tissue disease like scleroderma and other rheumatic diseases like lupus) are listed below:

Primary Raynaud's Secondary Raynaud's
Sex Female Male and female
Age at Onset Menarche Mid-20's or later
Frequency of Attacks >10 a day 0-5 a day
Finger edema No Frequent
Periungual erythema Rare Frequent
Arthritis No Frequent

Skin involvment in this disease always involves the distal extremities, and usually proceeds to involve the trunk and face. The skin becomes hard, and dense, resulting in a leather like feeling. The fibrosis results in joint contractures and progressive disability. Skin breakdown over bony prominences lead to infection and digital ischemia from Raynaud’s phenomenon can cause necrosis of the finger tips, autoamputation, and secondary osteomyelitis.

The lungs of affected patients can result in interstitial fibrosis or pulmonary hypertension. In limited scleroderma (a form of generalized scleroderma), formerly known as CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia), isolated pulmonary hypertension can occur. Marked intimal proliferation and medial thickening lead to narrowing of the vessel lumina. Pulmonary hypertension in these patients can sometimes lead to right sided heart failure. In patients with diffuse scleroderma (also a form of generalized scleroderma), the thin alveolar wall interstitial space seen in normal individuals is thickened because of excess deposition of collagen and other matrix components. The alveolar air space volumes decreases, and the A-a gradient (arterial-alveoli) widens. Pulmonary hypertension can follow from this fibrotic process as well as from the intimal proliferation of the pulmonary vasculature. As the diagnosis and treatment of scleroderma renal crisis has improved (see below), lung disease has now become a leading cause of death in patients with scleroderma.

Cardiac involvement in scleroderma can also occur. Pericarditis and pericardial effusions associated with fibrosis and constrictive pericarditis and fibrosis in the myocardium itself can lead to life threatening consequences.

One of the most serious manifestations of scleroderma is renal crisis. This affects only 10% of patients with scleroderma and most cases of scleroderma crisis occur early on in the disease, usually with the first four years. Rapidly developing hypertension is the clinical hallmark, sometimes leading to heart failure. Predictors of renal crisis include early disease, rapid progression of skin thickening, new anemia, and the administration of steroids. The presence of anti-Scl 70 does not predict renal failure. The small renal arteries and arterioles in these patients exhibit intimal proliferation, medial thickening, and narrowed lumina. Local ischemia can lead to shrunken glomeruli and end stage renal systemic sclerosis is characterized by sclerotic glomeruli in the infarcted renal cortex. Microangiopathic hemolytic anemia can also occur, as a result of erythrocytes traversing an abnormal renal circulation and the passage of erythrocytes through fibrin clots. The clinical manifestations of renal crisis include severe hypertension and pulmonary edema. Angiotensin converting enzyme inhibitors (captopril, enalapril) have significantly altered the prognosis of this condition. Despite their availability, renal failure can still occur, leading to the use of dialysis. Renal transplantation in selected patients is also another treatment option in patients whose renal function fails to normalize.

The gastrointestinal tract is the most common internal organ involved in progressive and limited scleroderma. Gastrointestinal involvement results from fibrosis within the smooth muscle layer, lamina propria, and submucosa.. This leads to diminished peristalsis, constipation, and the development of diverticula. Diminished peristalsis in the esophagus leads to reflux esophagitis, and possibly to Barrett’s esophagitis. The use of proton pump inhibitors (omeprazole) has been of great benefit in the treatment of severe reflux esophagitis in these patients.

The musculoskeletal system is involved in this disease in a variety of ways. The skeletal muscle can be diseased, due to expansion of perifascicular fibrous tissue. The clinical correlate is weakness and an elevation in the creatinine phosphokinase (CPK). Inflammation of the synovium (synovitis) can occur, but joint destruction like that seen in rheumatoid arthritis is not seen. Deposition of collagen within tendons results in joint contractures.

Autoantibody determinations may help the clinician diagnose progressive systemic sclerosis. Approximately 95% of patients have autoantibodies directed against the nucleus (antinuclear antibodies) when human epithelial cells are used as the substrate of the assay. The fluorescent pattern staining may be homogeneous or speckled or nucleolar. In addition, 60% of these patients also have antibodies to topoisomerase (previously know as anti-Scl 70). It is not understood whether these antibodies represent epiphenomenon or are pathogenic.

There is no known effective treatment for scleroderma and the treatment of its manifestations is directed at the specific system affected. PSS may lead to death from major organ involvement in the first three to five years of illness. Truncal skin involvement is associated with mortality at 5, 10, and 15 years greater than with either digital or proximal skin involvement. Low dose steroids may be used to treat some inflammatory manifestations (myositis, synovitis). Vasodilators like calcium channel blockers and isosorbide are helpful in treating severe Raynaud’s phenomenon. There is an emerging role for the use of endothelin antagonists (bosentan) for the treatment of Raynaud’s with digital ischemia. (Endothelin is a potent vasoconstrictor and exerts long term effects on vascular smooth muscle; there are two major endothelin receptors, and bosentan is a nonselective antagonist of these receptors.) The synthetic analogue of prostacylin, a potent vasodilator, has also been shown to be of some benefit for severe Raynaud’s as well. These agents (endothelin antagonists and prostacyclin like drugs) are also being used for the treatment of symptomatic pulmonary hypertension seen in progressive and limited scleroderma. Antacids, H-2 blockers and proton pump inhibitors are useful in the management of esophageal disease. ACE inhibitors may retard the progression of scleroderma renal crisis. Cyclophosphamide may be used in patients with interstitial fibrosis. Relaxin, a hormone like substance, was thought to be helpful in softening the skin of patients with scleroderma but randomized studies failed to show a benefit. Studies are now underway determining the utility of bone marrow transplantation in the treatment of severe PSS and organ transplantation for kidney and lung disease is also available.

7. Limited Scleroderma (lSSc; previously known as CREST)

This less severe form of generalized scleroderma also possesses cutaneous and visceral manifestations but differs from the former in its autoantibody association, extent, and prognosis. It is more prevalent than PSS and may take decades to become fully expressed.

Previous nomenclature defined this variant of scleroderma as CREST because the associated findings included calcinosis (generally not found in PSS), Raynaud's Phenomenon, esophageal dysmotility, sclerodactyly and telangiectasias. In addition to Raynaud's phenomenon, the organ involvement includes pulmonary hypertension. Isolated pulmonary hypertension is less common in PSS.

Anticentromere antibodies are characteristically associated with lSSc. These antibodies recognize antigenic determinants in the centromere. These antibodies appear early and remain constant. Again, it is not known whether they are pathogenic or simply represent disease markers.

The differences between PSS and lSSc are outlined in the following table:

Diffuse (PSS) Limited (lSSc)
Onset of Raynaud's <1 year years to decades
Skin truncal and acral acral or none
Tendon friction rubs present absent
Visceral disease early, frequent rare and late
Autoantibodies anti-topoisomerase (30-40%) anti-centromere (70-80%)

8. Other Scleroderma Like Syndromes

Though the cause of scleroderma is unknown, several disorders, which have been triggered by environmental or known factors, have led insight into the pathogenesis of the disease.

8.1. Toxic Oil Syndrome

Rapeseed oil, a toxic plant oil, was used inadvertently in cooking oil in Spain in 1981. Ingestion of this oil was linked to the occurrence of a scleroderma like disorder characterized by acute onset, myalgias, rash, and noncardiogenic pulmonary edema. Several months into the illness scleroderma like features and peripheral neuropathy developed. The cooking oil may have been altered by the presence of the rapeseed oil causing the formation of free radicals and secondary endothelial cell injury. This suggests that the vascular lesion may be primary, and that the fibrosis follows.

8.2. Drug induced Disease

Bleomycin, a chemotherapeutic agent commonly used to treat some malignancies like testicular cancer, can lead to a scleroderma like condition characterized by Raynaud’s phenomenon and interstitial pulmonary fibrosis. L-tryptophan, an amino acid that has been used for sleep, resulted in a syndrome resembling eosinophilic fasciitis in patients exposed to a contaminant of L-tryptophan that was manufactured by a single company. The contaminant appeared to be an isomer of L-tryptophan, which triggered inflammatory cells, eosinophils, and the synthesis of connective tissue components. The acute illness was in some ways like the toxic oil syndrome seen in Spain and notable for myalgias, cough, rash and an excessively high peripheral eosinophil count. A small percentage of these patients went on to develop findings compatible with eosinophilic fasciitis as well as respiratory failure, interstitial fibrosis, paralysis, and severe axonal neuropathy.

8.3. Graft Versus Host Disease

Bone marrow transplantation may result in the expression of a severe sclerodermatous disorder caused by donor marrow cells. Organ systems that may be affected by this fibrotic process include the heart, lung, and kidney-- the same organs affected in progressive systemic sclerosis.