Systemic scleroderma


Systemic scleroderma, or systemic sclerosis, is an autoimmune rheumatic disease characterised by excessive production and accumulation of collagen, called fibrosis, in the skin and internal organs and by injuries to small arteries. There are two major subgroups of systemic sclerosis based on the extent of skin involvement: limited and diffuse. The limited form affects areas below, but not above, the elbows and knees with or without involvement of the face. The diffuse form also affects the skin above the elbows and knees and can also spread to the torso. Visceral organs, including the kidneys, heart, lungs, and gastrointestinal tract can also be affected by the fibrotic process.
Prognosis is determined by the form of the disease and the extent of visceral involvement. Patients with limited systemic sclerosis have a better prognosis than those with the diffuse form. Death is most often caused by lung, heart, and kidney involvement. The risk of cancer is increased slightly.
Survival rates have greatly increased with effective treatment for kidney failure. Therapies include immunosuppressive drugs, and in some cases, glucocorticoids.

Signs and symptoms

, Raynaud's phenomenon, Esophageal dysfunction, Sclerodactyly, and Telangiectasia are associated with limited scleroderma. Other symptoms include:

Skin symptoms

In the skin, systemic sclerosis causes hardening and scarring. The skin may appear tight, reddish, or scaly. Blood vessels may also be more visible. Where large areas are affected, fat and muscle wastage may weaken limbs and affect appearance. Patients report severe and recurrent itching of large skin areas. The severity of these symptoms varies greatly among patients: Some having scleroderma of only a limited area of the skin and little involvement of the underlying tissue, while others have progressive skin involvement. Digital ulcers—open wounds especially on fingertips and less commonly the knuckles—are not uncommon.

Other organs

Diffuse scleroderma can cause musculoskeletal, pulmonary, gastrointestinal, renal, and other complications. Patients with greater cutaneous involvement are more likely to have involvement of the internal tissues and organs. Most patients have vascular symptoms and Raynaud's phenomenon, which leads to attacks of discoloration of the hands and feet in response to cold. Raynaud's normally affects the fingers and toes. Systemic scleroderma and Raynaud's can cause painful ulcers on the fingers or toes, which are known as digital ulcers. Calcinosis is also common in systemic scleroderma, and is often seen near the elbows, knees, or other joints.
;Musculoskeletal
The first joint symptoms that patients with scleroderma have are typically nonspecific joint pains, which can lead to arthritis, or cause discomfort in tendons or muscles. Joint mobility, especially of the small joints of the hand, may be restricted by calcinosis or skin thickening. Patients may develop muscle weakness, or myopathy, either from the disease or its treatments.
;Lungs
Some impairment in lung function is almost universally seen in patients with diffuse scleroderma on pulmonary function testing, but it does not necessarily cause symptoms, such as shortness of breath. Some patients can develop pulmonary hypertension, or elevation in the pressures of the pulmonary arteries. This can be progressive, and can lead to right-sided heart failure. The earliest manifestation of this may be a decreased diffusion capacity on pulmonary function testing. Other pulmonary complications in more advanced disease include aspiration pneumonia, pulmonary hemorrhage and pneumothorax.
;Digestive tract
Image:Peptic stricture.png|right|thumb|200px|Endoscopic image of peptic stricture, or narrowing of the esophagus near the junction with the stomach due to chronic gastroesophageal reflux: This is the most common cause of dysphagia, or difficulty swallowing, in scleroderma.
Diffuse scleroderma can affect any part of the gastrointestinal tract. The most common manifestation in the esophagus is reflux esophagitis, which may be complicated by esophageal strictures or benign narrowing of the esophagus. This is best initially treated with proton pump inhibitors for acid suppression, but may require bougie dilatation in the case of stricture.
Scleroderma can decrease motility anywhere in the gastrointestinal tract. The most common source of decreased motility is the esophagus and the lower esophageal sphincter, leading to dysphagia and chest pain. As scleroderma progresses, esophageal involvement from abnormalities in decreased motility may worsen due to progressive fibrosis. If this is left untreated, acid from the stomach can back up into the esophagus, causing esophagitis and gastroesophageal reflux disease. Further scarring from acid damage to the lower esophagus many times leads to the development of fibrotic narrowing, also known as strictures, which can be treated by dilatation.
In patients with neuromuscular disorders, particularly progressive systemic sclerosis and visceral myopathy, the duodenum is frequently involved. Dilatation may occur, which is often more pronounced in the second, third, and fourth parts. The dilated duodenum may be slow to empty, and the grossly dilated, atonic organ may produce a sump effect.
The small intestine can also become involved, leading to bacterial overgrowth and malabsorption of bile salts, fats, carbohydrates, proteins, and vitamins. The colon can be involved, and can cause pseudo-obstruction or ischemic colitis.
Rarer complications include pneumatosis cystoides intestinalis, or gas pockets in the bowel wall, wide-mouthed diverticula in the colon and esophagus, and liver fibrosis. Patients with severe gastrointestinal involvement can become profoundly malnourished.
Scleroderma may also be associated with gastric antral vascular ectasia, also known as "watermelon stomach". This is a condition in which atypical blood vessels proliferate, usually in a radially symmetric pattern around the pylorus of the stomach. It can be a cause of upper gastrointestinal bleeding or iron-deficiency anemia in patients with scleroderma.
;Kidneys
Image:Thrombotic microangiopathy - very high mag.jpg|thumb|Micrograph showing thrombotic microangiopathy, the histomorphologic finding seen in scleroderma renal crisis, kidney biopsy, PAS stain
Kidney involvement, in scleroderma, is considered a poor prognostic factor and frequently a cause of death.
The most important clinical complication of scleroderma involving the kidney is scleroderma renal crisis, the symptoms of which are malignant hypertension, hyperreninemia, azotemia, and microangiopathic hemolytic anemia. Apart from the high blood pressure, hematuria and proteinuria may be indicative of SRC.
In the past, SRC was almost uniformly fatal. While outcomes have improved significantly with the use of ACE inhibitors, the prognosis is often guarded, as a significant number of patients are refractory to treatment and develop kidney failure. About 7–9% of all diffuse cutaneous scleroderma patients develop renal crisis at some point in the course of their disease. Patients who have rapid skin involvement have the highest risk of renal complications. It is most common in diffuse cutaneous scleroderma, and is often associated with antibodies against RNA polymerase. Many proceed to dialysis, although this can be stopped within three years in about a third of cases. Higher age and a lower blood pressure at presentation make dialysis more likely to be needed.
Treatments for SRC include ACE inhibitors. Prophylactic use of ACE inhibitors is currently not recommended, as recent data suggest a poorer prognosis in patient treated with these drugs prior to the development of renal crisis. Transplanted kidneys are known to be affected by scleroderma, and patients with early-onset renal disease are thought to have the highest risk for recurrence.

Causes

No clear cause for scleroderma and systemic sclerosis has been identified. Genetic predisposition appears to be limited, as genetic concordance is small; still, a familial predisposition for autoimmune disease is often seen. Polymorphisms in COL1A2 and TGF-β1 may influence severity and development of the disease. Evidence implicating cytomegalovirus as the original epitope of the immune reaction is limited, as is parvovirus B19. Organic solvents and other chemical agents have been linked with scleroderma.
One of the suspected mechanisms behind the autoimmune phenomenon is the existence of microchimerism, i.e. fetal cells circulating in maternal blood, triggering an immune reaction to what is perceived as foreign material.
A distinct form of scleroderma and systemic sclerosis may develop in patients with chronic kidney failure. This form, nephrogenic fibrosing dermopathy or nephrogenic systemic fibrosis, has been linked to exposure to gadolinium-containing radiocontrast.
Bleomycin and possibly taxane chemotherapy may cause scleroderma, and occupational exposure to solvents has been linked to an increased risk of systemic sclerosis.

Pathophysiology

Overproduction of collagen is thought to result from an autoimmune dysfunction, in which the immune system starts to attack the kinetochore of the chromosomes. This would lead to genetic malfunction of nearby genes. T cells accumulate in the skin; these are thought to secrete cytokines and other proteins that stimulate collagen deposition. Stimulation of the fibroblast, in particular, seems to be crucial to the disease process, and studies have converged on the potential factors that produce this effect.
A significant player in the process is transforming growth factor. This protein appears to be overproduced, and the fibroblast also overexpresses the receptor for this mediator. An intracellular pathway is responsible for the secondary messenger system that induces transcription of the proteins and enzymes responsible for collagen deposition. Sp1 is a transcription factor most closely studied in this context. Apart from TGFβ, connective tissue growth factor has a possible role. Indeed, a common CTGF gene polymorphism is present at an increased level in systemic sclerosis.
Damage to endothelium is an early abnormality in the development of scleroderma, and this, too, seems to be due to collagen accumulation by fibroblasts, although direct alterations by cytokines, platelet adhesion, and a type II hypersensitivity reaction similarly have been implicated. Increased endothelin and decreased vasodilation have been documented.
Jimenez and Derk describe three theories about the development of scleroderma:
  • The abnormalities are primarily due to a physical agent, and all other changes are secondary or reactive to this direct insult.
  • The initial event is fetomaternal cell transfer causing microchimerism, with a second summative cause leading to the actual development of the disease.
  • Physical causes lead to phenotypic alterations in susceptible cells, which then effectuate DNA changes that alter the cells' behavior.