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This article is about the disease. For the mushroom, see Scleroderma citrinum.

Systemic sclerosis
Classifications and external resources

ICD-10	M34.
ICD-9	710.1
OMIM	181750
DiseasesDB	12845
MedlinePlus	000429
eMedicine	med/2076

Scleroderma is a rare, chronic disease characterized by excessive deposits of collagen. Progressive systemic scleroderma or systemic sclerosis, the generalised type of the disease, can be fatal. The localised type of the disease tends not to be fatal. The term "localised, generalised scleroderma" can be used to describe cases where the disease covers a large area of the body - typically more than 40%.

Contents 1 Signs and symptoms 2 Complications 2.1 Musculoskeletal complications 2.2 Pulmonary complications 2.3 Gastrointestinal complications 2.4 Renal complications 3 Diagnosis 4 Types 4.1 Diffuse scleroderma 4.2 Limited scleroderma/CREST syndrome 4.3 Morphea/linear scleroderma 5 Therapy 6 Causes 7 Pathophysiology 8 Epidemiology 9 Patients' advocacy 10 References 11 External links

[edit] Signs and symptoms

Scleroderma affects the skin, and in more serious cases it can affect the blood vessels and internal organs. The most evident symptom is the hardening of the skin and associated scarring. Typically, the skin appears reddish or scaly in appearance. Blood vessels may also be more visible. Where large areas are affected, fat and muscle wastage will weaken limbs and affect appearance.

The seriousness of the disease varies hugely between cases. The two most important factors to consider are the level of internal involvement (beneath the skin) and the total area covered by the disease. For example, there have been cases where the patient has no more than one or two lesions (affected areas), perhaps covering a few inches. Less serious cases tend not to involve the internal bodily functions.

There is discoloration of the hands and feet in response to cold. Most patients (over 80%) have Raynaud's phenomenon, a vascular symptom that can affect 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.

[edit] Complications

Diffuse scleroderma can cause musculoskeletal, pulmonary, gastrointestinal, renal and other complications.<ref name=Primer>Systemic sclerosis and related syndromes. Primer on the rheumatic diseases, 11th edition, The Arthritis Society, p. 269, 1997</ref> Patients with larger amounts of cutaneous involvement are more likely to have involvement of the internal tissues and organs.

[edit] Musculoskeletal complications

The first joint symptoms that patients with scleroderma have are typically non specific joint pains, which can lead to arthritis, or cause discomfort in tendons or muscles.<ref name=Primer/> Joint mobility, especially of the small joints of the hand, may be restricted by calcinosis or skin thickening.<ref>Valentini G, Black C. Systemic sclerosis. Best Pract Res Clin Rheumatol. 2002 Dec;16(5):807-16. PMID 12473275</ref> Patients who have progressed later in their disease may develop muscle weakness, or myopathy, either from the disease, or its treatments.<ref>Olsen NJ, King LE Jr, Park JH. Muscle abnormalities in scleroderma. Rheum Dis Clin North Am. 1996 Nov;22(4):783-96. PMID. 8923596. </ref>

[edit] Pulmonary complications

Some impairment in lung function is almost universally seen in patients with diffuse scleroderma on pulmonary function testing;<ref>Steen VD. The lung in systemic sclerosis. J Clin Rheumatol 2005 Feb;11(1):40-6. PMID 16357695</ref> however, 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 veins. This can be progressive, and 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.<ref name=Primer/>

[edit] Gastrointestinal complications

Diffuse scleroderma can affect any part of the gastrointestinal tract.<ref name=Sallam>Sallam H, McNearney TA, Chen JD. Systematic review: pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis (scleroderma). Aliment Pharmacol Ther. 2006 Mar 15;23(6):691-712. PMID 16556171</ref> The most common manifestation in the esophagus is reflux esophagitis, which may be complicated by peptic stricturing, or benign narrowing of the esophagus.<ref name=Rose>Rose S, Young MA, Reynolds JC. Gastrointestinal manifestations of scleroderma. Gastroenterol Clin North Am. 1998 Sep;27(3):563-94. PMID 9891698</ref> This is best initially treated with proton pump inhibitors for acid suppression,<ref>Hendel L, Hage E, Hendel J, Stentoft P. Omeprazole in the long-term treatment of severe gastro-oesophageal reflux disease in patients with systemic sclerosis. Aliment Pharmacol Ther. 1992 Oct;6(5):565-77. PMID 1420748</ref> but may require bougie dilatation in the case of stricture.<ref name=Sallam/>

Scleroderma can decrease motility anywhere in the gastrointestinal tract.<ref name=Sallam/> The commonest source of motility involvement is the esophagus, which can also lead to difficulty swallowing or dysphagia, or to chest pain. The esophagus can become massively dilated (megaesophagus).<ref name=Primer/> This can be treated with esophageal dilatation or with botulinum toxin injection. 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.<ref name=Primer/>

Rarer complications include pneumatosis cystoides intestinalis, or gas pockets in the bowel wall, wide mouthed diverticulae in the colon and esophagus, and liver fibrosis. Patients with severe gastrointestinal involvement can become profoundly malnourished.<ref name=Rose/>

Scleroderma may also be associated with gastric antral vascular ectasia (GAVE), also known as watermelon stomach. This is a condition where atypical blood vessels proliferate usually in a radially symmetric pattern around the pylorus of the stomach. GAVE can be a cause of upper gastrointestinal bleeding or iron deficiency anemia in patients with scleroderma.<ref name=Rose/>

[edit] Renal complications

Renal involvement, in scleroderma, is considered a poor prognostic factor and not infrequently a cause of death in patients with scleroderma.<ref>Ruangjutipopan S, Kasitanon N, Louthrenoo W, Sukitawut W, Wichainun R. Causes of death and poor survival prognostic factors in thai patients with systemic sclerosis. J Med Assoc Thai. 2002 Nov;85(11):1204-9. PMID 12546318.</ref>

The most important clinical complication of scleroderma involving the kidney is scleroderma renal crisis.

Symptoms of scleroderma renal crisis are:<ref>Steen VD, Mayes MD, Merkel PA. Assessment of kidney involvement. Clin Exp Rheumatol. 2003;21(3 Suppl 29):S29-31 PMID 12889219.</ref>

• Malignant hypertension,
• Hyperreninemia,
• Azotemia,
• Microangiopathic hemolytic anemia and
• Renal failure.

Complications of renal crisis include:<ref>Steen VD. Renal involvement in systemic sclerosis. Clin Dermatol. 1994 Apr-Jun;12(2):253-8. PMID 8076263.</ref>

• Hematuria (blood in the urine),
• Hypertension and
• Proteinuria.

In the past scleroderma renal crisis was almost uniformily fatal.<ref name=steen>Steen VD. Scleroderma renal crisis. Rheum Dis Clin North Am. 2003 May;29(2):315-33. Review. PMID 12841297.</ref> While outcomes have improved significantly with the use of ACE inhibitors<ref>Rhew EY, Barr WG. Scleroderma renal crisis: new insights and developments. Curr Rheumatol Rep. 2004 Apr;6(2):129-36. Review. PMID 15016343.</ref><ref name=steen11033587>Steen VD, Medsger TA Jr. Long-term outcomes of scleroderma renal crisis. Ann Intern Med. 2000 Oct 17;133(8):600-3. PMID 11033587. [Free Full Text http://www.annals.org/cgi/reprint/133/8/600.pdf].</ref> the prognosis is often guarded, as a significant number of patients are refractory to treatment and develop renal failure. Approximately 10% of all scleroderma patients develop renal crisis at some point in the course of their disease.<ref name=jimenez>Jimenez S, Koenig AS. Scleroderma. eMedicine.com. URL: http://www.emedicine.com/MED/topic2076.htm. Accessed: May 22, 2006.</ref> Patients that have rapid skin involvement have the highest risk of renal complications.<ref name=jimenez/>

Treatments for scleroderma renal crisis include ACE inhibitors, which are also used for prophylaxis,<ref name=jimenez/><ref name=steen11033587/> and renal transplantation. Transplanted kidneys are known to be affect by scleroderma and patients with early onset renal disease (within one year of the scleroderma diagnosis) are thought to have the highest risk for recurrence.<ref>Pham PT, Pham PC, Danovitch GM, Gritsch HA, Singer J, Wallace WD, Hayashi R, Wilkinson AH. Predictors and risk factors for recurrent scleroderma renal crisis in the kidney allograft: case report and review of the literature. Am J Transplant. 2005 Oct;5(10):2565-9. PMID 16162209.</ref>

[edit] Diagnosis

Diagnosis is by clinical suspicion, presence of autoantibodies (specifically anti-centromere and anti-scl70/anti-topoisomerase) and occasionally by biopsy. Of the antibodies, 90% have a detectable anti-nuclear antibody. Anti-centromere is more common in the limited form (80-90%) than in the systemic form (10%), and anti-scl70 is more common in the diffuse form (30-40%) and in African-American patients (who are more prone to the systemic form).<ref name=Jimenez>Jimenez SA, Derk CT. Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis. Ann Intern Med 2004;140:37-50. PMID 14706971.</ref>

In 1980 the American College of Rheumatology agreed upon diagnostic criteria for scleroderma.<ref>http://www.rheumatology.org/publications/classification/systsclr.asp.</ref>

[edit] Types

There are three major forms of scleroderma: diffuse, limited (CREST syndrome) and morphea/linear. Diffuse and limited scleroderma are both a systemic disease, whereas the linear/morphea form is localized to the skin. (Some physicians consider CREST and limited scleroderma one and the same, others treat them as two separate forms of scleroderma.) There is also a subset of the systemic form known as "systemic scleroderma sine scleroderma", meaning the usual skin involvement is not present.

[edit] Diffuse scleroderma

Diffuse scleroderma is the most severe form - it has a rapid onset, involves more widespread skin hardening, will generally cause much internal organ damage (specifically the lungs and gastrointestinal tract), and is generally more life threatening.

[edit] Limited scleroderma/CREST syndrome

The limited form is much milder: it has a slow onset and progression, skin hardening is usually confined to the hands and face, internal organ involvement is less severe, and a much better prognosis is expected.

In typical cases of limited scleroderma, Raynaud's phenomenon may precede scleroderma by several years. Raynaud's phenomenon is due to vasoconstriction of the small arteries of exposed peripheries - particularly the hands and feet - in the cold. It is classically characterised by a triphasic colour change - first white, then blue and finally red on rewarming. The scleroderma may be limited to the fingers - known as sclerodactyly.

The limited form is often referred to as "CREST" syndrome. CREST is an acronym for:

• Calcinosis
• Raynaud's syndrome
• Esophageal dysmotility
• Sclerodactyly
• Telangiectasia

These five are the major symptoms of the CREST syndrome.

[edit] Morphea/linear scleroderma

Morphea/linear scleroderma involves isolated patches of hardened skin - there generally is no internal organ involvement.

[edit] Therapy

There is no cure for scleroderma, though there is treatment for some of the symptoms, including drugs that soften the skin and reduce inflammation. Some patients may benefit from exposure to heat.

A range of NSAIDs (nonsteroidal anti-inflammatory drugs) can be used to ease symptoms, such as Naproxen. If there is oesophageal dysmotility (in CREST or systemic sclerosis), care must be taken with NSAIDs as they are gastric irritants, and so a proton pump inhibitor (PPI) such as omeprazole can be given in conjunction.

Immunosuppressant drugs, such as mycophenolate mofetil (Cellcept®) or cyclophosphamide are sometimes used to slow the progress.

Digital ulcerations can be helped by prostacyclin (iloprost) infusion. Iloprost being a drug which increases blood flow by relaxing the arterial wall.

[edit] Causes

There is no clear obvious cause for scleroderma and systemic sclerosis. Genetic predisposition appears to be limited: genetic concordance is small; still, there often is a familial predisposition for autoimmune disease. Polymorphisms in COL1A and TGF-β1 may influence severity and development of the disease. There is limited evidence implicating cytomegalovirus (CMV) as the original epitope of the immune reaction, and organic solvents and other chemical agents have been linked with scleroderma.<ref name=Jimenez/>

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<ref name=Bianchi>Bianchi DW. Fetomaternal cell trafficking: a new cause of disease? Am J Med Genet 2000;91:22-8. PMID 10751084.</ref>.<ref name=Jimenez/>

[edit] Pathophysiology

The overproduction of collagen is thought to result from an autoimmune dysfunction, in which the immune system would start 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.<ref name=Jimenez/>

A significant player in the process is transforming growth factor (TGFβ). This protein appears to be overproduced, and the fibroblast (possibly in response to other stimuli) also overexpresses the receptor for this mediator. An intracellular pathway (consisting of SMAD2/SMAD3, SMAD4 and the inhibitor SMAD7) 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 (CTGF) has a possible role.<ref name=Jimenez/>

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 have similarly been implicated. Increased endothelin and decreased vasodilation has been documented.<ref name=Jimenez/>

Jimenez & Derk<ref name=Jimenez/> 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 (e.g. environmental) leading to the actual development of the disease.
• Physical causes lead to phenotypic alterations in susceptible cells (e.g. due to genetic makeup), which then effectuate DNA changes which alter the cell's behavior.

[edit] Epidemiology

Scleroderma affects approximately 300,000 people in the United States. It is four times as common in women than in men. Incidence rates are estimated at 2-20 per million per year in the United States.

[edit] Patients' advocacy

The Scleroderma Foundation is a leading organization dedicated to raising awareness of the disease and assisting those who are affected. Its national spokesperson is Jason Alexander. Bob Saget is also very active in advocacy as his sister died of the disease.

[edit] References

<references/>

[edit] External links

• Scleroderma Foundation
• International Scleroderma Network
• The Scleroderma Research Foundation
• UK Scleroderma Societyde:Sklerodermie

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