Scleroderma

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Systemic sclerosis
Scleroderma-301.jpg
MCP, PIP and DIP joints destructions in patient with Scleroderma.
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ICD-10 M34.
ICD-9 710.1
OMIM 181750
DiseasesDB 12845
MedlinePlus 000429
MeSH D012595

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]

Click here for The heart in Scleroderma

Overview

Scleroderma is a rare, chronic disease characterized by excessive deposits of collagen in the skin or other organs. The localized type of the disease, while disabling, tends not to be fatal. Diffuse scleroderma or systemic sclerosis, the generalized type of the disease, can be fatal as a result of heart, kidney, lung or intestinal damage.[1]

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.
  • Juvenile scleroderma affects approximately 7,000 children in the United States.
  • The most common form of Juvenile Scleroderma is Localized Scleroderma - Morphea and/or Linear.

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.[2]

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.[2]

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.[2]

Jimenez & Derk[2] 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.

Etiology

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 COL1A2 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.[2]

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.[3][2]

A distinct form of scleroderma and systemic sclerosis may develop in patients with chronic renal failure. This entity, nephrogenic fibrosing dermopathy or nephrogenic systemic fibrosis,[4] has been linked to the exposure to gadolinium-containing radiocontrast.[5]

Bleomycin[6] (a chemotherapeutic agent) and possibly taxane chemotherapy[7] may cause scleroderma, and occupational exposure to solvents has been linked with an increased risk of systemic sclerosis.[8]

Types of Scleroderma

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.

Diffuse scleroderma

Diffuse scleroderma (progressive systemic sclerosis) 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.

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.[9] "CREST" is an acronym for the five main features:

Morphea/linear scleroderma

Morphea/linear scleroderma involves isolated patches of hardened skin - there generally is no internal organ involvement.[10]

Diagnosis

Diagnosis is by clinical suspicion, presence of autoantibodies (specifically anti-centromere and anti-scl70/anti-topoisomerase antibodies) and occasionally by biopsy. Of the antibodies, 90% have a detectable anti-nuclear antibody. Anti-centromere antibody 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 susceptible to the systemic form).[2]

In 1980 the American College of Rheumatology agreed upon diagnostic criteria for scleroderma.[11]

Diffuse scleroderma can cause musculoskeletal, pulmonary, gastrointestinal, renal and other complications.[1]Patients with larger amounts of cutaneous involvement are more likely to have involvement of the internal tissues and organs.

Cardiovascular Symptoms

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Skin 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. 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, 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 phenomenon 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.


Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Musculoskeletal System Related Symptoms

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.[1] Joint mobility, especially of the small joints of the hand, may be restricted by calcinosis or skin thickening.[12] Patients who have progressed later in their disease may develop muscle weakness, or myopathy, either from the disease, or its treatments.[13]

Image courtesy of RadsWiki

Respiratory System Symptoms

Some impairment in lung function is almost universally seen in patients with diffuse scleroderma on pulmonary function testing;[14] 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 arteries. 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.[1]

Images courtesy of RadsWiki

Gastrointestinal System Related Symptoms

Diffuse scleroderma can affect any part of the gastrointestinal tract.[15] The most common manifestation in the esophagus is reflux esophagitis, which may be complicated by peptic stricturing, or benign narrowing of the esophagus.[16] This is best initially treated with proton pump inhibitors for acid suppression,[17] but may require bougie dilatation in the case of stricture.[15]

Scleroderma can decrease motility anywhere in the gastrointestinal tract.[15] The most common source of decreased motility involvement 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 (scarring). If this is left untreated, acid from the stomach can back up into the esophagus causing esophagitis, and GERD. 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, and Barrett's esophagus. 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.[1]

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.[16]

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.[16]


Renal Symptoms

Renal involvement, in scleroderma, is considered a poor prognostic factor and not infrequently a cause of death in patients with scleroderma.[18]

The most important clinical complication of scleroderma involving the kidney is scleroderma renal crisis. Symptoms of scleroderma renal crisis are malignant hypertension (high blood pressure with evidence of acute organ damage), hyperreninemia (high renin levels), azotemia (kidney failure with accumulation of waste products in the blood) and microangiopathic hemolytic anemia (destruction of red blood cells).[19] Apart from the high blood pressure, hematuria (blood in the urine) and proteinuria (protein loss in the urine) may be indicative.[20]

In the past scleroderma renal crisis was almost uniformily fatal.[21] While outcomes have improved significantly with the use of ACE inhibitors[22][23] 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.[24] Patients that have rapid skin involvement have the highest risk of renal complications.[24]

Therapy

There is no cure for every patient with 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.[25]

Digital ulcerations and pulmonary hypertension can be helped by prostacyclin (iloprost) infusion. Iloprost being a drug which increases blood flow by relaxing the arterial wall.[26]

Topical/symptomatic

Topical treatment for the skin changes of scleroderma do not alter the disease course, but may improve pain and ulceration. A range of NSAIDs (nonsteroidal anti-inflammatory drugs) can be used to ease painful symptoms, such as naproxen. There is limited benefit from steroids such as prednisone. Episodes of Raynaud's phenomenon sometimes respond to nifedipine or other calcium channel blockers; severe digital ulceration may respond to prostacyclin analogue iloprost, and the dual endothelin-receptor antagonist bosentan may be beneficial for Raynaud's phenomenon.[27] The skin tightness may be treated systemically with methotrexate and cyclosporin.[27] If there is esophageal 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.

Kidney disease

Scleroderma renal crisis, the occurrence of acute renal failure and malignant hypertension (very high blood pressure with evidence of organ damage) in people with scleroderma, is effectively treated with drugs from the class of the ACE inhibitors. The benefit of ACE inhibitors extends even to those who have to commence dialysis to treat their kidney disease, and may give sufficient benefit to allow the discontinuation of renal replacement therapy.[27] ACE inhibitors are also used for prophylaxis,[24][23] and renal transplantation. Transplanted kidneys are known to be affected 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.[28]

Lung disease and pulmonary hypertension

Active alveolitis is often treated with pulses of cyclophosphamide, often together with a small dose of steroids. The benefit of this intervention is modest.[29][30]

Pulmonary hypertension may be treated with epoprostenol, bosentan and possibly aerolized iloprost.[27]

Experimental treatments

Given the difficulty in treating scleroderma, treatments with a smaller evidence base are often tried to control the disease. These include antithymocyte globulin and mycophenolate mofetil; some reports have reported improvements in the skin symptoms as well as delaying the progress of systemic disease, but neither of them have been subjected to large clinical trials.[27]

While still experimental (given its high rate of complications), hematopoietic stem cell transplantation is being studied in patients with severe systemic sclerosis; improvement in life expectancy and severity of skin changes has been noted.[31]

Case Examples

Case #1

Clinical Summary

A 29-year-old black female had a history of scleroderma involving the lung, kidney, heart, and skin. Her main clinical problems centered on her restrictive lung disease. She was able to live at home with supplemental oxygen but recently she had developed edema, chest pain, weakness, lightheadedness, and a loss of appetite. The patient was admitted to the hospital with a working diagnosis of congestive heart failure brought on by her lung disease.

Echocardiographic evaluation revealed a pericardial effusion that was tapped. Soon after this procedure her respiratory status degenerated and she required intubation. Despite aggressive supportive treatment for her cardiac and pulmonary problems, she could not be weaned from the ventilator. Two weeks after admission she became febrile and Gram positive cocci were isolated from sputum culture. She was placed on antibiotics but her condition deteriorated and she developed bradycardia followed by electromechanical dissociation (EMD).

Autopsy Findings

Upon opening the thorax there was 600 cc of cloudy serous fluid in each hemithorax and 100 cc of similar fluid in the pericardial sac. The heart weighed 530 grams and there was thickening of both the left and right ventricular walls. The liver weighed 1880 grams and was congested. The spleen weighed 200 grams and was also congested. The combined lung weight was 1875 grams; the lungs were markedly fibrotic with severe emphysema. In addition, dermal thickening was evident throughout the body and the wall of the esophagus was thickened and firm.

Histopathological Findings

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

This is a gross photograph of cut section of the lungs from this patient. Note the extensive fibrosis of the lung parenchyma.


This is a gross photograph of a cut section of one lung from this patient. Note the extensive fibrosis lower lobe (arrows).


This is a closer view of the cut section of lung from this patient. Note the extensive fibrosis and the severe emphysematous changes.


This is a closer view of the cut section of lung from this patient showing the extensive fibrosis and the severe emphysematous change.


This is a gross photograph of the heart from this case. There is thickening of the left ventricular wall and some thickening of the right ventricle as well.


References

  1. 1.0 1.1 1.2 1.3 1.4 Klippel J (ed). Systemic sclerosis and related syndromes. Primer on the rheumatic diseases, 11th edition. The Arthritis Society. 1997;269. ISBN 1-91242-316-2.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Jimenez SA, Derk CT (2004). "Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis". Ann. Intern. Med. 140 (1): 37-50. PMID 14706971.
  3. Bianchi DW (2000). "Fetomaternal cell trafficking: a new cause of disease?". Am. J. Med. Genet. 91 (1): 22-8. PMID 10751084.
  4. Galan A, Cowper SE, Bucala R (2006). "Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy)". Current opinion in rheumatology 18 (6): 614-7. doi:10.1097/01.bor.0000245725.94887.8d. PMID 17053507.
  5. Boyd AS, Zic JA, Abraham JL (2007). "Gadolinium deposition in nephrogenic fibrosing dermopathy". J. Am. Acad. Dermatol. 56 (1): 27-30. doi:10.1016/j.jaad.2006.10.048. PMID 17109993.
  6. Sharma SK, Handa R, Sood R, et al (2004). "Bleomycin-induced scleroderma". The Journal of the Association of Physicians of India 52: 76-7. PMID 15633728.
  7. Farrant PB, Mortimer PS, Gore M (2004). "Scleroderma and the taxanes. Is there really a link?". Clin. Exp. Dermatol. 29 (4): 360-2. doi:10.1111/j.1365-2230.2004.01519.x. PMID 15245529.
  8. Kettaneh A, Al Moufti O, Tiev KP, et al (2007). "Occupational exposure to solvents and gender-related risk of systemic sclerosis: a metaanalysis of case-control studies". J. Rheumatol. 34 (1): 97-103. PMID 17117485.
  9. Winterbauer RH (1964). "Multiple telangiectasia, Raynaud'S phenomenon, sclerodactyly, and subcutanious calcinosis: a syndrome mimicking hereditary hemorrhagic telangiectasia". Bulletin of the Johns Hopkins Hospital 114: 361-83. PMID 14171636.
  10. Morpea CNN.com, (May 05, 2006).
  11. "Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee". Arthritis Rheum. 23 (5): 581-90. PMID 7378088. Available online at Criteria for the Classification of Systemic Sclerosis 1980.
  12. Valentini G, Black C (2002). "Systemic sclerosis". Best practice & research. Clinical rheumatology 16 (5): 807-16. PMID 12473275.
  13. Olsen NJ, King LE, Park JH (1996). "Muscle abnormalities in scleroderma". Rheum. Dis. Clin. North Am. 22 (4): 783-96. PMID 8923596.
  14. Steen VD (2005). "The lung in systemic sclerosis". Journal of clinical rheumatology 11 (1): 40-6. PMID 16357695.
  15. 15.0 15.1 15.2 Sallam H, McNearney TA, Chen JD (2006). "Systematic review: pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis (scleroderma)". Aliment. Pharmacol. Ther. 23 (6): 691-712. doi:10.1111/j.1365-2036.2006.02804.x. PMID 16556171.
  16. 16.0 16.1 16.2 Rose S, Young MA, Reynolds JC (1998). "Gastrointestinal manifestations of scleroderma". Gastroenterol. Clin. North Am. 27 (3): 563-94. PMID 9891698.
  17. Hendel L, Hage E, Hendel J, Stentoft P (1992). "Omeprazole in the long-term treatment of severe gastro-oesophageal reflux disease in patients with systemic sclerosis". Aliment. Pharmacol. Ther. 6 (5): 565-77. PMID 1420748.
  18. Ruangjutipopan S, Kasitanon N, Louthrenoo W, Sukitawut W, Wichainun R (2002). "Causes of death and poor survival prognostic factors in thai patients with systemic sclerosis". Journal of the Medical Association of Thailand 85 (11): 1204-9. PMID 12546318.
  19. Steen VD, Mayes MD, Merkel PA (2003). "Assessment of kidney involvement". Clin. Exp. Rheumatol. 21 (3 Suppl 29): S29-31. PMID 12889219.
  20. Steen VD (1994). "Renal involvement in systemic sclerosis". Clin. Dermatol. 12 (2): 253-8. PMID 8076263.
  21. Steen VD (2003). "Scleroderma renal crisis". Rheum. Dis. Clin. North Am. 29 (2): 315-33. PMID 12841297.
  22. Rhew EY, Barr WG (2004). "Scleroderma renal crisis: new insights and developments". Current rheumatology reports 6 (2): 129-36. PMID 15016343.
  23. 23.0 23.1 Steen VD, Medsger TA (2000). "Long-term outcomes of scleroderma renal crisis". Ann. Intern. Med. 133 (8): 600-3. PMID 11033587.
  24. 24.0 24.1 24.2 Jimenez S, Koenig AS. Scleroderma. eMedicine.com. Accessed: May 22, 2006.
  25. Oliver GF, Winkelmann RK (1989). "The current treatment of scleroderma". Drugs 37 (1): 87-96. PMID 2651089.
  26. Zandman-Goddard G, Tweezer-Zaks N, Shoenfeld Y (2005). "New therapeutic strategies for systemic sclerosis--a critical analysis of the literature". Clin. Dev. Immunol. 12 (3): 165-73. PMID 16295521.
  27. 27.0 27.1 27.2 27.3 27.4 Zandman-Goddard G, Tweezer-Zaks N, Shoenfeld Y (2005). "New therapeutic strategies for systemic sclerosis--a critical analysis of the literature". Clin. Dev. Immunol. 12 (3): 165–73. PMID 16295521. Full text at PMC: 2275417
  28. 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.
  29. Tashkin DP, Elashoff R, Clements PJ, et al (June 2006). "Cyclophosphamide versus placebo in scleroderma lung disease". N. Engl. J. Med. 354 (25): 2655–66. doi:10.1056/NEJMoa055120. PMID 16790698.
  30. Hoyles RK, Ellis RW, Wellsbury J, et al (December 2006). "A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma". Arthritis Rheum. 54 (12): 3962–70. doi:10.1002/art.22204. PMID 17133610.
  31. Nash RA, McSweeney PA, Crofford LJ, et al (2007). "High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the U.S. multicenter pilot study". Blood 110 (4): 1388–96. doi:10.1182/blood-2007-02-072389. PMID 17452515.

External links

Cost Effectiveness of Scleroderma

| group5 = Clinical Trials Involving Scleroderma | list5 = Ongoing Trials on Scleroderma at Clinical Trials.govTrial results on SclerodermaClinical Trials on Scleroderma at Google


| group6 = Guidelines / Policies / Government Resources (FDA/CDC) Regarding Scleroderma | list6 = US National Guidelines Clearinghouse on SclerodermaNICE Guidance on SclerodermaNHS PRODIGY GuidanceFDA on SclerodermaCDC on Scleroderma


| group7 = Textbook Information on Scleroderma | list7 = Books and Textbook Information on Scleroderma


| group8 = Pharmacology Resources on Scleroderma | list8 = AND (Dose)}} Dosing of SclerodermaAND (drug interactions)}} Drug interactions with SclerodermaAND (side effects)}} Side effects of SclerodermaAND (Allergy)}} Allergic reactions to SclerodermaAND (overdose)}} Overdose information on SclerodermaAND (carcinogenicity)}} Carcinogenicity information on SclerodermaAND (pregnancy)}} Scleroderma in pregnancyAND (pharmacokinetics)}} Pharmacokinetics of Scleroderma


| group9 = Genetics, Pharmacogenomics, and Proteinomics of Scleroderma | list9 = AND (pharmacogenomics)}} Genetics of SclerodermaAND (pharmacogenomics)}} Pharmacogenomics of SclerodermaAND (proteomics)}} Proteomics of Scleroderma


| group10 = Newstories on Scleroderma | list10 = Scleroderma in the newsBe alerted to news on SclerodermaNews trends on Scleroderma</small>


| group11 = Commentary on Scleroderma | list11 = Blogs on Scleroderma

| group12 = Patient Resources on Scleroderma | list12 = Patient resources on SclerodermaDiscussion groups on SclerodermaPatient Handouts on SclerodermaDirections to Hospitals Treating SclerodermaRisk calculators and risk factors for Scleroderma


| group13 = Healthcare Provider Resources on Scleroderma | list13 = Symptoms of SclerodermaCauses & Risk Factors for SclerodermaDiagnostic studies for SclerodermaTreatment of Scleroderma

| group14 = Continuing Medical Education (CME) Programs on Scleroderma | list14 = CME Programs on Scleroderma

| group15 = International Resources on Scleroderma | list15 = Scleroderma en EspanolScleroderma en Francais

| group16 = Business Resources on Scleroderma | list16 = Scleroderma in the MarketplacePatents on Scleroderma

| group17 = Informatics Resources on Scleroderma | list17 = List of terms related to Scleroderma


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